TAP Vol 3 Issue 3 by Harborside Press LLC

Lung Cancer 20, 21

Conversation with Monica Morrow, MD, FACS 41

VOLUME 3, ISSUE 3

Hematology for the Oncologist 44

FEBRUARY 15, 2012

ASCOPost.com

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

53rd American Society of Hematology Annual Meeting

Maintenance Rituximab vs Retreatment Rituximab in Patients with Low–Tumor-Burden Follicular Lymphoma

Cost of Care: A Multidisciplinary Responsibility

By Caroline Helwick

or patients with low– tumor-burden follicular lymphoma treated upfront with rituximab (Rituxan), retreating upon disease progression was as effective as extended dosing, or maintenance therapy, in a randomized phase III study that comBrad Kahl, MD pared the approaches.1 Given the excellent outcomes, lack of a difference in quality of life, and fewer doses required with retreatment, “rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in low–tumor-burden follicular lymphoma,” said Brad Kahl, MD, Associate Professor of Medicine at the University of Wisconsin School of Medicine and

By Daniel A. Vorobiof, MD

Public Health in Madison, who presented the latebreaking abstract at the 2011 ASH Annual Meeting.

Trial Results The Eastern Cooperative Oncology Group conducted the RESORT trial (Rituximab Extended Schedule or Retreatment Trial) to compare maintenance rituximab vs retreatment upon progression. The study included 545 untreated patients with stage III or IV indolent non-Hodgkin lymphoma and low tumor burSEE PAGE 59 den, including 384 with follicular lymphoma histology who formed the basis of this analysis. The presentation at the ASH Annual Meeting was restricted to those patients with follicular lymphoma only. The other histologies will continued on page 3

Issues in Oncology

Drug Shortages Hit Oncology Hard: Experts Weigh in on Challenges and Solutions By Ronald Piana

eriodic drug shortages are an unavoidable reality in our complicated pharmaceutical supply chain; however, over the past several years, drug shortages have expanded to crisis levels, putting vulnerable patients at risk. In 2010, there were 178 drug shortages reported to the FDA, 132 of which were sterile injectable products. Since most chemotherapy is delivered by injection, the shortages have hit the oncology community especially hard. Despite the inevitable finger-pointing, this is a complex issue with no single cause and no clear

end in sight, puzzling the regulators and legislators looking for solutions. The ASCO Post recently spoke with several leading health-care experts to gain insight into the drug shortage problem.

FDA: Faster Communication Needed

Capt. Valerie Jensen, RPh, Associate Director of FDA’s Drug Shortage Program, told The ASCO Post that drug manufacturers are not required by law to report information about shortages. “We usually find out about shortages through interactions with health-care professionals or associations. Our primary role is to contact manufacturers that are having problems Our primary role is to contact manufacturers and offer assistance to ramp that are having problems and offer assistance up production by, for instance, helping them find additional to ramp up production. manufacturing sites or new suppliers,” said Capt. Jensen. — Capt. Valerie Jensen, RPh

read the interview with Dr. Ezekiel Emanuel (The ASCO Post, December 15, 2011) with much interest, as the health-care policy problems that America is currently experiencing have plagued other countries for some time. Despite proactive measures and attempts to amend those situations elsewhere, little improvement has yet been achieved. One of the reasons these problems remain such a challenge is that although we treat a patient with cancer using a multidisciplinary team approach, the main focus in health policy is currently on the cost of chemotherapeutic agents. We tend to forget that the disease is managed by a large number of disciplines and not just by medical oncologists in a solitary therapeutic approach.

Drugs Only Part of the Problem There is no doubt that the cost of drugs is one of the greatest hurdles in health care that continued on page 2

Dr. Vorobiof is Director of the Sandton Oncology Centre in Johannesburg, South Africa, and a member of The ASCO Post’s International Editorial Board.

MORE IN THIS ISSUE Oncology Meetings Coverage San Antonio Breast Cancer Symposium �� 4, 6 53rd ASH Annual Meeting �� 8, 9 97th Annual American College of Surgeons Clinical Congress �� 12 FDA Update �� 2, 22-27, 40 Direct from ASCO �� 28

continued on page 17

A Harborside Press® Publication

The ASCO Post | FEBRUARY 15, 2012

PAGE 2

Opinion

Cost of Care continued from page 1

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

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

George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

William C. Wood, MD Winship Cancer Institute, Emory University

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

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 Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan

London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations; artwork on page 36 by DNA Illustrations, Inc.

Disclosure information available at ASCOPost.com.

SEE PAGE 59

More Than One Front As a medical oncologist in South Africa who has been in private practice for many years, I am astonished to sometimes see patients come to us with exhausted insurance coverage and lack of any

Medical oncologists should not be considered the exclusive gatekeepers of cancer costs; that accountability should be shared by the entire multidisciplinary team.

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

Robert W. Carlson, MD Stanford University Medical Center

E. David Crawford, MD University of Colorado

every country and every patient with cancer must confront. In this global recession, it has become a major issue that in some instances precludes us from delivering optimal therapy to our patients. Dr. Emanuel correctly stated that “we have to get to a point where we’re delivering care efficiently and we’re delivering the best care at the lowest price.” I couldn’t agree more with that statement. Further, in my opinion, the cost of drugs in oncology is only a

Indeed, all other disciplines involved in the diagnosis and treatment of cancer patients also have a major impact on those elevated costs.

fraction of the general costs incurred in treating patients. From surgeries and long stays in hospitals, to numerous consultations and expensive, repetitive tests (biochemistry, pathology, radiology, etc) culminating in multiple therapies (radiotherapy, chemotherapy, supportive care, etc), the bill grows day by day. The cost of chemotherapy represents only a portion of all the money involved. Nevertheless, it has become popular in many countries, and in many circles, to implicate medical oncologists for prescribing costly and sometimes ineffective therapies. But radiotherapy is also an expensive treatment, and sometimes more fractions are administered when fewer will give the same benefit, as was touched on briefly by Dr. Emanuel.

other funds, even before any therapy is begun for their newly diagnosed cancer. We need to start somewhere, and therefore, efforts to reduce the price of therapeutic agents are extremely important, but that is not enough. We need to work on more than one front to bring down costs all along the process, from the beginning of the first diagnostic procedures. Responsibilities should be distributed among all those involved in the diagnosis and treatment of cancer patients. Medical oncologists should not be considered the exclusive gatekeepers of cancer costs; that accountability should be shared by the entire multidisciplinary team.

■

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

Axitinib Receives FDA Approval in Advanced Renal Cell Carcinoma

he FDA has approved the kinase inhibitor axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. The approval is based on an international, randomized, open-label trial that enrolled 723 patients: 361 were assigned to receive axitinib at 5 mg orally twice daily, and 362 patients were assigned to receive sorafenib (Nexavar) at 400 mg orally twice daily. All patients

had received one prior systemic therapy that contained one of the following treatments: sunitinib (Sutent), temsirolimus (Torisel), bevacizumab (Avastin), or cytokine(s) (interleukin-2 [Proleukin] or interferon-alfa). The trial excluded patients who had uncontrolled hypertension. The trial demonstrated a statistically significant improvement in progrescontinued on page 22

ASCOPost.com | FEBRUARY 15, 2012

PAGE 3

53rd ASH Annual Meeting Follicular Lymphoma continued from page 1

be analyzed later. Patients were treated with rituximab in the standard manner, and the 274 (71%) responders were randomly assigned to single-dose rituximab every 3 months until treatment failure or to observation and retreatment upon disease progression. “At a median follow-up of 3.8 years, there was absolutely no difference in the primary endpoint of time to treatment failure,” Dr. Kahl reported. Time to rituximab fail-

ure—defined as progression within 6 months of last rituximab, no response to rituximab retreatment, initiation of alternative therapy, or inability to complete protocol therapy—was 3.9 years for maintenance rituximab and 3.6 years with retreatment (P = .80). Rituximab failures occurred in 69 patients on the maintenance arm and 65 in the retreatment arm. Time to first chemotherapy treatment was longer in the maintenance arm, with 95% of patients remaining chemotherapy-free compared to 86% in the retreatment arm (P = .03).

RESORT Study in Follicular Lymphoma ■■ For patients with low–tumor-burden follicular lymphoma who received

induction treatment with four weekly doses of rituximab and then retreatment upon disease progression, investigators found no difference in treatment failure or survival at 3.8 years of follow-up.

■■ Prolonged follow-up will be required to see whether differences in survival are associated with higher doses of rituximab

■■ Patients in the watchful waiting arm received four times less rituximab: median of 4 doses vs 16 in the maintenance arm.

“But both strategies appear to delay time to chemotherapy, compared to historical controls,” he observed.

Additional Findings There were no appreciable differences in toxicity, or the development continued on page 8

EXPERT POINT OF VIEW

Andrew D. Zelenetz, MD

he findings of RESORT1 have tremendous implications, both clinically and economically, commented Andrew D. Zelenetz, MD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York, in an interview. “The maintenance arm received rituximab [Rituxan] every 3 months indefinitely, for a median of 16 doses, while retreated patients received 4 doses. We are in an era when, without question, we have to figure out how to give effective high-quality care without breaking the bank. Retreatment may give us the same benefit at a much lower cost,” he said.

Trial Could Shake up Standard of Care The results suggest the clinical outcomes are similar, and “this will raise questions for some,” he suggested, referring to the population of hematologists accustomed to giving maintenance rituximab as the standard of care. According to Dr. Zelenetz, 72% of attendees at an ASH satellite symposium indicated they routinely prescribe maintenance. “Some people in the field say that maintenance is unequivocally the standard of care. I happen not

to share that opinion,” Dr. Zelenetz told The ASCO Post. “The guidelines of the National Comprehensive Cancer Network suggest that maintenance is an option, and not mandatory, because it delays progression and time to next treatment but it does not impact overall survival.” The lack of survival benefit might stem from the observation that “the more treatment you use up front, the less effective it is going to be out back,” Dr. Zelenetz added. “RESORT raises the question of whether it might make more sense to re-treat when necessary rather than give rituximab automatically, to derive the same benefit and probably at a much lower cost.”

Joseph M. Connors, MD

Trial Is Confirmatory, Will Produce Useful Data Joseph M. Connors, MD, Clinical Director of the British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, told The ASCO Post that data from RESORT are “entirely congruent with other studies suggesting that today’s patients with follicular lymphoma who previously were thought best initially managed with watchful waiting may do at least as well if initially

treated with rituximab.” Just 10 years ago, he continued, “Ardeshna and colleagues reported 5-year mortality of over 40% for the watchful waiting control arm.2 Today, as reported in the RESORT trial and in the control (watchful waiting) arm of a more recent study led by Ardeshna,3 5-year mortality is less than 10%,” he said. “This improvement is due to a constellation of different factors, especially improvements in primary treatment once the lymphoma becomes symptomatic, incorporation of maintenance rituximab after primary chemotherapy plus rituximab, and better management of recurrent disease. Overall, we are better at managing follicular lymphoma and these patients do well.” Presently, investigators are looking for a strategy that allows patients who otherwise might be considered for watchful waiting to avoid treatments that are more toxic than initial rituximab, Dr. Connors noted. “The RESORT trial, taken together with the more recent Ardeshna trial, helps identify a strategy involving a short course of ritixumab, with the drug then reserved until needed (vs continuous treatment), as quite attractive. This approach may produce the highest quality of life with the least amount of treatment and lowest cost, yet still keep patients alive and free of additional treatments.” Dr. Connors did have one reservation concerning RESORT: The combination of patients who had already been under a watchful waiting policy with newly diagnosed patients. “Once a patient has a track record of

his or her disease not progressing, or very slowly progressing, it is likely to continue to behave that way, no matter the intervention,” he pointed out. “We need to know the proportion of patients in each of these groups and to determine if their outcomes are different. We all have patients under watching waiting now, and we question whether we should put them on rituximab after having watched them for some time. We hope this study will eventually provide some answers to this question.”

■

Disclosure: Dr. Connors’ institution receives funding for research and clinical trials from Roche Canada. Dr. Zelenetz serves as a consultant for Genentech/Roche.

References 1. Kahl B, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 53rd American Society of Hematology Annual Meeting. Abstract LBA-6. Presented December 13, 2011. 2. Ardeshna KM, Smith P, Norton A, et al: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomized controlled trial. Lancet 362:615-622, 2003. 3. Ardeshna KM, Smith P, Qian W, et al: An Intergroup Randomised Trial of Rituximab Versus a Watch and Wait Strategy In Patients with Stage II, III, IV, Asymptomatic, Non-Bulky Follicular Lymphoma (Grades 1, 2 and 3a). A Preliminary Analysis. 52nd American Society of Hematology Annual Meeting. Abstract 6. Presented December 5, 2010.

The ASCO Post | FEBRUARY 15, 2012

PAGE 4

34th Annual San Antonio Breast Cancer Symposium AVEREL Trial Shows Benefit of Bevacizumab in HER2-positive Locally Recurrent or Metastatic Breast Cancer By Susan London

n findings likely to intensify the debate about the role of bevacizumab (Avastin) in advanced breast cancer, the AVEREL trial concludes that adding this antiangiogenic antibody to standard therapy prolongs progression-free survival by about 3 months in women with HER2-positive locally recurrent or metastatic breast cancer. Results of the randomized phase III trial were presented at the 2011 San Antonio Breast Cancer Symposium.1

tween groups, but follow-up is not yet mature for this outcome, according to Dr. Gianni, who is Director of Medical Oncology at the San Raffaele Cancer Center in Milan, Italy.

Which Subgroup Benefits? An additional, exploratory finding was that among the roughly one-third

a different mechanism of action, such as bevacizumab,” he said. “A global biomarker study known as MERiDian is planned to treat patients with bevacizumab and paclitaxel, with stratification by plasma VEGF-A level, to validate prospectively the meaning of this marker.” Given that the FDA recently reLisa Carey, MD, ScM

Bevacizumab in HER2-positive Breast Cancer ■■ AVEREL = AVastin [bevacizumab] in combination with HERceptin

[trastuzumab]/docetaxEL in HER2-positive metastatic breast cancer.

■■ The randomized phase III AVEREL trial showed that adding bevacizumab

to standard therapy prolongs progression-free survival by about 3 months in women with HER2-positive locally recurrent or metastatic breast cancer.

■■ Overall survival did not differ between groups, but follow-up is not yet mature for this outcome.

■■ Given the FDA’s decision to revoke bevacizumab’s breast cancer indication, the drug’s regulatory fate based on the AVEREL data is uncertain.

Luca Gianni, MD

The 424 women being treated in the first-line setting had better median progression-free survival as assessed by investigators—the trial’s primary endpoint—with addition of bevacizumab to docetaxel and trastuzumab (Herceptin) than without its addition (16.5 vs 13.7 months), although the difference did not attain statistical significance, lead investigator Luca Gianni, MD, reported. The difference was significant, however, as assessed by an independent review committee, a step taken to comply with FDA’s criteria of assessment. Overall survival did not differ be-

■■ Identifying predictive biomarkers will be key in establishing a subset of

patients with breast cancer who might benefit from bevacizumab therapy.

of patients having biosamples, adding bevacizumab seemed to yield greater benefit in patients who had higher circulating levels of vascular endothelial growth factor A (VEGF-A) at baseline. “The most relevant element emerging from our trial is that bevacizumab is doing something in this group of women also, as in the HER2-negative subset of cases [in previous trials], but that we need to invest more in trying to figure out which subgroup of HER2-positive disease really deserves the addition of yet another drug with

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

voked its approval of bevacizumab for breast cancer treatment, the drug’s regulatory fate based on the AVEREL data is uncertain, Dr. Gianni said. “According to the FDA suggestions and the general indications, the endpoint that they would look at has been met. But the [manufacturer’s] decision as to whether to try to get a label for HER2 will have to consider the extent of benefit and the large number of therapeutic options already available for women with HER2-positive metastatic breast cancer,” he elaborated.

Valuable Debate The AVEREL results give “more fodder for the controversy,” commented Lisa Carey, MD, ScM, Professor in the Department of Medicine, University of North Carolina at Chapel Hill, in a related press conference. Other bevacizumab trials in breast cancer have shown a consistent pattern: improvements in response rate and progression-free survival, but not overall survival, “and I suspect in the end, this will be the same.” The debate as to what should be the definitive endpoint for approval is “a very valuable one,” she said. “I am a little bit concerned that in breast cancer, because of its heterogeneity and because of the number of drugs that we give to patients over the course of their metastatic disease, the introduction of a lot of noise may mask effects that a very tightly controlled study might see.... On the other hand, it would be nice to see some hint of a survival advantage.” At the end of the day, having access to bevacizumab, at least for a subset of continued on page 7

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; email: 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.

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 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.

NOW APPROVED FOR MYELOFIBROSIS (MF)*

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION *Intermediate or high-risk MF.

Jakafi™ demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2†‡ Significantly more patients receiving Jakafi achieved a ≥35% reduction from baseline in spleen volume vs those taking placebo (41.9% vs 0.7%, P < 0.0001)1 A significantly higher proportion of patients receiving Jakafi had a ≥50% reduction in Total Symptom Score (TSS) vs those taking placebo (45.9% vs 5.3%, P < 0.0001)1 Responses in spleen volume reduction were seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

†

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

‡

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

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

RUX-1004R

01/12

The ASCO Post | FEBRUARY 15, 2012

PAGE 6

34th Annual San Antonio Breast Cancer Symposium Study Questions Use of Partial Breast Brachytherapy in Older Women By Susan London

artial breast brachytherapy is less effective and more toxic than whole-breast irradiation when used after lumpectomy, suggests an analysis of 07 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1 Medicare claims data.

In the 2000–2007 study of more than 130,000 older women with breast cancer—the largest of its kind to date— the rate of mastectomy in the 5 years after treatment (a surrogate of treatment

effectiveness) was doubled for those who received brachytherapy compared with those who received whole-breast irradiation, although still very low (4% vs 2%).

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

Benjamin D. Smith, MD

The brachytherapy group also had higher rates of postoperative complications (24% vs 14%) and postradiation complications (26% vs 18%), coinvestigator Benjamin D. Smith, MD, reported at the 2011 San Antonio Breast Cancer Symposium.1 Collectively, the results call into question the role of brachytherapy, which has advantages in terms of treatment duration and potentially compliance, but is inSEE PAGE 59 creasingly being used despite a lack of long-term randomized data.

Study Limitations Dr. Smith acknowledged several study limitations, such as the inability to determine the reason for mastectomy (although most were likely done for recurrence) and the role of unmeasured confounders. “There are other important outcomes that may not generate claims or a medical encounter in the treatment of breast cancer,” he added. “One of these outcomes would be the aesthetic outcome of the breast after breast-conserving therapy.” Whether the results still apply today is unclear, according to Dr. Smith, who is an Assistant Professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. “We don’t know the extent to which there is a learning curve with brachytherapy or the extent to which newer brachytherapy techniques may or may not improve outcomes,” he explained. Also unknown is whether the findings apply to younger women. “We have an ongoing intergroup study evaluating partial breast compared to whole-breast irradiation in women under the age of 50, and I think such patients interested in partial breast irradiation are ideally suited for enrollment on that trial rather than off-protocol treatment,” he said.

ASCOPost.com | FEBRUARY 15, 2012

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34th Annual San Antonio Breast Cancer Symposium is billed to Medicare at a higher rate, according to Dr. Gralow.

■■ In a study of Medicare claims data from over 130,000 older women with

Study Details

Lori J. Pierce, MD

Long-term Data to Come “This is an interesting study, though it is only looking at one way of giving APBI [accelerated partial breast irradiation]—brachytherapy,” Lori J. Pierce, MD, Professor of Radiation Oncology at the University of Michigan in Ann Arbor, commented in an interview. “And while there are limitations in how best to interpret the data, it is a large study, and the results should be considered while we await results from randomized trials of partial-breast vs whole-breast radiotherapy.” Julie Gralow, MD, Director of Breast Oncology at the University of Washington, cautioned that the field has other examples where practice has gotten ahead of the research. “We’ve jumped into some things in breast cancer where we start rolling down the road and we can’t pull back and wait for randomized clinical trial data, and one of them has been partial breast irradiation,” she commented in an interview. Importantly, the study did not assess the costs of brachytherapy, which

AVEREL Trial continued from page 4

patients, would be helpful, according to Dr. Carey.

Predictive Biomarkers Needed Gabriel Hortobagyi, MD, Chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, stressed that identifying predictive biomarkers will be key here. “We do not have a biomarker to tell us that we can treat less than 100% of patients to observe the benefit,” yet bevacizumab almost certainly improves outcomes in only some, he said. “That is an ongoing challenge, and we really need to invest in that and redouble our efforts so that we can develop those biomarkers.” The drug still has a role in breast cancer, Dr. Hortobagyi agreed. “Bevacizumab in my book is alive and well: I continue to treat patients with bevacizumab in my clinic, and we continue

Partial Breast Brachytherapy in Breast Cancer

Investigators analyzed Medicare data, identifying women aged 67 years or older who had an early invasive breast cancer diagnosis between 2000 and 2007 and underwent lumpectomy followed by some type of radiation therapy. Using claims data, they compared outcomes between 123,244 women who received whole-breast irradiation and 7,291 who received brachytherapy (about three-fourths of

Julie Gralow, MD

whom had single-entry catheter–based brachytherapy, codes suggested). The patients were 75 years old, on average. About 76% had some type of axillary surgery. Only a minority received chemotherapy (14%) and had axillary node involvement (12%). Their median follow-up was 3.8 years. Analysis of temporal trends showed that use of brachytherapy increased significantly and sharply over time. It to run clinical trials that include bevacizumab,” he said. “I have gone public several times criticizing the decision of the FDA, although I understand the challenges they face in making these decisions.”

Trial Data Women were eligible to participate in the AVEREL trial if they had previously untreated HER2-positive locally recurrent or metastatic breast cancer. They were assigned 1:1 to receive docetaxel plus trastuzumab, either with or without added bevacizumab, with all agents given every 3 weeks. The trial did not permit crossover. The women had a median age of about 54 years. Slightly more than half had hormone receptor–positive tumors, and about three-fourths had visceral disease. Only a minority had received adjuvant or neoadjuvant HER2-targeted therapy (13%), anthracyclines (44%), and taxanes

breast cancer, partial breast brachytherapy proved less effective and more toxic than whole-breast irradiation.

■■ At 5 years post-treatment, the mastectomy rate was doubled for

brachytherapy recipients vs those who underwent whole-breast irradiation (4% vs 2%).

■■ The brachytherapy group had higher rates of postoperative complications (24% vs 14%) and postradiation complications (26% vs 18%).

was used in less than 1% of patients overall in 2000 but in 13% by 2007. Patients in the brachytherapy group had a significant doubling of the rate of mastectomy at 5 years relative to their counterparts in the whole-breast irradiation group (4% vs 2%). The difference persisted in multivariate analysis (HR = 2.22) and was similar regardless of the broad type of brachytherapy. “It’s very plausible to think that the majority of these mastectomies were done for recurrence,” Dr. Smith commented. “The most intuitive explanation is that some patients who are treated with brachytherapy had residual tumor cells in the breast that were outside the confines of the target volume for brachytherapy.”

Other Key Results The difference between groups was greater in patients who had had axillary lymph node involvement (HR = 4.69) than in those who had not (HR = 2.06). Overall survival, another measure of effectiveness, did not differ (18%). The median duration of followup was 26 months. Main results showed that median progression-free survival was marginally better with added bevacizumab than without it as assessed by investigators (16.5 vs 13.7 months; HR = 0.82; P = .08) and significantly better as assessed by the independent review committee with censoring of patients for nonprotocol therapy (16.8 vs 13.9 months; HR = 0.72; P = .02). The findings were similar across most subgroups, except for notably greater benefit of added bevacizumab among patients aged 65 years or older and patients with measurable disease. The objective response rate was significantly higher in the bevacizumab group as assessed by the independent review committee (77% vs 66%).

Adverse Events and Survival “There were no new safety signals observed in this patient population

between groups. Patients had significantly higher 1-year rates of postoperative complications after brachytherapy than after whole-breast irradiation, in terms of both infections and other complications. The brachytherapy group also had significantly higher 5-year cumulative rates of certain postradiation complications. The whole-breast irradiation group had a significantly higher rate of radiation.

■

Disclosure: Dr. Smith has received research funding from Varian Medical Systems, but that funding was not used for any part of this study, which was funded by a grant from the Department of Defense and by institutional sources. Drs. Gralow and Pierce reported no potential conflicts of interest.

Reference 1. Smith GL, Xu Y, Buchholz TA, et al: Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. San Antonio Breast Cancer Symposium. Abstract S2-1. Presented December 7, 2011.

with respect to what we already know from other patient populations exposed to [bevacizumab],” Dr. Gianni reported. The rate of grade 3 or higher adverse events of special interest, such as hypertension and cardiac events, was 48% with bevacizumab and 38% without it.

■

Disclosure: Dr. Gianni is a consultant to Roche, Genentech, GSK, Wyeth, Novartis, Eisai, Pfizer, Millennium Takeda, SanofiAventis, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, and Celgene. Dr. Hortobagyi has served as a consultant to Genentech with compensation.

Reference 1. Gianni L, Romieu G, Lichinitser M, et al: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/ metastatic breast cancer (LR/mBC). San Antonio Breast Cancer Symposium. Abstract S4-8. Presented December 9, 2011.

The ASCO Post | FEBRUARY 15, 2012

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53rd ASH Annual Meeting Hematology

New Anti-CD20 Monoclonal Antibody Studied in B-cell Non-Hodgkin Lymphoma By Alice Goodman

he new anti-CD20 monocolonal antibody obinutuzumab is being studied in the treatment of patients with relapsed CD20-positive indolent B-cell non-Hodgkin lymphoma. GAUSS is the first clinical trial to compare obinutuzumab head-to-head against rituximab (Rituxan) induction therapy.

Laurie Sehn, MD

“In this first head-to-head trial, we are encouraged to see a trend toward higher response rates without appreciable differences in safety. Given the promising efficacy of this drug, definitive phase III trials are currently underway,” said Laurie Sehn, MD, Clinical Associate Professor at the University of British Columbia and the British Columbia Cancer Center Agency, Center for Lymphoid Cancer, Vancouver, Canada, at the 53rd Annual Meeting of the American Society of Hematology in San Diego.1

Study Design Obinutuzumab is the only engineered type II monoclonal anti-CD20

Follicular Lymphoma continued from page 3

of second cancers, between the arms. More patients in the maintenance arm withdrew from the trial—26 vs 16 in the retreatment arm. “We also wondered if there might be a psychological benefit to being maintained in remission, but at 1 year postrandomization we found no difference in quality of life,” Dr. Kahl reported. One difference, however, did stand out: The amount of rituximab delivered per patient was 15.8 doses in the maintenance arm compared to only 4.5 for retreated patients. Number of doses ranged from 5 to 31 with maintenance and from 4 to 16 with observation and retreatment.

antibody to enter clinical trials thus far. The open-label phase II GAUSS study randomly assigned 149 patients with follicular lymphoma to induction therapy with four courses of rituximab at 375 mg/m2 per week or obinutuzumab at 1,000 mg. Patients who had progressive disease following induction went off study; the remainder continued on maintenance therapy every 2 months for 2 years with the same drug they were assigned to for induction therapy. Median age was about 61 years, about 50% of patients were male, and about 80% had stage III/IV disease. Disease characteristics between the two arms were generally comparable.

Principal Findings Both investigator review and independent radiology review found higher overall response rates at the end of induction with obinutuzumab compared with rituximab: Investigator review found an overall response rate of 44.6% with obinutuzumab vs 33.3% with rituximab; and complete remission (plus unconfirmed complete response) rates of 12.2% vs 5.2%, respectively. Best overall response as determined by independent review was 60.8% for obinutuzumab vs 46.7% for rituximab, a statistically significant difference of 14.1% in favor of the novel agent (P = .04). At a median follow-up of 15 months, no difference in progression-free survival was seen, but follow-up was too short to detect a difference, Dr. Sehn said. “Rituximab retreatment was as effective as maintenance rituximab in terms of time to treatment failure. And

Time to Treatment Failure in the RESORT Study Defined as any of the following: ■■ Progression within 6 months of last rituximab ■■ No response to rituximab retreatment ■■ Initiation of alternative therapy ■■ Inability to complete protocol therapy

Obinutuzumab in Non-Hodgkin Lymphoma ■■ Obinutuzumab is an engineered type II anti-CD20 antibody. ■■ Safety is comparable to that of rituximab, although there were more infusion reactions and cough with obinutuzumab

■■ The novel antibody is entering phase III trials in non-Hodgkin lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.

Overall, the novel agent was well tolerated but produced a higher rate of infusion reactions (generally mild and transient) that did not significantly affect treatment discontinuation. Adverse events were similar between the two arms, with the exception of more infusionrelated reactions and cough in the obinutuzumab arm: 74% vs 51% for infusion-related reactions and 21% vs 6% for cough. Twelve patients on each arm experienced severe adverse events on treatment (induction and maintenance). The phase III program includes two major trials launched recently; one trial will compare chemotherapy plus rituximab vs chemotherapy plus obinutuzumab in advanced-stage non-Hodgkin lymphoma, and the second trial will compare standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) vs obinutuzumab plus CHOP in diffuse large B-cell lymphoma. Other trials are planned in chronic lymphocytic leukemia. while maintenance was superior to retreatment in terms of time to cytotoxic therapy, this came at a cost of nearly 4 times more rituximab,” Dr. Kahl concluded. “There was also no benefit in terms of quality of life or less anxiety at 12 months with maintenance.”

■

Engineered Antibody Commenting on the study, Jane N. Winter, MD, moderator of the press conference where these results were presented, said, “This agent has been engineered for enhanced performance. The study doesn’t definitively show obinutuzumab is better than rituximab, but the efficacy is promising enough to warrant phase III trials comparing it to rituximab.” Dr. Winter is Professor of Medicine at the Feinberg School of Medicine, Northwestern University, Chicago.

■

Disclosure: Dr. Sehn is a consultant for and has received honoraria and research support from Roche/Genentech. Dr. Winter reported no potential conflicts of interest.

Reference 1. Sehn L, Goy A, Offner, FC, et al: Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non‑Hodgkin lymphoma: Preliminary analysis of the GAUSS study. 53rd Annual Meeting of the American Society of Hematology. Abstract 269. Presented December 12, 2011.

The ASCO Post Watch future issues for important news from key oncology meetings. Treating pNET 22

Disclosure: Dr. Kahl is a consultant for Genentech and Roche.

Biosimilars in cancer treatment 37

NOVEMBER 15, 2011

ASCOPost.com

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

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

Reference 1. Kahl B, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 53rd American Society of Hematology Annual Meeting. Abstract LBA-6. Presented December 13, 2011

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 1 in Stockholm. months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States. Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era

What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I A small piece of thought he had Hodgkin disease, so I arinformation or a major ranged a lymph node biopsy. I remember breakthrough in one scientific looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematodiscipline can translate logic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that othvaluable information into ers could not. To my surprise, he said another scientific area. this pathology was something he’d never seen before. —Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ................15, 24, 41, 49 53rd ASTRO Annual Meeting ............................. 8–11, 14, 30 AACR Basic Cancer Research Meeting ..................................... 39 AACR Conference on Cancer Health Disparities ..................................... 52 Direct from ASCO ....................................... 27

continued on page 20

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PAGE 9

53rd ASH Annual Meeting Hematology

Is Gemtuzumab a Therapeutic Option in Older Patients with Acute Myeloid Leukemia? Drug was withdrawn from U.S. market in June 2010. By Alice Goodman

study presented at the Plenary Session of the 53rd Annual Meeting of the American Society of Hematology (ASH) breathes new life into an older drug for acute myeloid leukemia (AML) that is no longer available in the United States.1 Gemtuzumab ozogamicin (Mylotarg) appears to be a promising therapeutic option for older patients with acute myeloid leukemia with favorable cytogenetics when used in relatively low, frequently repeated doses, according to results of the Acute French Leukemia Association (ALFA) phase III trial.

drug increased mortality and added no benefit over conventional therapies for AML.

Study Results The phase III, prospective, openlabel, randomized trial enrolled 280

newly diagnosed de novo AML patients aged 50 to 70 years. A regicontinued on page 10

Sylvie Castaigne, MD

New Dosing Regimen “Research has demonstrated that [gemtuzumab] has very potent anticancer properties, and with this study, we have identified a dosing regimen that gives patients the therapeutic benefit of the drug without some of the toxicities reported at higher doses,” stated lead author Sylvie Castaigne, MD, Professor in the Department of Hematology at Hôpital de Versailles, Versailles, France. “The standard of care has been daunorubicin plus cytarabine for many years. There hasn’t been a new therapeutic option for several decades, and with this research we are encouraged that [gemtuzumab] may be able to improve overall outcomes for these AML patients with limited alternatives.” Gemtuzumab is an anti-CD33 antibody conjugated with a toxin; the antibody binds to the surface of CD33positive leukemia cells and releases the toxin (ie, chalicheamicin) into the leukemia cells. The antibody is specifically targeted to the leukemia cells and theoretically spares toxicity to other cells that don’t express CD33. Gemtuzumab was withdrawn from the U.S. market in June 2010, after a clinical trial demonstrated that the

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PAGE 10

53rd ASH Annual Meeting Acute Myeloid Leukemia continued from page 9

men of 3 mg/m2 gemtuzumab IV on days 1, 4, and 7 was designed to give lower but repeated doses that might enhance gemtuzumab’s efficacy and

standard chemotherapy vs 34 months with chemotherapy plus gemtuzumab (P = .046). Improvement in event-free and overall survival was not observed in the subset of patients with unfavorable

Gemtuzumab in Acute Myeloid Leukemia ■■ A new regimen using lower, more frequent doses of gemtuzumab

ozogamicin combined with standard chemotherapy achieved significant improvement in survival vs standard chemotherapy alone in a phase III trial in patients 50 to 70 years of age with newly diagnosed acute myeloid leukemia.

■■ The new regimen appears to have less toxicity compared with the

originally studied regimen, although the addition of gemtuzumab did increase grade 3 adverse events, including thrombocytopenia and venoocclusive disease.

■■ This regimen may become a new standard of care, but this would require regaining FDA approval for gemtuzumab in the United States.

minimize hepatic and hematologic toxicities reported earlier with this antibody. Patients were randomly assigned to arm A (standard daunorubicin plus cytarabine) or arm B (the same chemotherapy plus the gemtuzumab regimen). Those who achieved remission on two cycles of treatment SEE PAGE 59 received two courses of consolidation therapy with the same treatments. Patients with persistent bone marrow blasts at day 15 after the first induction course received a second cycle of treatment, which was given without additional doses of gemtuzumab. The experimental arm extended event-free survival by just under 8 months. At 2 years, median event-free survival was 11.9 months with standard therapy vs 19.6 months with the addition of gemtuzumab, a result that was highly significant (P = .00018). The addition of gemtuzumab also extended overall survival: Median overall survival was 19.2 months with

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cytogenetics, Dr. Castaigne said. The rate of fatal events was higher in the experimental arm: 6.7% with standard therapy vs 8.7% in the arm that included gemtuzumab. In the experimental arm, prolonged grade 3 thrombocytopenia was reported in 19 patients and veno-occlusive disease or sinusoidal obstructive syndrome was seen in 3 patients (2 cases were fatal). No differences were observed between the two treatment arms in the rate of severe sepsis or intensive care admission during therapy.

■

Disclosure: Sylvie Castaigne received consultant fees from Wyeth from 2006 to 2008.

Reference 1. Castaigne S, Pautas C, Terre C, et al: Fractionated doses of gemtuzumab ozogamicin (GO) combined with standard chemotherapy improves event-free survival in newly-diagnosed de novo AML patients aged 50-70 years old: A prospective randomized phase 3 trial from the Acute Leukemia French Association (ALFA). 53rd Annual Meeting of the American Society of Hematology. Abstract 6. Presented December 11, 2011.

EXPERT POINT OF VIEW

revious studies of gemtuzumab ozogamicin (Mylotarg) had variable results in acute myeloid leukemia (AML). Before trials reported at the 2011 ASH Annual Meeting, two major studies had compared chemotherapy with or without gemtuzumab in patients with AML, said Martin Tallman, MD, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, New York. One study from the Medical Research Council in London, showed a benefit of gemtuzumab in favorable-risk patients only,1 while the Martin Tallman, MD second study, from the Southwest Oncology Group (SWOG), showed increased toxicity and greater mortality with no significant benefit for gemtuzumab.2 In 2010, gemtuzumab was withdrawn from the market in the United States due to reports of fatal toxicity in the SWOG trial. “This drug is not available and no one is using it,” Dr. Tallman said. “Here comes this study by the French showing a benefit in event-free survival and disease-free survival in patients with generally favorable and intermediate risk.3 The curves look impressive.” Dr. Tallman explained that the standard of treatment for AML (ie, daunorubicin and cytaraine) hasn’t changed in 4 decades. “I think this study has the potential to change the standard of care,” he said. If this study proves to be practice-changing, there will be tremendous pressure on Pfizer to resubmit an application for approval for gemtuzumab, Dr. Tallman predicted. A Pfizer spokesperson said that the results of the French study and another positive study in older patients with AML also presented at the ASH meeting4 are currently being reviewed, and a decision will be made as to whether to go forward with a new submission to FDA.

■

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

References 1. Burnett AK, Hills RK, Milligan D, et al: Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29:369-377, 2010. 2. Petersdorf S, Kopecky K, Stuart RK, et al: Preliminary results of Southwest Oncology Group study S0106: An international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 114:Abstract 790, 2009. 3. Castaigne S, Pautas C, Terre C, et al: Fractionated doses of gemtuzumab ozogamicin (GO) combined with standard chemotherapy improves event-free survival in newly-diagnosed de novo AML patients aged 50-70 years old: A prospective randomized phase 3 trial from the Acute Leukemia French Association (ALFA). 53rd Annual Meeting of the American Society of Hematology. Abstract 6. Presented December 11, 2011. 4. Burnett AK, Hills RK, Hunter AE, et al: The addition of gemtuzumab ozogamicin to intenstive therapy in older patients with AML produces a significant improvement in overall survival: Results of the UK NCRI AML 16 randomized trial. 53rd Annual Meeting of the American Society of Hematology. Abstract 582. Presented December 12, 2011.

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Approved in 3 indications

2.5mg 5mg 10mg

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09/11

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The ASCO Post | FEBRUARY 15, 2012

PAGE 12

97th Annual American College of Surgeons Clinical Congress Breast Cancer

Ablation of Small Primary Breast Tumors: The Next Step in Local Therapy? By Caroline Helwick

Michael S. Sabel, MD

ocal treatment of breast cancer is trending toward less invasive procedures that achieve comparable outcomes to standard interventions. What will the next step along this continuum be? According to Michael S. Sabel, MD, a surgical oncologist at the University of Michigan Comprehensive Cancer Center, Ann Arbor, “In situ ablation of small breast cancer tumors is the future of breast cancer.” Dr. Sabel described this emerging, though still unproven, modality during the “Debates in Surgical Oncology” session at the 97th Annual American College of Surgeons Clinical Congress in San SEE PAGE 59 Francisco. Surgeons in attendance agreed, with 73% predicting (via an audience response system) that ablation will become an option for a small subset of women eligible for breast-conserving therapy within 10 years. “The techniques are already routine in some cancers, so there is a certain degree of inevitability about this,” he commented. Indeed, some “ablation centers” are already trolling for patients, but this is jumping the gun, he acknowledged. “We need to resist the urge to adopt an unproven therapy, but we don’t want to discard a potentially promising one,” Dr. Sabel said.

Three Techniques The most promising approaches are radiofrequency ablation, imageguided focused ultrasound, and cryoablation. Improvements in imaging and image-guided procedures have made these novel approaches feasible.

Radiofrequency ablation generates heat via an electrical current that produces high-frequency vibrations of electrons. Probes are deployed into the tumor, target temperatures are achieved within 15 minutes, and the result is a 3- to 5-cm diameter lesion. Replacing lumpectomy with in situ ablation could conceivably reduce the complexity and cost of care and significantly improve cosmesis. But due to its complexity and its potential for complications, radiofrequency ablation has not gained favor as a primary method of ablating tumor. Recently, investigators used excision followed by radiofrequency ablation in an attempt to ensure eradication of micrometastases, replacing the role of radiation therapy. In a study of 41 patients (average tumor size 1.6 cm, 25% with inadequate margins), lumpectomy followed by radiofrequency ablation allowed 24 patients

Focused Ultrasound Ablation and Cryoablation An even less invasive approach—no surgery is involved—is focused ultrasound ablation. When the procedure was performed under MRI guidance, no local recurrences were seen among 47 patients followed for 43 months in a Japanese study.3 “The images seen in that study exemplify the cosmetic potential of ablative technologies over lumpectomy,” Dr. Sabel said. The American College of Radiology Imaging Network (ACRIN) will soon evaluate MRI-guided focused ultrasound ablation followed by excision in the ACRIN 6674 trial. Dr. Sabel has been researching cryoablation, and in his feasibility study of 29 patients, the approach was highly effective for tumors of any histology < 1.0 cm and for ductal cancers without an extensive in situ component < 1.5 cm.4

Ablative Approaches to Small Breast Tumors ■■ Promising approaches to breast tumor ablation include radiofrequency

ablation, image-guided focused ultrasound, and cryoablation, all of which have benefited from improvements in imaging and image-guided procedures.

■■ Despite encouraging findings with these techniques in clinical trials,

questions about efficacy, impact of imaging, and long-term cosmesis remain.

■■ Potential drawbacks of breast tumor ablation include the loss of potential pathologic findings and calcification of ablated lesions complicating follow-up.

to avoid radiation therapy, and it reduced the need for re-excision by 91%. At a median follow-up of 24 months, there were no local recurrences in this study by Klimberg et al.1 The multicenter ABLATE trial will evaluate lumpectomy followed by radiofrequency ablation as a way to extend the “final” negative margin and decrease rates of reoperation and local recurrence. The next evolution of this strategy is to combine it with percutaneous excision, an even less invasive method than lumpectomy plus radiofrequency ablation. In a recent study of percutaneous excision followed by radiofrequency ablation, all 15 patients demonstrated 100% ablation and clear margins.2

Such encouraging findings led to a phase II trial, American College of Surgeons Oncology Group (ACOSOG) Z1072, in which cryoablation will be followed by lumpectomy, with pre- and post-treatment MRI to determine residual disease. The trial will also assess the power of cryoablation to stimulate a systemic antitumor immune response. Unresolved issues include questions of efficacy (long-term local recurrence rates), impact of imaging (ability to detect local recurrence after ablation), and long-term cosmesis (lesions may persist, which may worry patients and physicians). “We need long-term follow-up evidence of good local control, and this requires well organized trials,” he said.

Seema A. Khan, MD

Others Are Doubtful Not all surgeons view ablation as promising. “I am concerned that you lose the pathologic details when you don’t take out the tumor and view it under the microscope. We don’t know how this might affect overall treatment planning; there is a potential for impact beyond just the local control,” Seema A. Khan, MD, Professor of Surgery and the Bluhm Family Professor of Cancer Research at Northwestern University Feinberg School of Medicine, Chicago, told The ASCO Post. “With surgery, we already achieve good cosmesis. But some of the ablated lesions calcify and become hard to follow. Ablation needs careful study, and the details need to be worked out. In addition, treatment times with some of the ablation techniques can be quite long. At this point, I am skeptical, but open to persuasion with data,” she said.

■

Disclosure: Drs. Sabel and Khan reported no potential conflicts of interest.

References 1. Klimberg VS, Kepple J, Shafirstein G, et al: eRFA: Excision followed by RFA—a new technique to improve local control in breast cancer. Ann Surg Oncol 13:14221433, 2006. 2. Klimberg VS, Boneti C, Adkins LL, et al: Feasibility of percutaneous excision followed by ablation for local control in breast cancer. Ann Surg Oncol 18:3079-3087, 2011. 3. Furusawa H: Plenary presentation. 2nd International Symposium on MRguided Focused Ultrasound. Washington, DC, October 2010. 4. Sabel MS, Kaufman CS, Whitworth P, et al: Cryoablation of early-stage breast cancer: Work-in-progress report of a multiinstitutional trial. Ann Surg Oncol 11:147156, 2004.

ADCETRIS is the ﬁrst approved CD30directed antibody-drug conjugate (ADC)

Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • H L in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • S ystemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A therapeutic alternative for relapsed patients

73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.1

Contraindication Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.1

Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.1

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS is an ADC designed to target cells expressing CD301

Antibody The antibody, brentuximab, specific for CD301

Cytotoxic agent

Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1

The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1

CD30 is prevalent in both HL and sALCL2 • B inding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • B inding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1

Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials: • 102 patients with HL who relapsed after ASCT1

Neutropenia Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1

• 58 patients with relapsed sALCL1

Tumor lysis syndrome

ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1

Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3

Progressive multifocal leukoencephalopathy (PML) JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS induced complete and partial remissions in clinical trials1 Efﬁcacy in relapsed patients1

Relapsed HL

Relapsed sALCL

Median treatment duration: 27 weeks

Median treatment duration: 24 weeks

(N = 102)

Duration of response in months

Response, % (95% CI)

Complete remission (CR) Partial remission (PR) Objective response rate (ORR)

(N = 58)

Median (95% CI)

Range

20.5

1.4-21.9+

(23-42)

(12.0-NE*)

3.5

(32-49)

(2.2-4.1)

1.3-18.7

6.7

(65-83)

(4.0-14.8)

Duration of response in months

Response, % (95% CI)

1.3-21.9+

Median (95% CI)

Range

13.2

0.7-15.9+

(44-70)

(10.8-NE*)

2.1

(18-41)

(1.3-5.7)

0.1-15.8+

12.6

(77-95)

(5.7-NE*)

0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.

• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 7 2% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4

Adverse reactions occurring in ≥20% of patients regardless of causality1 HL (N = 102)

sALCL (N = 58)

% of patients

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

Neutropenia

Peripheral sensory neuropathy

Fatigue

Nausea

Anemia

Upper respiratory tract infection

Diarrhea

Pyrexia

Rash

Thrombocytopenia

Cough

Vomiting

Adverse Reaction

• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1 Recommended dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes every 3 weeks1 • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete blood counts should be monitored prior to each dose of ADCETRIS1

Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 – 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 – 3% discontinued due to peripheral motor neuropathy1

Monitor patients for PN and institute dose modiﬁcation accordingly1 New or worsening Grade 2 or 3

old dose until PN improves to Grade 1 or baseline and then H restart at 1.2 mg/kg

Grade 4

Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors

Hold dose until resolution to baseline or Grade 2 or lower Consider growth factor support for subsequent cycles Discontinue or reduce dose to 1.2 mg/kg

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent page. Please see full Prescribing Information at ADCETRIS.com. REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504. US/BV/2011/0029b

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PAGE 17

Issues in Oncology

Drug Shortages continued from page 1

Capt. Jenson explained that most of the injectable shortages that affect oncologic agents stemmed from product quality-assurance issues and manufacturing delays (Fig. 1 on page 18). “We’ve seen an upswing in particulate contamination occurring

in injectable product vials. There’s also been an increase in sterility-issue production delays,” commented Capt. Jensen. Moreover, during the past few decades, the pharmaceutical manufacturing industry has consolidated. Consequently, most sterile injectables have only one manufacturer

that produces at least 90% of a particular drug. “Getting a product line up and running is an involved, time-consuming process. With fewer manufacturers, the market has less capacity to produce sterile injectable drugs if a production problem occurs at one site. To that end, we are encouraging companies to report prob-

lems early and to have backup plans, such as alternative production sites,” said Capt. Jensen.

Joseph M. Hill, MA

Legislative Proposals Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin 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 ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established. The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined. The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritis, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

—Joseph M. Hill, MA

Hepatic impairment

Use in pregnancy

Adverse reactions

The shortage problem is multifactorial, but what we are hearing about most are production line issues, such as line contaminations that force shutdowns.

Renal impairment

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Joseph M. Hill, MA, Director of Federal Legislative Affairs for the American Society of Health-System Pharmacists (ASHP) echoed FDA’s assertion that manufacturing issues are the biggest cause of shortages. “The shortage problem is multifactorial, but what we are hearing about most are production line issues, such as line contaminations that force shutdowns.” Mr. Hill, who has done considerable work on Capitol Hill, commented that the President’s recent Executive Order 13588 (Reducing

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150

Prescription Drug Shortages) has helped call attention to the seriousness of the problem. “The Order gives no new authority, but it signals that no one can hide from the problem, because it’s reached the White House,” said Mr. Hill. Asked about legislative solutions, Mr. Hill noted that there are two bills—one in the House, one in the Senate—that establish early warning systems that would mandate manufacturers to notify the FDA as soon as a problem occurs, or within 6 months in the case of impending discontinued on page 18

The ASCO Post | FEBRUARY 15, 2012

PAGE 18

Issues in Oncology

Drug Shortages continued from page 17

continuation of a drug. The Preserving Access to Life Saving Medications Act (S. 296 and H.R. 2245) was introduced by Sens. Amy Klobuchar (D-MN) and Robert Casey (D-PA) in the Senate and by Reps. Diane DeGette (D-CO) and Thomas Rooney (R-FL) in the House of Representatives. “This legislation would simply subject companies to civil monetary penalties for failure to report problems that might cause shortages or delays in production,” said Mr. Hill. ASHP is supportive of both bills, Mr. Hill explained, because the FDA has cited that the agency has been able to avoid 195 shortages this year alone, when they had early warning information available. “Both bills require manufacturers to work with the FDA on contingency plans for the production of injectable drugs. For instance, if the issue were related to raw materials, companies would need a backup source. Or manufacturing redundancies could be created with additional inventory,” said Mr. Hill. Although the details of the contingency plans are not spelled out, ASHP felt it was a way to get the ball rolling. “We really need to think about having sustainable and robust backup plans in place, especially in the case of lifesaving medications,” concluded Mr. Hill.

Is the Physician Payment Model to Blame? In a recent New England Journal of Medicine editorial that garnered much attention in the lay press,1 the authors wrote that two economic incentives are the culprits for the shortage crisis: Manufacturers have slowed production of generic drugs due to lowering profits, and oncologists have more financial incentive to administer brand-name drugs than injectable generics. Responding to the latter supposition, Derek Raghavan, MD, PhD, President, Levine Cancer Institute, commented, “I appreciate the authors’ attempt to address the complex and vexing problem of drug shortages, in which the end result is suboptimal care for our patients. For instance, several drugs on the shortage list are used in acute leukemia, which is an example of a disease where the gains have been

hard fought and hard won. For a doctor to have to deviate from the best management strategy for his or her patient because of a drug shortage is nothing short of a national disgrace,” he noted. “That said,” Dr. Raghavan continued, “the editorial attributed part of the shortage problem to private practice community oncologists who are

costly alternative. To assert that private practice oncologists are making treatment decisions based only on profitability of one drug over another, leading to drug shortages, is an offensive and unfounded theory,” concluded Dr. Raghavan.

Take Medicare Out of Pricing Asked to weigh in on the shortage issue, internationally regarded policy expert Ezekiel J. Emanuel, MD, PhD, Head of the Department of Bioethics at the NIH Clinical Center, said, “At this juncture, it’s important to note that we are not exactly sure what’s driving the shortages.” Dr. Emanuel explained that because of a lack of resources, the FDA’s ability to help manufacturers that are experiencing production issues get back on line has been hampered, which contributes somewhat to the problem. “However, the payment system, particularly the advent of the Medicare Modernization Act (MMA), which substantially lowered drug reimbursement rates, is a larger part of the problem. If manufacturers were

Derek Raghavan, MD, PhD

supposedly purchasing and hoarding more expensive brand-name agents. As an academic physician, I’ll defend my colleagues in the community setting by stating that I am unaware of any reliable data to support this proposition, and I actually think it is illogical—many of the current short-

Other shortages, 4%

Loss of site, 3% Problems with components, 2%

Raw material problems, 5%

Discontinuation, 11% Lack of capacity or other delay, 21%

Product quality issue, 54%

Ezekiel J. Emanuel, MD, PhD

pharmacy benefit managers handle them and you’ll see market-driven fluctuations,” said Dr. Emanuel, adding that if the law of supply and demand is allowed to work, drug shortages will cause the prices to rise, giving manufacturers incentives to fill the need.

From ASCO ASCO President Michael Link, MD, commented, “Everyone agrees that the drug shortage crisis is a multifactorial problem. Production issues in the supply chain are definitely part of the problem that needs to be addressed. However, many of us believe that the underpinning issue is an economic factor. The reality is that many of these generic drugs are priced so low that there’s no incentive for manufacturers to produce them or invest in the necessary infrastructure to prevent or fix a production problem.” “For our part,” he continued, “the Society has been at the forefront of this issue, getting the message out so that it gains the national attention it deserves. This is not just a cancer problem; it is a widespread issue affecting many generic drugs that patients across the country depend on. From our perspective, although multiple issues come into play, the most straightforward way, although

Fig. 1: Causes of drug shortages. From data presented September 26, 2011, at the FDA Drug Shortages Workshop, Silver Spring, Maryland.

ages relate to nononcological agents and pain medications, and have nothing to do with patterns of oncology practice.” Dr. Raghavan stressed that, absent hard data, the most likely explanation for the problem is actually a growing number of generic drugs that do not have a sustainable level of profitability for the manufacturer. “It has nothing to do with purported practice patterns in which physicians opt to use higherpriced drugs to increase their margins. In fact, with respect to patient costs, many oncologists choose the least

making larger per-dose profits on generic drugs, they wouldn’t allow their production lines to go down.” Dr. Emanuel conceded that there is no “magic bullet” cure for the shortages. Although he does not advocate returning to the pre-MMA reimbursement model that created perverse incentives, he offered that taking Medicare out of the pricing system would help stabilize the market. “When these injectable drugs come off patent, put them on Part B. After about 18 to 24 months, the prices would drop by about 90%. Let

Michael Link, MD

admittedly difficult in today’s economic environment, would be to find creative ways to increase the market price of generics—as in Europe, where the shortages are less of a problem—so that companies have enough profit margin to make pro-

ASCOPost.com | FEBRUARY 15, 2012

PAGE 19

Issues in Oncology

duction, safety, and distribution viable.”

Conclusions As Dr. Emanuel noted, there is no magic bullet that can prevent all drug shortages. The complexity of manufacturing processes, the requirement for safe and high-quality products, and consolidation and globalization of the pharmaceutical supply chain all contribute to fluctuating product supplies.

Moreover, various economic factors driven by Medicare reimbursement policy and the stressors of free-market supply and demand cycles influence profitability incentives for drug manufacturers. With all these factors in mind, there are fundamental measures that Congress, FDA, and other stake-

holders can apply to ensure that the U.S. health-care system does not again experience the crisis-level shortages that doctors and their patients are currently struggling with (see sidebar on “Policy Recommendations”).

■

Disclosure: Dr. Link has received research support from Seattle Genetics.

Capt. Jensen, Mr. Hill, and Drs. Emanuel and Raghavan reported no potential conflicts of interest.

Reference 1. Gatesman ML, Smith TJ: The shortage of essential chemotherapy drugs in the United States. N Engl J Med 365:16531655, 2011.

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

Policy Recommendations from the Food and Drug Law Institute for Avoiding Future Drug Shortage Crises Congress

37%

changed

■■ Expand FDA authority to

require manufacturers to notify supply interruptions and product discontinuations.

63% confirmed

■■ Allow FDA to require

manufacturers to develop continuity of supply plans.

■■ Require development of an

expedited approval pathway for “pre-1938 drugs” that are technically unapproved for use by FDA but have been on the market for years (eg, concentrated oral morphine solution, emergency epinephrine syringes).

FDA

■■ Encourage confidential

notification to FDA when there is a single-source active pharmaceutical ingredient.

■■ Explore incentives that

encourage manufacturers to enter the market, stay in the market, or implement processes that minimize the potential for shortages.

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

■■ Collaborate with the Drug

Enforcement Administration to alter active pharmaceutical ingredient quotas for controlled substance products in short supply.

Adapted, with permission, from Hill JM, Reilly C: Can the United States ensure an adequate supply of critical medications? FDLI’s Food SEE PAGE 59 and Drug Policy Forum 1(16):2, August 24, 2011.

www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)

The ASCO Post | FEBRUARY 15, 2012

PAGE 20

Patient’s Corner

I Never Expected to Get Lung Cancer But no one is immune to this disease. By Meryl L. Bralower, as told to Jo Cavallo

hen intermittent chest pains sent me to the emergency room nearly a decade ago, I worried that I was having some kind of cardiac event. The ER doctor wanted to make sure that I didn’t have a pulmonary embolism, so in addition to ordering a complete cardiac workup, she also ordered a chest x-ray to make sure my lungs were clear. When the test came back showing a shadow on my left lung, she wasn’t concerned because, she said, “You’ve never smoked.” Still, she recommended that I get a CT scan, which showed that my left lung was clear but that I had a lesion on my right lung. Even then I wasn’t too concerned. Because the lesion was in a difficult place to biopsy and cancer seemed such a remote possibility, my surgeon suggested watchful waiting. But when the tumor started growing, I immediately had a lobectomy. The pathology test of the tumor found stage II adenocarcinoma.

the Lung Cancer Research Foundation found that 15% of lung cancer cases occur in people who have never smoked.

Importance of Molecular Testing A psychotherapist and management consultant by profession, I now dedicate my life to patient advocacy. Soon after my surgery and an adjuvant chemotherapy regimen of cisplatin and gemcitabine, my oncologist asked if he could do a genetic test on my tumor to see if I had the epidermal growth factor receptor (EGFR) gene mutation, which was the only molecular test available in 2005. I didn’t have the EGFR mutation, but 2 years ago I was tested again and was positive for the anaplastic lymphoma kinase (ALK) gene mutation. Hopefully, my lung cancer will never recur, but if it does, I’ll have

All oncologists should offer their patients with lung cancer molecular testing so they have the best shot at receiving the most effective therapy and maintaining a good quality of life. — Meryl L. Bralower

The diagnosis was shocking. I’ve always led a healthy lifestyle. I’m careful about what I eat, I exercise regularly, and I’ve never smoked a cigarette. My diagnosis came just before the death of Dana Reeve, also a never-smoker, who died of lung cancer in 2006. Reeve’s fame and high-profile death helped catapult the message to the general public that lung cancer isn’t just a disease of smokers and that people shouldn’t be complacent about their chances of getting lung cancer just because they don’t smoke or have quit smoking. In fact, research from

the benefit of targeted therapy based on my molecular profile. And that’s the message I give to every person with lung cancer I encounter through my patient advocacy work and fund-raising efforts for lung cancer research, as well as in the articles I write. Indeed, all oncologists should offer their patients with lung cancer molecular testing so they have the best shot at receiving the most effective therapy and maintaining a good quality of life. Given my experience over the past decade, I have two mantras that I repeat to everyone I meet: (1) You don’t

Lung Cancer Advocates Seek to Raise Awareness (and Research Funding) By Jo Cavallo

lthough lung cancer is the leading cause of cancer death in the United States for both men and women—nearly 157,000 deaths from lung cancer occurred in 2011, according to the American Cancer Society—survey results from the Lung Cancer Research Foundation (LCRF) show that 60% of Americans are unaware of the high rate of deaths due to the disease. In fact, nearly a quarter of respondents said that breast cancer was the leading cause of cancer death, followed by 15% who believe that colon cancer causes the most fatalities. In addition, funding for lung cancer research lags far behind federal research dollars for breast cancer—just 5% and 12.1%, respectively, of the NCI’s budget.

Reasons for Lag in Funding One possible reason for the huge discrepancy in federal spending is that understanding the molecular pathogenesis of the disease has only developed over the past decade, limiting research opportunities, says James B. Dougherty, MD, Medical and Scientific Advisor to the LCRF. “Until the past 10 years, I’m not sure the biology and the ability to ask the questions with relevant research opportunities really gained the momentum of where it is today,” says Dr. Dougherty. Another reason Dr. Dougherty cites for limited research funding is the amount of private donations patients with lung cancer are able to generate compared with other cancer survivors. “I think lung cancer resources lag behind other types of cancer like breast and prostate, in part, because patients with lung cancer get sick and stay sick and often don’t survive long enough to become self-advocates in the way that other cancer patients do,” says Dr. Dougherty. With 5-year survival rates for patients with lung cancer at a dismal 15%, the LCRF is funding research focused on the genomic structure of lung cancer cells to determine ways to prevent lung cancer as well as to find the most effective treatments.

Molecular Testing Genomic testing of lung cancer tumors is also starting to take place outside of the clinical trial setting as the test becomes more available to the general public. To encourage patients with lung cancer to undergo molecular testing so their physicians can learn whether there are identifiable genetic mutations and prescribe the most effective treatment, a number of lung cancer organizations and Pfizer Oncology have joined together to launch a patient education website called Lung Cancer Profiles (lungcancerprofiles. com). Although molecular profiling on lung cancer tumors is not universally available yet, many large cancer institutions offer the test to patients. Not all insurance carriers, however, pay for the cost of the test.

■

have to be a smoker to get lung cancer; and (2) If you’ve been diagnosed with cancer, get your tumor genetically profiled.

■

Meryl L. Bralower lives in Boston, Massachusetts, and is on the board of Uniting Against Lung Cancer, a nonprofit lung cancer research foundation.

ASCOPost.com | FEBRUARY 15, 2012

PAGE 21

Spotlight on Research

Epigenetic Therapy Shows Positive Results in Late-stage Lung Cancer Phase I/II study shows anticancer gene activity in solid tumors. By Jo Cavallo

small phase I/II clinical study from Johns Hopkins University in Baltimore found that epigenetic therapy with a combination of azacitidine (Vidaza) and entinostat (an investigational agent) produced responses in some patients with refractory advanced non–small cell lung cancer. The study results, published in a recent issue of Cancer Discovery,1 showed a median survival of 6.4 months in patients who had a median of three prior therapies for their lung cancer, more than 2 months longer than the usual 4-month survival rate in this population. Of the 45 patients enrolled in the study, all of whom received the epigenetic treatment, 19 were able to undergo subsequent chemotherapy and several had positive responses to treatment. One patient had a complete response to the epigenetic therapy, and one patient had a partial response. In all, seven patients remain alive, including two who began the therapy nearly 4 years ago. The azacitidine/entinostat combination has been used successfully in patients with myelodysplastic syndrome and tested in leukemia patients with positive results. This study of the two drugs is believed to be the first to show anticancer activity in solid tumors—a pivotal finding, said the study researchers. Non-small cell lung cancer accounts for nearly 80% of all lung cancer cases and is the main cancer-related cause of death. Azacitidine is a DNA methyltransferase inhibitor and entinostat inhibits histone deacetylation,

a closely related process that also contributes to gene silencing. Laboratory studies of epigenetic therapy suggest that while the treatment does not kill cancer cells directly, it may reprogram malignant cells’ pattern of gene expression so that they lose their ability to grow uncontrollably.

Impressive Results in Patient Subset “This study looked at a combination of two drugs that target two different levels of epigenetic silencing to see if we could get synergy and gene re-expression, and with that, induce anticancer responses,” said Charles Rudin, MD, PhD, Professor of Oncology; Associate Director of Clinical Research at Johns Hopkins University

discovery of blood-based DNA methylation biomarkers of four genes: CDKN2A, CDH13, APC, and RASSF1A, which were identified as being strongly associated with disease recurrence and death in early-stage lung cancer and may allow physicians to predict which patients would benefit most from this type of treatment. “What excited us perhaps more than anything else is when we looked at the methylation signature in four target genes that we think are important in lung cancer,” said Dr. Rudin. “The cohort of patients who had methylation of at least two of these targeted genes at baseline, and demethylated with therapy—suggesting that they were responding epigenetically to the treatment—actually did quite well and had a median survival of about 10.4 months, quite long for heavily pretreated patients. So we think we might have a biomarker for benefit from this therapy.”

Determining Prognostic and Diagnostic Biomarkers

Charles Rudin, MD, PhD

Kimmel Cancer Center; and one of the lead investigators of the epigenetic study. “This therapy did not work in the majority of patients, but we did see a subset of patients who clearly benefited from the therapy, including some really impressive responses as well as some interesting periods of disease stabilization.” Another result of the study was the

Azacitidine/Entinostat in Lung Cancer ■■ A phase I/II study found that epigenetic therapy with a combination of azacitidine and entinostat produced responses in some patients with refractory advanced non–small cell lung cancer.

■■ DNA methylation biomarkers of four genes were identified as being

strongly associated with disease recurrence and death in early-stage lung cancer, and may enable the selection of patients who would benefit most from this type of treatment.

■■ Additional studies are planned to further test the combination.

To test that theory, the study researchers are planning a follow-up trial to determine if the DNA methylation biomarkers are accurate predictors of who the best candidates are for this treatment. “You could imagine blood screening patients for the presence of these methylation markers and then treating patients with a single cycle of treatment to see whether they demonstrate a methylation response,” said Dr. Rudin. Another interesting finding from the study was that a number of trial participants had positive responses to subsequent chemotherapy following their epigenetic therapy, raising the possibility that epigenetic therapy primes the tumor for a better response to conventional chemotherapy. “When you look at patients with advanced non–small cell lung cancer who have had previous treatments—some of our study patients had fourth- and fifth-line therapy by the time they got subsequent therapies—the response rates are generally very low, and they don’t see very good news with subse-

Stephen B. Baylin, MD

quent therapies,” said Stephen B. Baylin, MD, Professor and Deputy Director of the Johns Hopkins University Kimmel Cancer Center, and a coprincipal investigator of the epigenetics study. “In this clinical trial, among the 34 patients who got more than one cycle of epigenetic therapy before they stopped, 20% had stable to really robust responses to their subsequent therapies, so that looks very unusual. It raises the hypothesis, but does not prove, that sensitization might have occurred.”

Future Research To test the sensitization theory, the study researchers are developing another study and have applied to the NCI for approval to move ahead. “In the trial we are submitting to the NCI, the epigenetic therapy will start much earlier than in the trial we just completed. Patients will have had only one prior therapy, and then we will test them for sensitization. If this works, it will change the landscape of this disease, but we have to do the trials,” said Dr. Baylin. The Johns Hopkins researchers have already launched a phase II adjuvant therapy trial to study the combination of azacitidine and entinostat in patients with early-stage lung cancers that have been surgically removed.

■

Disclosure: Dr. Rudin has been a consultant for Syndax. Dr. Baylin has been a consultant for, has research support from, and holds a patent licensed to MDxHealth.

Reference 1. Juergens RA, Wrangle J, Vendetti FP, et al: Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Discovery 1(7):598-607, 2011.

The ASCO Post | FEBRUARY 15, 2012

PAGE 22

FDA Update

FDA Approves Vismodegib for Basal Cell Carcinoma partial response. The most common side effects observed in patients treated with vismodegib were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased ap-

continued from page 2

sion-free survival in patients receiving the kinase inhibitor axitinib compared to patients receiving sorafenib (HR = 0.67; 95% CI = 0.54–0.81; P < .0001, log-rank test). The median progression-free survival of patients receiving axitinib was 6.7 months (95% CI = 6.3–8.6) compared to 4.7 months (95% CI = 4.6–5.6) for the sorafenib arm. This improvement in progression-free survival was greater in the cytokine-pretreated subgroup compared to the sunitinib-pretreated subgroup. The most common (≥ 20%) adverse reactions in patients treated with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia syndrome, weight decrease, vomiting, asthenia, and constipation.

■

severe birth effects to a fetus. Pregnancy status must be verified prior to the start of treatment. Male and female patients should be warned about these risks and the need for birth control.

■

Start With SPRYCEL (dasatinib) SPRYCEL: Superior Response Rates vs Imatinib • Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259) vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519) at a minimum follow-up of 12 months1,2

— Primary endpoint was conﬁrmed complete cytogenetic response (CCyR)† by 12 months

Major Molecular Response (MMR)‡ at Any Time1

52% SPRYCEL (95% CI, 46-58)

P<0.0001§

34%

SPRYCEL (n=259) Imatinib (n=260)

Imatinib (95% CI, 28-40)

Axitinib Approved for Kidney Cancer

petite, constipation, vomiting, and loss of taste function in the tongue. Vismodegib is being approved with a Boxed Warning alerting patients and health-care professionals of the potential risk of death or

An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients…

MMR at Any Time

he FDA has approved vismodegib (Erivedge) to treat adult patients with basal cell carcinoma, the most common type of skin cancer. The drug is intended for use in patients with locally advanced basal cell cancer who are not candidates for surgery or radiation and for patients with metastatic disease. Vismodegib is the first FDA-approved drug for metastatic basal cell carcinoma. The drug was reviewed under the FDA’s priority review program, which provides for an expedited 6-month review of drugs that may offer major advances in treatment. An oral agent, vismodegib is taken once a day and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles. The safety and effectiveness of vismodegib was evaluated in a single, multicenter clinical study in 96 patients with locally advanced or metastatic basal cell carcinoma. The clinical study’s primary endpoint was objective response rate (ie, complete plus partial response). Of the patients with metastatic disease receiving vismodegib, 30% experienced a partial response and 43% of patients with locally advanced disease experienced a complete or

50 MMR (%)

100

• Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1 • Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1 • Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with imatinib (n=177)1

Select Important Safety Information • SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related events; fluid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial infarction; pulmonary arterial hypertension; and use in pregnancy • The most frequently reported serious adverse events in patients with newly diagnosed CP CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) • The most frequently reported adverse reactions reported in ≥10% of patients with newly diagnosed CP CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash • Please see detailed Important Safety Information on adjacent pages

Indication SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to

determine long-term outcome.

ASCOPost.com | FEBRUARY 15, 2012

PAGE 23

FDA Update

Ingenol Mebutate Approved for Topical Actinic Keratosis Therapy

he FDA has approved ingenol mebutate (Picato) gel for the topical treatment of actinic keratosis. At a concentration of 0.015%, the gel is used once daily on the face and scalp for 3 consecutive days, whereas a 0.05% dos-

age form is used once daily on the trunk and extremities for 2 consecutive days. Ingenol mebutate gel is the first topical actinic keratosis therapy that can be used for as little as 2 or 3 days. Studies show that about 65% of

squamous cell carcinomas begin as untreated actinic keratosis, and guidelines from the American Academy of Dermatology estimate that 60% of predisposed persons older than 40 have at least one actinic keratosis.

for Superior Response vs Imatinib in 1st Line Start With Convenient Once-Daily Dosing

1 pill 100 mg 1 time per day

One tablet taken consistently, either in the morning or in the evening Tablets should not be crushed or cut; they should be swallowed whole Tablet not actual size.

• In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient1

SPRYCEL Can Be Taken Either With or Without Food1 SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with:

FASTING

• No fasting requirements • No need to alter meal schedules • No need to take with food

Important Safety Information About Drug Interactions • Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should be avoided • Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided • Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided • Concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy is needed, the dose should be given 2 hours before or after SPRYCEL *Stratified by Hasford risk score.2 Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1 ‡ MMR (at any time) was defined as BCR-ABL ratios ≤0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples standardized on the International Scale.1 § Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1 †

Please see detailed Important Safety Information, including Important Safety Information on Drug Interactions, on adjacent pages.

In four phase III studies of more than 1,000 patients, a significantly higher proportion of those treated with ingenol mebutate gel (n = 503) saw complete clearance of actinic keratoses in the field of treatment, compared to placebo.

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The ASCO Post | FEBRUARY 15, 2012

PAGE 24

FDA Update

Glucarpidase Approved to Treat Methotrexate Toxicity

he FDA has approved intravenous glucarpidase (Voraxaze) to treat patients with toxic levels of methotrexate in their blood due to kidney failure. Glucarpidase is an enzyme that rapidly reduces methotrex-

ate levels by breaking down the chemotherapy drug to a form that can be eliminated from the body. It has been granted orphan drug status. A single clinical study of 22 patients evaluated the effectiveness of

glucarpidase. All patients received the treatment. The study considered treatment a success if the methotrexate level fell below a critical level within 15 minutes and stayed below the critical level for 8 days. Of

the 22 patients studied, 10 achieved this standard, but glucarpidase eliminated 95% of the methotrexate in all

Important Safety Information Myelosuppression: • Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities — Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated — Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation — Hematopoietic growth factor has been used in patients with resistant myelosuppression Bleeding-Related Events: • SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans — In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients • Most bleeding events were associated with severe thrombocytopenia — Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants Fluid Retention: • SPRYCEL is associated with fluid retention — In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported • Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray • Severe pleural effusion may require thoracentesis and oxygen therapy • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids QT Prolongation: • In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval) • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms • In clinical trials of patients treated with SPRYCEL (N=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH, which may occur anytime after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed SPRYCEL should be permanently discontinued. Use in Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL. Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.

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FDA Update

patients. The most common side effects observed were hypotension, headache, nausea, vomiting, flushing, and paraesthesia. A separate clinical study evaluated the safety of glucarpidase in 290 patients experiencing problems clearing methotrexate from their blood.

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Shared REMS Approved for all Transmucosal Immediate-release Fentanyl Products

he FDA has approved a new transmucosal immediate-release fentanyl Risk Evaluation and Mitigation Strategy (REMS) access pro-

gram. The REMS is a single shared system for all transmucosal immediate-release fentanyl products. Among the goals of the REMS access program

Drug Interactions: SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4. • Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided • Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. • In newly diagnosed chronic phase CML patients: — The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) — The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash — Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%) • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML — Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption — Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

Please see brief summary of full Prescribing Information on adjacent pages. References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb. 2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

For more information online, visit www.sprycel.com.

are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication continued on page 26

The ASCO Post | FEBRUARY 15, 2012

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FDA Update

Shared REMS continued from page 25

errors by prescribing and dispensing such medicines only to appropriate patients; preventing inappropriate conversion between fentanyl products; and preventing accidental exposure to children and others for whom

the drug was not prescribed. Transmucosal immediate-release fentanyl products are available only through REMS programs, which require enrollment by prescribers, their patients, pharmacies, and distributors. Currently, manufacturers of these drugs have separate REMS programs,

and a health-care provider and pharmacy must enroll in multiple REMS programs to prescribe or dispense each product.

Program Live in March 2012 The shared REMS will go live in March 2012, when prescribers, phar-

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SPRYCEL® (dasatinib) Tablet for Oral Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data will be required to determine long-term outcome. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens. Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse Reactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens. QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms. Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pulmonary Arterial Hypertension: SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur anytime after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued. Use in Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings and Precautions]. • Bleeding related events [see Warnings and Precautions]. • Fluid retention [see Warnings and Precautions]. • QT prolongation [see Warnings and Precautions]. • Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions]. • Pulmonary Arterial Hypertension [see Warnings and Precautions]. 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 data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively). The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 1).

macies, patients, and distributors may all be enrolled in a single program for these products. All stakeholders currently enrolled in any of the individual REMS programs will be automatically enrolled in the shared system in March. For more information, visit fda.gov.

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The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and Table 2 for CML patients with resistance or intolerance to prior imatinib therapy. Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML Grade 3/4 All Grades SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 cardiac dysfunctiona 2 <1 <1 0 Pericardial effusion Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 0 <1 Musculoskeletal pain 12 16 Rashb 11 17 0 1 21 Nausea 9 0 0 11 Fatigue 8 <1 0 12 Myalgia 6 0 0 Hemorrhagec 6 5 1 1 Gastrointestinal bleeding 2 <1 1 0 d Other bleeding 5 5 0 1 CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage. Table 2:

Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 140 mg Once Daily 100 mg Once Daily Myeloid Lymphoid Chronic Accelerated Blast Blast (n=165) (n=157) (n=74) (n=33) All Grade Grade All Grade All Grade All Preferred Term Grades 3/4 3/4 Grades 3/4 Grades 3/4 Grades Percent (%) of Patients Fluid Retention 34 4 35 8 34 7 21 6 Superficial 18 0 18 1 14 0 3 0 localized edema Pleural effusion 18 2 21 7 20 7 21 6 Generalized edema 3 0 1 0 3 0 0 0 Pericardial effusion 2 1 3 1 0 0 0 0 Congestive heart failure/ 0 0 0 0 4 0 0 0 a cardiac dysfunction 1 Pulmonary edema 0 0 0 4 3 0 0 Headache 1 1 18 1 15 3 33 27 Diarrhea 2 3 20 5 18 0 27 31 Fatigue 2 2 20 1 9 3 24 19 Dyspnea 2 3 15 3 3 3 20 20 Musculoskeletal pain 2 0 8 1 0 0 19 11 Nausea 1 1 23 1 21 3 18 19 b Skin rash 17 2 15 0 16 1 21 0 Myalgia 13 0 1 7 1 3 0 7 Arthralgia 12 1 10 0 5 1 0 0 1 6 14 7 9 0 12 10 Infection (including bacterial, viral, fungal, and non-specified) Abdominal pain 1 0 8 3 3 0 12 6 Hemorrhage 1 8 19 9 24 9 11 26 Gastrointestinal bleeding 1 9 7 9 3 2 8 6 CNS bleeding 0 1 0 0 3 3 0 1 Vomiting 1 1 12 0 15 0 7 11 Pyrexia 1 2 18 3 6 0 5 11 Febrile neutropenia 1 4 12 12 12 12 1 4 a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

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FDA Update

FDA Completes Work on Three Drug User Fee Programs

he FDA recently completed its recommendations for three user fee programs that will help speed safe and effective drugs and lower-cost generic drug and biosimilar biologic products to patients, according to FDA Commis-

sioner Margaret A. Hamburg, MD. The programs include the fifth authorization of the Prescription Drug User Fee Act (PDUFA), and new user fee programs for human generic drugs and biosimilar biologic products.

Under a user fee program, industry agrees to pay fees to help fund a portion of the FDA’s drug review activities, while the FDA agrees to overall performance goals such as reviewing a certain percentage of applications within a par-

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In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions]. Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL Imatinib (n=258) (n=258) Percent (%) of Patients Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 4. Table 4:

CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML Advanced Phase CML 140 mg Once Daily Accelerated Myeloid Lymphoid 100 mg Phase Blast Phase Blast Phase Once Daily (n=157) (n=74) (n=33) (n=165) Percent (%) of Patients Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L).

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased.

Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib). 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. Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, pulmonary arterial hypertension. DRUG INTERACTIONS Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information]. Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1) in Full Prescribing Information]. Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL. H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy. Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. Nursing Mothers: It is unknown whether SPRYCEL 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 SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established. Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment. Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGE Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse Reactions], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2). Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1284903A0 DS-B0001A-10-11

Rev October 2011

ticular time frame. The proposed user fee programs for generic drugs and biosimilars are modeled on the successMargaret A. Hamburg, MD ful PDUFA program, “which has ensured a predictable, consistent, and streamlined premarket program for prescription drugs,” Dr. Hamburg said. PDUFA was created by Congress in 1992 and must be reauthorized every 5 years.

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Subcutaneous Bortezomib Approved

he FDA has approved a supplemental new drug application for bortezomib (Velcade), updating the label to include the subcutaneous administration in all indications approved for intravenous administration, ie, multiple myeloma and mantle cell lymphoma after at least one prior therapy. The approval was based on results from a randomized, phase III, openlabel, international, noninferiority trial conducted in 222 bortezomib-naive patients with relapsed multiple myeloma. The primary objective of the trial was to demonstrate that single-agent subcutaneous bortezomib retained at least 60% of the overall response rate after four cycles relative to single-agent intravenous bortezomib. Patients receiving bortezomib subcutaneously achieved a four-cycle overall response rate of 43% and complete response rate of 7%, while patients receiving bortezomib intravenously achieved an overall response rate of 42% and a complete response rate of 8%. The overall safety profile was similar between the two arms. However, in the subcutaneous arm of the trial, 6% of patients experienced peripheral neuropathy of grade 3 or higher, compared with 16% in the intravenous arm. The updated label also includes a contraindication for intrathecal administration of bortezomib. More FDA Update on page 40.

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The ASCO Post | FEBRUARY 15, 2012

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Direct from ASCO

QOPI® Certifies 100th Practice for Delivering High-quality Cancer Care

ess than 2 years since launching the first national program to help oncology practices deliver the highest quality of cancer care, ASCO and its affiliate, the Quality Oncology Practice Initiative (QOPI®) Certification Program, announced that more than 100 practices have achieved QOPI certification. The QOPI Certification Program certifies that outpatient oncology offices meet the highest national standards in quality and safety for cancer care delivery. “We are delighted that more than 100 oncology practices in the United States have already taken steps to ensure that the cancer care they provide is consistent with the highest national quality standards,” said Allen S. Lichter, MD, CEO of ASCO and President of the QOPI Certification Program. “QOPI certification demonstrates a practice’s commitment to excellence and ongoing quality measurement and improvement. Achieving the QOPI standard of excellence signifies that a practice is providing the highest quality treatment and care for their patients.”

Certification Program Background

Launched by ASCO in 2006, QOPI enables practices to examine the quality of care they provide to patients based on evidence-based guidelines and established quality measures. Its rigorous set of more than 100 quality measures was de-

The QOPI Certification Program was launched in January 2010. The first 16 practices were certified just 6 months later, and the milestone of 100 certified practices was achieved

veloped by practicing oncologists and quality experts, and spans the continuum of cancer care. Practices that participate receive detailed reports that indicate their performance on these quality metrics and offer insights into specific areas for improvement.

in a little less than 2 years. The first step toward achieving QOPI certification is participation in QOPI data collection. Beyond that, practices/institutions must undergo an extensive review by a team of ASCO professionals and oncology physicians and nurses at least once

every 3 years. A practice’s performance is evaluated in terms of: ■■ Participation in QOPI and achieving above the threshold score across the 24 rigorous measures required for certification. ■■ Meeting 17 Certification Standards based on the ASCO/ONS Chemotherapy Administration Safety Standards, which address: Treatment planning Excellence in staff training and education Chemotherapy orders and drug preparation Patient consent and education Safe chemotherapy administration Monitoring and assessment of patient well-being For a continuously updated list of QOPI-certified practices, please go to http://qopi.asco.org/certifiedpractices. For more information about the program, please visit http://qopi.asco.org/certification.

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Integration of QOPI® Helps Michigan Insurer Earn ‘Best of Blue’ Award

y working to improve oncology care in practices in Michigan through integration of ASCO’s Quality Oncology Practice Initiative (QOPI) into its Physician Group Incentive Program, Blue Cross Blue Shield of Michigan (BCBSM) has been selected as a 2011 “Best of Blue Clinical Distinction Award” winner by the Blue Cross Blue Shield Association. The Best of Blue Clinical Distinction Award showcases best practices that focus on reducing medical costs while improving quality, affordability, and patient safety and is open to all Blue plans nationally. In 2011, 48 programs underwent a rigorous and objective review for the award, and in early December, eight were named as “Best of Blue” winners in this category. “QOPI is a unique approach to supporting oncology practices in

providing high quality care in the most efficient manner to patients undergoing treatment for cancer,” said Kimberley Harrison, BCBSM’s initiative leader for QOPI. “The ‘Best

Data Requirements QOPI is the first national program to help outpatient oncology practices assess and improve the quality of care they deliver. Oncol-

Our hope is that the recognition from Blue Cross Blue Shield will encourage increased collaboration between payers and providers to provide the highest quality care to people living with cancer. — Allen S. Lichter, MD

of Blue Award’ is a testament to the successful collaboration between the payer and the provider community to lead quality improvements and the oncology provider community’s desire to provide the best care possible to their patients with cancer,” Ms. Harrison said.

ogy practices participating through BCBSM are required to enter data on core measures, care-at-the-endof-life measures, and one additional module of their choice from QOPI’s domain-specific or disease-specific modules. They then receive semiannual data reports on these measures

to guide their quality improvement efforts. Through a data use agreement with the Michigan Oncology Quality Consortium, a quality collaborative funded by BCBSM to improve care provided to patients with cancer in Michigan, the participating practices review the information and identify focused projects to improve their scores “We are pleased to see the positive impact participation in QOPI has had on oncology practices in Michigan,” said Allen S. Lichter, MD, CEO of ASCO. “Our hope is that the recognition from Blue Cross Blue Shield will encourage increased collaboration between payers and providers to provide the highest quality care to people living with cancer.”

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ASCOPost.com | FEBRUARY 15, 2012

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Direct from ASCO

ASCO Membership Categories Offer a Place for Everyone

staff have worked to come up with appealing benefits tailored to each group, including grant opportunities and specific educational offerings. ASCO currently has 31,276 oncology professionals represented in its membership, a 70% increase from just a decade ago. Most of its membership categories have existed since just after the organization’s inception, but a few are new.

Medical Students, Come Aboard To help foster a new generation of oncologists, in 2011 a new category was approved for medical students, medical residents, graduate students, and undergraduate students who are enrolled in a biomedical, nursing, or allied health program and who have a predominant interest in the biology, diagnosis, prevention, or treatment of human cancer. Members in this category, Student/Non-Oncology Resident, pay no annual dues

and get a subscription to The ASCO Post (TAP), as well as significant discounts on the Journal of Clinical Oncology ( JCO) and the Journal of Oncology Practice ( JOP) ($50 each, an 83% savings on JCO and 60% on JOP). Another fairly new category, the International Corresponding membership category, was created in 2004. This category is offered to physicians in countries with low per capita income as defined by the World Bank list of economies. To benefit these members, ASCO offers a sliding dues scale from $50

Volume 29, Issue 15

May 20, 2011

What’s Hot in

JOP Volume 7, Issue 3

2. US Cancer Center Implementation of ASCO/Oncology Nursing Society Chemotherapy Administration Safety Standards Saul N. Weingart, et al DOI: 10.1200/JOP.2011.000379

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

3. US Food and Drug Administration Regulation of Medical Devices and Radiation Oncology: Can Reform Improve Safety? Jona A. Hattangadi, et al DOI: 10.1200/JOP.2011.000290 4. Exposure to and Intention to Discuss Cancer-Related Internet Information Among Patients With Breast Cancer Carma L. Bylund, et al DOI: 10.1200/JOP.2011.000271

www.jop.ascopubs.org

jop.ascopubs.org

5. Response to a Treatment Summary and Care Plan Among Adult Survivors of Pediatric and Young Adult Cancer Peter D. Spain, et al DOI: 10.1200/JOP.2011.000345

The largest membership category is that of Full Member, constituting continued on page 30

What’s Hot in

Official Journal of the American Society of Clinical Oncology

JCO

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

1. Revisions to the 2009 American Society of Clinical Oncology/ Oncology Nursing Society Chemotherapy Administration Safety Standards: Expanding the Scope to Include Inpatient Settings Joseph O. Jacobson, et al DOI: 10.1200/JOP.2011.000339

Full Member: Still the Largest Category

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

JOURNAL OF CLINICAL ONCOLOGY

www.jco.org

Top 5 articles recently published in Journal of Oncology Practice

to $210, and membership includes free, full-text online-only subscriptions to JCO, JOP, and TAP, in addition to savings of up to 60% off the nonmember registration rate at the ASCO Annual Meeting. These applicants have the option of joining ASCO as a Full Member or an International Corresponding Member.

2011

f your work touches those who have cancer, you have a place within ASCO. That’s the message that the organization, during its 48 years, has gotten across in many ways, not the least of which is its membership categories, which have expanded right along with the field of cancer care. “ASCO is unique in that we are the only organization that encompasses all oncology specialties, allowing our members to grow from the professional and personal expertise of their colleagues worldwide and across disciplines,” said Allen S. Lichter, MD, ASCO chief executive officer. ASCO membership is available to a broad constituency both in the United States and abroad, from oncologists of all subspecialties to researchers, nurses, radiologists, practice managers, fellows, and as of very recently, to medical students. As new categories have been created, ASCO member volunteers and

JCO.org 1. Addition of Bevacizumab to Chemotherapy for Treatment of Solid Tumors: Similar Results but Different Conclusions Alberto Ocaña, et al 29(3): 254 2. Prostate Cancer: Evolution or Revolution? Eric J. Small, et al 29(27): 3595 3. Myeloproliferative Neoplasms: Molecular Pathophysiology, Essential Clinical Understanding, and Treatment Strategies Ayalew Tefferi, et al 29(5): 573 4. FOLFIRINOX: A Small Step or a Great Leap Forward? Andrew H. Ko 29(28): 3727 5. Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma David H. Henry, et al 29(9): 1125

6. Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update Ching-Hon Pui, et al 29(5): 551 7. Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214) R. Timothy D. Oliver, et al 29(8): 957 8. Therapeutic Advances in Acute Myeloid Leukemia Alan Burnett, et al 29(5): 487 9. Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications Guido Marcucci, et al 29(5): 475 10. Palliative Care and the Quality of Life Diane E. Meier, et al 29(20): 2750

The ASCO Post | FEBRUARY 15, 2012

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Direct from ASCO

Membership Categories continued from page 29

65% of ASCO’s membership. Oncologists from every specialty are welcomed as Full Members and receive JCO, JOP, and TAP with their membership. Annual dues for Full Members are $550. All physicians eligible

for Full membership who are within 3 years of completion of an approved oncology subspecialty training program qualify for discounted dues of $295 for those 3 years. Another popular category is that of Member in Training. Twelve percent of ASCO’s membership belongs

to this category, which is available at no cost to physicians and other health professionals at the doctoral level who are participating in a subspecialty training program in oncology or another field that would lead to eligibility for Full or Allied Physician/Doctoral Scientist membership.

Membership includes a subscription to TAP and discounts on subscriptions to JCO and JOP, as well as discounted registration for the ASCO Annual Meeting and ASCO symposia and savings of 20% to 50% off all ASCO educational products and resources.

Nononcologists: Pleased to be Part of the Family

Now Enrolling A Randomized Phase 3 Trial

R A N D O M I Z E D

Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine

OS Primary endpoint

Ganitumab (AMG 479) is an investigational IGF1R inhibitor that has not been approved by the FDA.

KEY INCLUSION CRITERIA: • Histologically or cytologically conﬁrmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV)

Useful Tools Created for Affiliated Health Professionals

• Previously untreated with chemotherapy or radiation • ECOG Performance Status 0 or 1 For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20060540) • www.ClinicalTrials.gov (NCT01231347)

ASCO 2011 Journal Ad_AMG479_090611.indd 1

Seven percent of ASCO’s membership belongs to the Allied Physician/Doctoral Scientist membership category. Vivian Weinberg, PhD, biostatistician at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco is in that number. She’s been an ASCO member for over 30 years and in that time has held leadership positions on committees, a role she was pleased to take on because of the recognition for the need to consider statistical integrity in oncology research. “ASCO has always been important to me professionally,” she said. “The organization has always recognized that people from different disciplines bring their own strengths and abilities, and that each role is valuable.” The Allied Physician/Doctoral Scientist membership category is available to physicians and other health professionals at the doctoral level (such as epidemiologists, biostatisticians, public health specialists, nurses, and other scientists) or individuals with equivalent academic ranks who are not eligible for Full membership and who have a predominant interest in the biology, diagnosis, prevention, or treatment of human cancer. Annual dues are $150. Membership includes subscriptions to TAP and JOP, as well as substantially discounted member access to JCO in print and online.

Oncology

9/6/2011 5:08:17 PM

A small but important portion (4%) of the membership falls within the Affiliated Health Professional membership category. This category is available to oncology nurses, nurse practitioners, physician assistants, practice management professionals, and other health specialists who devote a majority of their professional

ASCOPost.com | FEBRUARY 15, 2012

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Direct from ASCO

activity to the care and treatment of patients with cancer. Recognizing the important role that practice management professionals and other health-care specialists have in delivering quality care, ASCO has built a wide range of products and benefits for members in this category to help them provide the most effective cancer care. For example, these members have access to a variety of electronic health records tools, practice quality programs like the Quality Oncology Practice Initiative (QOPI®), and ASCO’s Coding and Reimburse ment Hotline. To join ASCO, no matter which membership category applies to you, visit benefits.asco.org. For personal service, contact ASCO Member Services at (703) 299-0158, (888) 2822552, or membermail@asco.org.

The 2012 Genitourinary Cancers Symposium takes place February 2–4 in San Francisco. Direct your patients to www.cancer. net/GUsymposium to find written summaries for patients and a podcast that highlights the research presented at the meeting, on prostate, bladder, kidney, testicular, and other genitourinary cancers.

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Save the Date

Show Your Patients the Latest Research on Genitourinary Cancers

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ASCO’12 Annual Meeting

Best of ASCO® Chicago

June 1-5, 2012

July 12-13, 2012

McCormick Place

Hyatt Regency Chicago

Chicago, Illinois

Best of ASCO® Boston August 3-4, 2012 Renaissance Boston Waterfront Hotel Boston, Massachusetts

Best of ASCO® San Diego August 10-11, 2012 Manchester Grand Hyatt San Diego, California

James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology The Conquer Cancer Foundation is honored to announce the creation of the James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology. Established by Dr. Nachman’s friends and colleagues in remembrance and celebration of his incredible legacy as an internationally renowned pediatric cancer expert, the award will be granted annually, beginning at the 2012 Annual Meeting to a junior faculty member who submits the highest-scoring abstract in pediatric oncology. We gratefully thank our donors for their support and generosity.

For more information about the James B. Nachman ASCO Junior Faculty Award, including a listing of donors, please visit www.conquercancerfoundation.org/merit

Photo courtesy of the University of Chicago Medical Center.

The ASCO Post | FEBRUARY 15, 2012

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Journal Spotlight Survivorship

Cancer Survivors at Greater Risk for Cutaneous Melanoma By Charlotte Bath

atients with a previously diagnosed cancer have an increased risk of developing cutaneous melanoma, with the highest risk among patients who have had a prior diagnosis of melanoma, according to a report published in the Archives of Dermatology.1

Cutaneous melanoma is the most common second primary cancer in patients with a first cutaneous melanoma. Key Findings Using Surveillance, Epidemiology, and End Results (SEER) data, researchers from the Case Western University School of Medicine compared a cohort of patients with cutaneous melanoma as a first primary cancer with a cohort of patients diagnosed with cutaneous melanoma after a previous cancer and calculated the relative risk (RR) of developing a primary cutaneous melanoma following a previous cancer. The greatest number of melanomas developed among patients with a previous melanoma diagnosis, a finding consistent with other studies, the investigators noted. The cohort of patients with cutaneous melanoma as a first primary cancer was larger—70,819 patients, compared to 6,353 patients with cutaneous melanoma following a previous cancer—and had a younger median age at the time of melanoma diagnosis—54 years compared to 70 years. Patients in the cohort diagnosed with cutaneous melanoma after a previous cancer were more likely to be male (67.1% vs 54.2%). “The finding that a greater number of patients in the second cohort were older and male compared with the first cohort is likely because many of the observed melanoma cases in the second cohort followed prostate cancer. In addition, men are at increased risk of developing cancers in SEE PAGE 59 general compared

with women, perhaps because of certain occupational exposures and social risk factors such as drinking and smoking,” the investigators stated. “The greater age at melanoma diagnosis in

the second cohort may also explain the increased rate of lentigo maligna melanoma, which usually occurs on the head and neck regions of older individuals with chronic sun-damaged skin.”

LITTLE THINGS MAY SEEM INSURMOUNTABLE FOR PATIENTS WITH CHEMOTHERAPY-INDUCED ANEMIA

Continued Surveillance Needed Patients younger than 45 years at first cancer diagnosis had a significantly higher risk of cutaneous mela-

ASCOPost.com | FEBRUARY 15, 2012

PAGE 33

Journal Spotlight

noma following an earlier cutaneous melanoma (RR = 11.89), other nonepithelial skin cancer (RR = 2.81), Kaposi sarcoma (RR = 3.26), female breast cancer (RR = 1.38), and lymphoma (RR = 1.79). Patients 45 years or older at first cancer diagnosis had a significantly higher risk of cutaneous

melanoma following prior cutaneous melanoma (RR = 8.36), other nonepithelial skin cancer (RR = 2.00), ocular melanoma (RR = 5.34), female breast cancer (RR = 1.12), prostate cancer (RR = 1.08), thyroid cancer (RR = 1.40), lymphoma (RR = 1.34), and leukemia (RR = 1.79).

“Characteristics associated with better survival in both cohorts included female sex, age younger than 45 years at melanoma diagnosis, being married, being white vs black, decreasing Breslow depth, lack of tumor ulceration, no nodal involvement, and absence of metastases,” the research-

ACTIVE MANAGEMENT OF CANCER-RELATED ANEMIA MAY HELP REDUCE ITS OVERALL IMPACT ANEMIA IS COMMON IN CANCER PATIENTS RECEIVING CHEMOTHERAPY In patients

receiving chemotherapy, anemia (Hb < 11 g/dL) was present in over 50% of those with ovarian, breast, and non-small cell lung cancer and approximately 40% of those with colorectal and head and neck cancer.* Anemia also was observed in approximately half of patients receiving platinum-, anthracycline-, taxane-, or gemcitabine-based chemotherapy regimens.*1

SYMPTOMS OF ANEMIA ARE OFTEN DUE TO THE HYPOXIA-RELATED EFFECTS ON ORGAN FUNCTION Signs and symptoms include

pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.2,3

HEMOGLOBIN LEVELS AND PERFORMANCE SCORES ARE CORRELATED The European

Cancer Anaemia Survey, a prospective observational survey that enrolled patients regardless of disease status or cancer treatment, showed a significant correlation between Hb level and performance status at enrollment (n = 14,912 evaluable).† Though poor performance status was observed in all Hb level groups (< 8 g/dL to ≥ 12 g/dL), the lower the Hb level, the more likely patients would be ambulatory but unable to work, would stay in bed or chair more than 50% of the day, or would be totally confined to bed or chair.4,5

Hb levels significantly correlate with performance status†4,5

% OF PATIENTS

WHO score at enrollment:

n‡ =

90 80 70 60 50 40 30 20 10 0

0–1 2 (eg, ambulatory but unable to work) 3 (eg, in bed/chair > 50% of the day) 4 (eg, bed/chair bound)

84.0

75.2 60.0 49.2

8750

Mean (SD) 0.8 (0.8) WHO score

10.1

5.0 0.5

2.3 0.2 ≥ 12.0

27.7

19.3

13.5

10.0 – 11.9

8.0 – 9.9

26.7 16.0 2.2

HEMOGLOBIN LEVELS (g/dL)

< 8.0

4214

1242

187

1.0 (0.8)

1.4 (1.0)

1.7 (1.1)

8.0

PATIENTS CAN BECOME ANEMIC WITHIN THE FIRST 2 CYCLES OF CHEMOTHERAPY

When data from 1,821 patients with cancer who began receiving chemotherapy at Hb ≥ 12 g/dL were analyzed to determine relative risk for anemia, 62% of patients experienced a Hb decline of 1.5 g/dL within a median of 6.1 to 7.2 weeks and 51% had a Hb decline of 2 g/dL within a median of 7.3 to 8.9 weeks.6 Low Hb levels have been associated with an increased likelihood of chemotherapy dose delays and dose reductions.7 How might clinicians reduce the overall impact of anemia?

PATIENT EDUCATION IS AN IMPORTANT ASPECT OF ACTIVE ANEMIA MANAGEMENT

NCCN recommends that Hb levels ≤ 11 g/dL or ≥ 2 g/dL below baseline prompt an evaluation of anemia in order to characterize the anemia and correct any underlying comorbidities. At this point, a detailed history, physical, and further laboratory tests are suggested, which include a CBC with indices, onset of symptoms (eg, syncope, dyspnea, headache, fatigue), comorbidities, and exposure to antineoplastic drugs and radiation.8 ASCO/ASH recommends that clinicians also discuss the benefits and harms of therapeutic options with patients undergoing myelotoxic chemotherapy who become anemic.9

For more information about chemotherapy-induced anemia, please visit anemia.com/professional/cia.

ers reported. “Given that cutaneous melanoma is the most common second primary cancer in patients with a first cutaneous melanoma (a risk that remains elevated for over 15 years), our results suggest the need for continued skin surveillance in melanoma survivors,” they concluded.

■

Reference 1. Yang GB, Barnholtz-Sloan JS, Chen Y, et al: Risk and survival of cutaneous melanoma diagnosed subsequent to a previous cancer. Arch Dermatol 147:13951402, 2011.

CONTACT

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

R IGHTS AND PER MISSIONS e-mail: Permissions@harborsidepress.com

ADVERTISING

*N (anemia patients evaluated) = 42,923. Data from January 1, 2000, through December 31, 2007, from a retrospective, observational, cohort study of 47,159 adult patients with cancer were obtained through electronic medical records at community and hospital-affiliated clinical oncology practices throughout the United States. The mean baseline Hb prior to initiating chemotherapy was 12.4 g/dL across all tumor types. †Observational, prospective, multisite survey of patients with solid or hematological tumors. Survey enrollment was conducted from January to July 2001, with data collected for up to 6 data points or 6 months of scheduled clinic visits. ‡Missing data for n = 519. References: 1. Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Clin Ther. 2009;31:2416-2432. 2. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed March 30, 2011. 3. Ludwig H, Strasser K. Semin Oncol. 2001;28:7‐14. 4. Ludwig H, Van Belle S, Barrett-Lee P, et al. Eur J Cancer. 2004;40:2293-2306. 5. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48. pdf. Accessed February 17, 2011. 6. Barrett-Lee J, Ludwig H, Birgegård G. Oncology. 2006;70:34-48. 7. Repetto L. Crit Rev Oncol Hematol. 2009;72:170-179. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia. v2.2012. Available at: http://www.nccn.org. Accessed September 28, 2011. 9. Rizzo DJ, Brouwers M, Hurley P, et al. J Clin Oncol. 2010;28:4996-5010.

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

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

The ASCO Post | FEBRUARY 15, 2012

PAGE 34

JCO Spotlight Genitourinary Cancer

Tyrosine Kinase Inhibitor Therapy Yields Complete Remission in Patients with Metastatic Renal Cell Carcinoma By Matthew Stenger

argeted therapies have markedly improved outcomes in patients with advanced renal cell carcinoma, with median overall survival of greater than 2 years having been observed with sunitinib (Sutent) treatment. Objective responses, consisting mostly of partial responses, are observed in approximately 8% to 39% of patients receiving targeted agents. Complete remission appears to be rare, occurring, for example, in 3% of patients in the phase III trial of sunitinib as firstline treatment in metastatic renal cell carcinoma.1 In a recent issue of Journal of Clinical Oncology, Albiges and colleagues report a retrospective analySEE PAGE 59 sis of complete remissions achieved in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors at 15 centers in the Groupe Française d’Immunothérapie.2 Patients included in the analysis had histologically confirmed metastatic renal cell carcinoma and had received sunitinib or sorafenib (Nexavar) monotherapy according to standard approved schedules. Sunitinib was given at 50 mg/d for 4 weeks with 2 weeks off. Sorafenib was given at 800 mg/d continuously in 4-week cycles. Patients must have achieved complete remission with tyrosine kinase inhibitor therapy alone or in combination with local treatment consisting of surgery, radiation therapy, or radiofre-

quency ablation. The investigators identified 64 patients with complete remission (59 receiving sunitinib and 5 receiving sorafenib). The denominators for patient groups receiving sunitinib or sorafenib were not available for all centers; for the main center in the study, complete remission occurred in 6 patients (1.7%) of a total of 353 patients receiving either sunitinib or sorafenib. Most patients (94%) had clear cell histology, all had prior nephrectomy, and 56% had received no prior treatment. French classification prognostic grouping was favorable for 34% and intermediate for 61%. The number of metastatic sites prior to tyrosine kinase inhibitor treatment was 1 in 41% of patients, 2 in 36%, and 3 or more in 23%.

a median of 10.3 months from the time of complete remission. Relapse occurred in 7 (44%) of the 16 patients who stopped tyrosine kinase inhibitor treatment at the time of complete remission, 4 (33%) of the 12 who stopped treatment after additional cycles, and 1 (13%) of the 8 who were still receiving a tyrosine kinase inhibitor. The median time from complete remission to relapse was 7.9 months (range, 3–32 months). Relapse occurred at a previously involved metastatic site in 5 of 12 patients with relapse. Thus, of the 28 patients who stopped tyrosine kinase inhibitor treatment, 17 (61%) remained in complete remission after a median follow-up of 8.5 months (range, 0.3–39.1 months).

Tyrosine Kinase Inhibitor Alone

Tyrosine Kinase Inhibitor Plus Local Treatment

Of the 64 patients with complete remission, 36 (56%) achieved that remission with tyrosine kinase inhibitor treatment alone (Fig. 1). In these patients, the median time from start of tyrosine kinase inhibitor treatment to complete remission was 12.6 months (range, 2–28 months). Of the 36 patients, 16 (44%) stopped tyrosine kinase inhibitor treatment at the time of complete remission, 12 (33%) continued treatment with the same agent for a median of 3.9 months after complete remission, and 8 (22%) were still on such therapy at the time of the analysis after

A total of 28 patients (44%) achieved complete remission with a tyrosine kinase inhibitor and local therapy (Fig. 2), consisting of surgery in 22 (79%), radiofrequency ablation in 2 (7%), and radiation therapy in 4 (14%). Most patients received local therapy for pulmonary metastases. The median time from starting tyrosine kinase inhibitor treatment to complete remission was 18.5 months (range, 5–45 months), reflecting the fact that these patients needed local treatment after prolonged beneficial tyrosine kinase inhibitor treatment to

CR with TKI alone (n = 36)

Laurence Albiges, MD

achieve complete remission. Residual viable tumor cells were present in each of 20 available samples from patients who underwent surgery. Of the 28 patients, 19 stopped tyrosine kinase inhibitor treatment at the time of complete remission, 6 continued to receive treatment cycles for a median of 3.5 months after complete remission, and 3 were still receiving a tyrosine kinase inhibitor at the time of analysis after a median of 8.2 months from the time of complete remission. Relapse occurred in 10 (52%) of 19 patients stopping the tyrosine kinase inhibitor at the time of complete remission, 3 (50%) of 6 who received additional cycles before stopping, and 1 (33%) of 3 who continued to receive a tyrosine kinase inhibitor at the time of the analysis. Relapse occurred in a previously involved metastatic site in 9 of 14 patients with relapse. Thus, of the 25 patients who stopped tyrosine kinase inhibitor treatment after complete remission, 12 (48%) remain in remission after a median follow-up of 10.7 months (range, 0.3–54.0 months).

CR after TKI + local treatment (n = 28)

TKI arrest at CR (n = 16; 44%)

TKI arrest after further cycles of same TKI (n = 12; 33%) Median duration of continued TKI after CR = 3.9 months (range, 1.06 to 32.5)

TKI ongoing (n = 8; 22%)

TKI arrest at CR (n = 19)

TKI arrest after further cycles of same TKI (n = 6) Median duration of continued TKI after CR = 3.5 months (range, 1.0 to 15.4)

TKI ongoing (n = 3)

Relapse (n = 7 of 16; 44%)

Relapse (n = 4 of 12; 33%)

Relapse (n = 1 of 8; 13%)

Relapse (n = 10 of 19;52%)

Relapse (n = 3 of 6; 50%)

Relapse (n = 1 of 3; 33%)

Fig. 1: Outcome of patients who achieved complete remission (CR) with a tyrosine kinase inhibitor (TKI) alone. Adapted with permission from Albiges L, et al.2 © 2012 by the American Society of Clinical Oncology. All rights reserved.

Fig. 2: Outcome of patients who achieved complete remission (CR) with a tyrosine kinase inhibitor (TKI) in combination with local treatment. Adapted with permission from Albiges L, et al.2 © 2012 by the American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | FEBRUARY 15, 2012

PAGE 35

JCO Spotlight

No Predictive Factors for Relapse Identified Complete remissions were achieved in patients with up to five metastatic sites, indicating that extent of disease is not prohibitive of complete remission. Most patients in the group had favorable or intermediate risk, although complete remissions were also seen in three poor-risk patients. The investigators could not identify any clinical or biologic factors that appeared to be predictive of complete remission.

No factors could be identified that distinguished patients who were more or less likely to relapse after discontinuation of tyrosine kinase inhibitor therapy. Due to the small numbers of patients in each group, no conclusions could be drawn about differences in relapse rates between patients who continued therapy and those who stopped when complete remission was achieved. The longer duration of treatment with a tyrosine kinase inhibitor in pa-

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

tients achieving complete remission with local therapy underscores the potential benefits of maintaining such therapy as long as there is persisting clinical benefit. As noted by the authors, even if prolonging that therapy in patients with a good quality partial response does not result in conversion to complete remission, “[in] the case of stabilization of the lesion(s) and in the absence of new lesions, a local treatment may then be considered to achieve [complete remission].”

References 1. Motzer RJ, Hutson TE, Tomczak P, et al: Overall survival and updated results for sunitinib versus interferon alfa in first-line treatment of patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584-3590, 2009. 2. Albiges L, Oudard S, Negrier S, et al: Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. January 9, 2012 (early release online.).

■

Liver Cancer

Laparoscopic Liver Resections Can Be Safe and Oncologically Efficient By Charlotte Bath

aparoscopic resection of priamong patients with neuroendomary and metastatic liver cancrine tumor metastasis. cers can be safe and oncologically Port-site Metastasis and efficient and reduce postoperative Margin Compromise length of stay, a single-center study “The oncological controversies from the United Kingdom found.1 The investigators cautioned, howin laparoscopic liver resection relate ever, that “adequate patient selection to the risk of port-site metastasis and extensive experience in hepatic and the risk of surgical resection and laparoscopic surgery are essenmargin compromise. In this series, tial prerequisites to optimize outwe did not observe port-site maligcomes.” nant seeding,” the investigators statThe study involved 128 patients ed. Only 6 of the 17 patients with (52 women and 76 neuroendocrine men) undergoing tumor metastasis The data confirm 133 laparoscopic had microscopic liver resections positive resecthat [laparoscopic for malignant tion margins, and liver resections] can diseases. Two pamost underwent tients had twodebulking and achieve disease-free stage laparoscopic cytoreductive resection margin(s) resections for bisurgery. “A microlobar colorectal scopic negative and disease-free carcinoma liver resection margin and overall patient metastasis, and was obtained in three patients had the remaining survival similar to repeated liver re112 of 116 resecthose of conventional section for recurtions (97%),” the open techniques. rent colorectal investigators recarcinoma liver ported. metastasis. The An invited cri2 median age was 65 years. Major tique accompanying the study report hepatectomies were performed in 42 in the Archives of Surgery noted that the patients (32%) and the median poststudy is important “because the data operative length of stay was 4 days, confirm that [laparoscopic liver resecwith a range of 1 to 15 days. Meditions] can achieve disease-free resecan overall survival has not yet been tion margin(s) and disease-free and reached, but the authors recorded overall patient survival similar to those 2-year overall survival rates of 80% of conventional open techniques.” The among patients with critique also pointed out that inclusion colorectal carcinocriteria for laparoscopic liver resections ma liver metastases, still need to be determined, and only a 77% among patients randomized controlled trial can deterwith hepatocellular mine if laparoscopic liver resection is SEE PAGE 59 carcinoma, and 91% better than the open technique.

■

References 1. Abu Hilal M, DiFabio F, Abu Salameh M, et al: Oncological efficiency analysis of laparoscopic liver resection for primary and metastatic cancer: A single-center UK Experience. Arch Surg 147:42-48, 2012.

2. Krige J, Kahn D: Laparoscopic vs open liver resection: Comment on “Oncological efficiency analysis of laparascopic liver resection for primary and metastatic cancer.” Arch Surg 147:48, 2012.

Coming in Future Issues of The ASCO Post Important Oncology News from:

■■ 2012 Gastrointestinal Cancers Symposium ■■ 2012 Genitourinary Cancers Symposium ■■ 2012 National Comprehensive Cancer Network Annual Meeting ■■ Original Columns and Perspectives from Oncology Leaders ■■ Conversations with Experts About Important Issues in Cancer Care ■■ Special Features: Hematology for the Oncologist; International Efforts in Management of Cancer Pain; Continuing Coverage on the Oncology Drug Shortage; 2012 Presidential Election: Impact on Oncology

Treating pNET 22

Biosimilars in cancer treatment 37

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era

November Is Lung Cancer Awareness Month

continued on page 20

A Harborside Press® Publication

Visit The ASCO Post online at ASCOPost.com.

The ASCO Post | FEBRUARY 15, 2012

PAGE 36

In the Clinic Genitourinary Cancer

Abiraterone: New Drug in the Treatment of Metastatic Castration-resistant Prostate Cancer 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

biraterone acetate (Zytiga) (an oral agent that inhibits CYP17 and thereby blocks androgen biosynthesis) was recently approved for use in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer who have received prior docetaxelcontaining chemotherapy.

Of Note In the trial leading to approval, treatment with abiraterone acetate plus prednisone reduced risk of death by 35% compared with placebo plus prednisone.

Approval was based on a trial comparing abiraterone (n = 797) with placebo (n = 398) in 1,195 patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-containing regimens. All patients received prednisone 5 mg twice daily. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded. A prespecified interim analysis of overall survival, performed when 552 events had occurred, showed a 35% reduction in risk of death with abiraterone treatment (HR = 0.646, P < .0001), with median

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1800-FDA-1088).

overall survival of 14.8 vs 10.9 months. An updated analysis, conducted after 775 events, showed median overall survival of 15.8 vs 11.2 months, representing a 26% risk reduction (HR = 0.740, 95% CI = 0.638–0.859).

■■ Abiraterone is a CYP17 inhibitor indicated for use in combination

How It Works

■■ The drug is administered orally at 1,000 mg once daily in combination

CYP17 (17α-hydroxylase/C17,20lyase) is an enzyme expressed in testicular, adrenal, and prostatic tumor tissue that is required for androgen biosynthesis. The enzyme catalyzes the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives via 17α-hydroxylase activity and the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione via C17,20-lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Abiraterone acetate is converted in vivo to abiraterone, which inhibits CYP17, thus blocking production of androgens (Fig 1).

How It Is Given The recommended dose of abiraterone is 1,000 mg orally once daily in combination with prednisone 5 mg orally twice daily. Abiraterone should be taken on an empty stomach, with no food being consumed for at least 2 hours before and for at least 1 hour after the dose. The starting dose should be reduced to 250 mg once daily in patients with moderate (Child-Pugh class B) hepatic impairment. Treatment should be discontinued until recovery in patients who develop hepatotoxicity during treatment and may be restarted at a reduced dose. Treatment should be discontinued permanently for severe hepatotoxicity.

Abiraterone in Prostate Cancer with prednisone to treat patients with metastatic castration-resistant prostate cancer who have received prior docetaxel-containing chemotherapy. with oral prednisone at 5 mg twice daily.

common electrolyte imbalances were hypokalemia (28%) and hypophosphatemia (24%). Following interruption of daily corticosteroids or with concurrent infection or stress, adrenocortical insufficiency (< 1%) has been reported in clinical trials in patients receiving abiraterone at the recommended dose in combination with prednisone.

Of Note Abiraterone treatment should be discontinued permanently for severe hepatotoxicity.

Cost The cost of abiraterone treatment is estimated at $5,000 per month, or

$40,000 for a median treatment course of 8 months.

■

Suggested Readings De Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011. US Food and Drug Administration: What’s New from the Office of Hematology Oncology Products. Abiraterone acetate. Available at http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm253139. htm. Accessed November 9, 2011. Yang LP: Abiraterone acetate: In metastatic castration-resistant prostate cancer. Drugs 2011;71:2067-2077. ZYTIGATM (abiraterone acetate) tablets prescribing information. Centocor Ortho Biotech Inc, April 2011. Available at http:// www.zytiga.com/pdf/prescribing_information.pdf. Accessed November 9, 2011.

Safety Profile In the trial supporting abiraterone approval, the most common adverse events in abiraterone patients (> 5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. The most common adverse events resulting in drug discontinuation were increased AST or ALT, urosepsis, and cardiac failure, each of which occurred in less than 1% of patients. The most

Fig. 1: Abiraterone mechanism of action. Abiraterone inhibits CYP17, an enzyme that catalyzes the conversion of pregnenolone and progesterone to 17-α-hydroxy derivatives, as well as the formation of the androgens DHEA and androstenedione, which are precursors of testosterone. Suppression of androgen levels results in tumor regression in androgen-sensitive prostate cancer. AR = androgen receptor; DHEA = dehydroepiandrosterone; ER = estrogen receptor. Artwork by Alexandra and David Baker © 2012 DNA Illustrations, Inc.

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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FDA Update

FDA Approves Imatinib for Expanded Use in GIST

he FDA has granted imatinib mesylate (Gleevec) regular approval for use in adult patients following surgical removal of CD117-positive gastrointestinal stromal tumors (GIST). The new approval also highlights an increase

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.

2008, imatinib received a subsequent accelerated approval for adjuvant use that is for the treatment of patients with GIST who had had potentially curative resection of GIST tumors, but who were at increased risk for a recurrence. Regular

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

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

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

approval for the metastatic GIST indication was also granted in 2008. “The development of [imatinib] over the past decade highlights the need to further study drugs after approval to truly characterize their benefits,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Although originally approved in the metastatic disease setting, this subsequent trial has demonstrated that longer use of [imatinib] can prolong patient’s lives in earlier disease settings.” The label is being updated to include clinical data from a large randomized clinical study comparing 12 to 36 months of imatinib. Treatment with imatinib for 36 months significantly prolonged overall survival and the time a patient lived without the disease recurring, compared to those receiving 12 months of imatinib. At 60 months, 92% of patients who received 36 months of imatinib were alive compared to 82% of patients who received 12 months of imatinib. For more FDA Update, see pages 2 and 22–27.

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2012 FDA Approvals ■■ Imatinib mesylate tablets (Gleevec) for the adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive gastrointestinal stromal tumors (GIST). ■■ Vismodegib (Erivedge) for the treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. ■■ Axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. ■■ Glucarpidase injection (Voraxaze) for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function. For more information, visit www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm279174.htm 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

in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment. Imatinib was originally granted accelerated approval for the treatment of advanced or metastatic GIST in 2002. In Safety:7"

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Expert’s Corner

Surgical Oncology: Advances and Challenges in Breast Cancer Surgery A Conversation with Monica Morrow, MD, FACS By Ronald Piana gin. The breast is fatty tissue that gets smashed flat when it gets to the pathologist, so some margins are made smaller by that flattening process, and some may actually increase. There are many variables, and there is no definition of a single surgical margin width that is appropriate for all women with breast cancer once you get past “no tumor” on the ink.

Role of Sentinel Node Biopsy Monica Morrow, MD, FACS

ortality rates for breast cancer have declined steadily in the United States since 1990, resulting in an improvement in survival. Multiple factors have contributed to this positive trend, one of which is the combination of earlier detection and more sophisticated surgical techniques. The ASCO Post recently spoke with internationally regarded breast cancer surgeon Monica Morrow, MD, FACS, Chief, Breast Service Department of Surgery, Memorial Sloan-Kettering Cancer Center, about the current state of breast cancer surgery.

Surgical Margins and Outcome Please shed light on the current clinical thinking about how margins in breast cancer surgery affect outcomes. We know that a positive surgical margin—defined as cancer cells touching the ink—increases the risk of local recurrence in the breast. Beyond that, it has never been demonstrated that more widely clear margins reduce the risk of local recurrence in the breast. Although many oncologists and pathologists believe wider margins decrease risk of recurrence, there are no definitive data to prove that theory. The margin debate was more important 20 years ago, when surgery was the primary method for local control. What we have learned in the past couple of decades is that the availability of effective systemic therapies dramatically reduces risk of local recurrence in the preserved breast. And to believe that one can precisely measure the difference between 1 and 2 mm in a margin is somewhat laughable. There is no standardization of pathology protocols across the United States in terms of how many sections are taken to look at the mar-

Moving to another clinical debate, do we have clear evidence in how sentinel node biopsy influences the decision for axillary dissection? For more than 100 years, axillary dissection was the only reliable method we had to determine if there was breast cancer involvement in the axillary lymph nodes. It has become apparent that a sentinel node biopsy that is negative reliably predicts that there are no cancer cells

not even the deciding factor for systemic therapy or for selecting the type of systemic therapy. The question then becomes: Does doing an axillary dissection contribute to survival, and is it necessary for local control? Do we have any data to address that question? That was the question that the American College of Surgeons Oncology Group (ACOSOG) Z11 study sought to answer. ACOSOG Z11 was a prospective randomized trial of axillary dissection vs no further axillary surgery in women undergoing lumpectomy and whole-breast radiation who were found to have three or fewer positive sentinel nodes. After a median follow-up of 6.3 years, Z11 showed was that there was no survival difference between the two study arms. The risk of cancer recur-

Whether one chooses to eliminate axillary dissection for all women meeting the Z11 eligibility criteria or to be more conservative and limit this to postmenopausal women with ER-positive breast cancer, I think it is clear that frozen section and routine axillary dissection for all women undergoing breastconserving therapy should be a thing of the past. —Monica Morrow, MD, FACS

in the rest of the axillary lymph nodes and, consequently, axillary dissection is not indicated. At this point, it is clinical standard of care that a negative sentinel lymph node biopsy indicates an axillary dissection is not needed. A clinical decision after a positive sentinel node on biopsy is not as evident. Can you clarify that debate? The big debate centers on the following question: Does a positive sentinel lymph node biopsy indicate the need to do an axillary dissection for every patient? This issue became a controversy because in about 70% of women, the sentinel node is the only node in the axilla with cancer. We no longer use the number of involved lymph nodes to choose systemic therapy; it is enough to know that a node is involved, and in many cases that’s

ring in the lymph nodes if you did not perform axillary dissection was 0.9%, compared with 0.4% in women who had the surgery. The trial showed no significant difference in total locoregional recurrence, and there was a lot more morbidity in the axillary dissection arm. So Z11 clearly tells us that not all women with positive lymph nodes need axillary dissection. On the other hand, some of these women do require axillary dissection, and they are those not included in the trial such as those who had mastectomy, preoperative chemotherapy, more advanced breast cancer, or grossly abnormal positive lymph nodes, and women who were not getting whole-breast irradiation. The Z11 results should not be extrapolated to these groups, and these women continue to require ax-

illary dissection for positive sentinel nodes. Did the results of Z11 have any effect on clinical practice? At Memorial Sloan-Kettering, we have adopted a policy for women who meet the eligibility criteria for the Z11 trial: We no longer perform axillary dissection in this group. We’ve been using that clinical policy for about a year now. It is considered fairly radical, and some in the community have expressed concerns that because most of the women in the Z11 trial were estrogen receptor (ER)-positive, the results only apply to that group of women and maybe also don’t apply to younger women. However, ER positivity and age are not predictors of the risk of recurrence in lymph nodes, so we don’t think that that is a particularly relevant argument. And most patients with breast cancer are ER-positive and most tend to be older women. That said, we are prospectively keeping track of the outcomes of our patients, and after we have a longer followup we will report the findings. Whether one chooses to eliminate axillary dissection for all women meeting the Z11 eligibility criteria or to be more conservative and limit this to postmenopausal women with ER-positive breast cancer, I think it is clear that frozen section and routine axillary dissection for all women undergoing breast-conserving therapy should be a thing of the past.

Patient Selection for Mastectomy Do we have a precise definition of women who would best be treated with mastectomy or lumpectomy? There are criteria to determine which women need mastectomy. If women have multicentric breast cancer, if we cannot get a negative margin around the cancer with a satisfactory cosmetic outcome, or if the mammographic picture is confusing, presenting with such widespread abnormal microcalcifications that we can’t reliably exclude the presence of cancer, then mastectomy is indicated. The other reason for mastectomy is if we can’t safely deliver radiotherapy, for instance, if the patient has already had irradiation that involved the breast as part of prior cancer treatment. The recontinued on page 42

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Expert’s Corner

Monica Morrow, MD, FACS continued from page 41

maining women are eligible for breastconserving surgery. Thirty years ago, women were the primary drivers of the movement to scientifically study breast-conserving surgery, contending that mastectomy was a mutilating procedure and demanding other options. Interestingly, today it’s women themselves who often elect to have a mastectomy even though they are eligible for lumpectomy, and even in the face of evidence showing that survival after lumpectomy has never been better. Further, the risk of local recurrence has declined significantly since the initial randomized trials. Many choose mastectomy not only in the affected breast, but also in the healthy breast. And this phenomenon is more frequent among younger women.

Breast cancer surgery has become a model for evidence-based cancer therapy, and that can be attributed largely to the work of the NSABP under the leadership of Dr. Bernard Fisher, and also the work of Milan’s Dr. Umberto Veronesi, who led prospective randomized trials that answered probing questions about this disease. —Monica Morrow, MD, FACS

Major Advances What have been the major advances in breast cancer surgery to occur during your career? Breast cancer management has undergone dramatic change since I began my career. When I was a medical student and junior resident, we were still

arguing about whether it was safe to get rid of the radical mastectomy. We did not have effective endocrine therapy, so we performed surgery for endocrine ablation—removing the ovaries and adrenal and pituitary glands—which certainly had unpleasant side effects. Since then, we have progressed to

an era in which breast cancer surgery is an outpatient procedure. Lumpectomy and sentinel node biopsy is an hourlong operation. Women can be back to their regular activities in a few days. JOB#: 10901B PROOF#: 1 advances Coupled with the enormous CLIENT: GENETECH in drug therapy, breastDESC: cancer Journal Adsurvival Color: 4c has markedly improved. The morbidAD: JD ity of treatment has decreased signifiTRAFFIC: EM OPERATOR: zv cantly, and so has the death rate. GALLEY#: 1 DATE:has 8/15/11become - 7:20 PM Breast cancer surgery a CREATED: 8/10/11 - 4:43 PM model for evidence-based theraFONTS: cancer Trade Gothic LT Std Regular, Trade Gothic LT Std Light, Trade py, and that can be attributed largely to Gothic LT Std Bold, Trade Gothic LT Std Light Oblique, Trade Gothic LT the work of the National Surgical AdjuStd Bold No. 2 vant Breast and Bowel Project (NSABP) IMAGES: BioOnc_WM_R_4C_ KO.ai, 10901B under the leadership Genentech_AMOTRG_KO.eps, of Dr.QRcode.eps, Bernard Fisher, and also the work of Milan’s Dr. 10901_B_JA_Antibodies_fn.tif COLORS: C=52 M=100 Y=0 Umberto Veronesi, who led prospective K=26, C=42 M=19 Y=100 K=1 NOTES: randomized trials that answered probing DOC PATH: Macintosh questions about this disease. HD:Users:vazz:Desktop:GNH_TDM_

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Q10901B_JA_D01.indd Disclosure: Dr. Morrow reported no DOC SIZE: 13” X 17” potential conflicts of interest. PRINT SCALE: 100%

Cosmos Communications 718.482.1800 1 Q1 LS 08.15.11 133 M8

ther sentinel lymph node biopsy or axillary lymph node dissection. Patients were considered cautionary if they met any of the following criteria: age 50–59 years; tumor size 2.1–3 cm; T0 or T2 stage; ER negative; invasive lobular histology; pure [ductal carcinoma in situ (DCIS)] ≤ 3 cm; or EIC ≤ 3 cm. Patients were considered unsuitable for APBI if any of the following crite-

tient and clinical factors. Women living farther from metropolitan areas and radiation facilities were less likely to get APBIb, even though the decreased overall treatment time for APBIb, 1 to 2 weeks vs 5 to 6 weeks for WBI, could potentially provide greater convenience and decreased travel time for the rural women. “The wide geographic disparity in use of APBIb suggests that unwar-

Surgical and radiation oncologists will hopefully continue to be mindful during discussions with patients to inform them about the quality of the published data thus far available concerning patient outcomes following treatment with APBI. ria were present: age < 50 years; tumor size > 3 cm; T3 or T4 stage; multicentric disease; pure DCIS > 3 cm; EIC > 3 cm; pN1, N2, or N3; or no nodal surgery performed.” The investigators found a wide range of utilization patterns, including substantial racial and ethnic disparities. “[Nonwhite] patients were half as likely to receive APBIb compared with white patients regardless of appropriateness for this technique and regardless of whether they had DCIS or invasive breast cancer,” the researchers reported. Specific geographic regions had higher APBIb use despite other pa-

ranted variation—practice variation not explained by illness, patient preference, or evidence-based medicine—may be present, which can have a profound impact on health care costs and patient outcomes,” the authors concluded.

Cautionary Note An accompanying editorial noted that this study and two others concerning increased use of APBIb “raise an alarm that the care delivered to patients with early-stage breast cancer has evolved prematurely in relation to the results of large randomized trials examining the equivalency of APBI to WBI.2

As published guidelines, financial reimbursement, and information in the popular press regarding APBI change over time, it may become increasingly difficult to determine the exact motivation driving the disparate practices occurring nationally. Surgical and radiation oncologists will hopefully continue to be mindful during discussions with patients to inform them about the quality of the published data thus far available concerning patient outcomes following treatment with APBI. Although population-based studies allow us to reflect on changes in patterns of practice, we are still left eagerly awaiting the results of large randomized trials that compare patient outcomes with WBI vs APBI.” Q2

As explained by the investigators from Dana-Farber Cancer Institute/ Brigham and Women’s Hospital and Harvard Medical School in Boston, “Patients were considered suitable if they met all of the following criteria: age 60 years and older; tumor 2 cm in diameter or less; T1 stage; [estrogen receptor (ER)] positive; unicentric tumor; invasive ductal, tubular, or mucinous histology; no pure DCIS; no [extensive intraductal component (EIC)]; pN0; and nodal surgery of ei-

Category Definitions

ccelerated partial breast irradiation using brachytherapy (APBIb) as an alternative to wholebreast irradiation (WBI) after breastconserving surgery has been rapidly adopted in the United States, but the majority of patients receiving APBIb may not be considered suitable for it. A retrospective analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database identified 138,815 patients who had received either APBIb or WBI between 2000 and 2007.1 The 3,576 women (2.6%) who had received APBIb were classified according to guidelines developed by the American Society for Radiation Oncology (ASTRO) in 2009. According to those guidelines, 32% would have been considered suitable for APBIb, 36.2% unsuitable, and 29.6% in the cautionary group.

By Charlotte Bath

20090a

Partial Breast Irradiation with Brachytherapy in Early Breast Cancer: Retrospective Analysis Looks at Trends and Guidelines

Breast Cancer

■

References 1. Hattangadi JA, et al: Accelerated partial breast irradiation using brachytherapy for breast cancer: Patterns in utilization and guideline concordance. J Natl Cancer Inst 104:29-41, 2012. 2. Shaitelman S: Sounding a warning bell? Documentation of the increased utilization of accelerated partial breast irradiation. J Natl Cancer Inst 104:5-7, 2012.

Partial Breast Brachytherapy For more on partial breast brachytherapy, see page 6 of this issue of The ASCO Post.

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6 They may provide higher tumor selectivity, enhancing the cell-killing potential of monoclonal antibodies and improving tolerability.2,7,10

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852. 10. Ducry L, Stump B. Antibody窶電rug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.

The ASCO Post | FEBRUARY 15, 2012

PAGE 44

Hematology for the Oncologist

JAK2 and MPL Mutation Screening: What Are the Indications and How to Interpret the Results By Ayalew Tefferi, MD

he World Health Organization system organizes myeloid malignancies into five major categories, which are subsequently further sub-

classified using a combination of bone marrow morphology and cytogenetic/ molecular information (Table 1).1 JAK2 and MPL mutations are not

disease-specific and occur across the spectrum of myeloid malignancies, including BCR/ABL1-negative myeloproliferative neoplasms (MPN),

Table 1: World Health Organization Classification of Myeloid Malignancies 1. Acute myeloid leukemia (AML) and related precursor neoplasmsa

4.1. Chronic myelomonocytic leukemia (CMML)

4.2. Atypical chronic myeloid leukemia, BCR/ABL1-negative

Indications for Screening

4.3. Juvenile myelomonocytic leukemia (JMML)

4.4. MDS/MPN, unclassifiable

Table 2 on page 46 outlines the indications for JAK2 or MPL mutation screening in routine clinical practice. Because JAK2V617F is present in the majority of patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis, it is reasonable to consider its screening during the evaluation of erythrocytosis, thrombocytosis, bone marrow fibrosis, or other symptoms that are characteristic of these diseases (eg, splanchnic vein thrombosis, aquagenic pruritus, and otherwise unexplained spleno-

2.1. Classic MPN

2.1.1. Chronic myelogenous leukemia, BCR/ABL1-positive (CML)

2.1.2. Polycythemia vera (PV)

2.1.3. Primary myelofibrosis (PMF)

2.1.4. Essential thrombocythemia (ET)

2.2. Nonclassic MPN

2.2.1. Chronic neutrophilic leukemia (CNL)

2.2.2. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)

2.2.3. Mastocytosis

2.2.4. Myeloproliferative neoplasm, unclassifiable (MPN-U)

3. Myelodysplastic syndromes (MDS)

3.1. Refractory cytopeniab with unilineage dysplasia (RCUD)

3.1.1. Refractory anemia (ring sideroblasts < 15% of erythroid precursors)

3.1.2. Refractory neutropenia

3.1.3. Refractory thrombocytopenia 3.2. Refractory anemia with ring sideroblasts (RARS; dysplasia limited to erythroid lineage and ring sidero-blasts ³ 15% of bone marrow erythroid precursors) 3.3. Refractory cytopenia with multilineage dysplasia (RCMD; ring sideroblast count does not matter)

3.4. Refractory anemia with excess blasts (RAEB) 3.4.1. RAEB-1 (2%–4% circulating or 5%–9% marrow blasts) 3.4.2. RAEB-2 (5%–19% circulating or 10%–19% marrow blasts or Auer rods present)

3.5. MDS associated with isolated del(5q)

3.6. MDS, unclassifiable

4. MDS/MPN

4.4.1. Provisional entity: Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) 5. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA,c PDGFRB,c or FGFR1

5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement

5.2. Myeloid neoplasms with PDGFRB rearrangement

5.3. Myeloid and lymphoid neoplasms with FGFR1 abnormalities

Acute myeloid leukemia-related precursor neoplasms include “therapy-related myelodysplastic syndrome” and “myeloid sarcoma”. Either mono- or bicytopenia: hemoglobin level < 10 g/dL, absolute neutrophil count < 1.8 × 109/L, or platelet count < 100 × 109/L. However, higher blood counts do not exclude the diagnosis in the presence of unequivocal histological/cytogenetic evidence for myelodysplastic syndrome. c Genetic rearrangements involving platelet-derived growth factor receptor a/b (PDGFRA/PDGFRB) or fibroblast growth factor receptor 1 (FGFR1). b

JAK2 Mutations JAK2V617F is the most frequent mutation in BCR/ABL1-negative MPN and is present in > 95% of patients with polycythemia vera or post– polycythemia vera myelofibrosis and 60% of those with essential thrombocythemia, post–essential thrombocythemia myelofibrosis, or primary myelofibrosis. JAK2V617F is also found in approximately 50% of patients with a specific MDS/MPN entity referred to as “refractory anemia with ring sideroblasts and thrombocytosis (RARS-T),” but mutational frequency is less than 5% in acute myeloid leukemia, MDS, or other myeloid malignancies including chronic myelomonocytic leukemia. JAK2 mutations other than JAK2V617F (eg, JAK2 exon 12 mutations) occur in approximately 50% of patients with JAK2V617F-negative polycythemia vera. In almost all instances, polycythemia vera cases with JAK2 exon 12 mutations display subnormal serum erythropoietin levels. MPL mutational frequencies are estimated at 8% in primary myelofibrosis and 4% in essential thrombocythemia, but they also infrequently occur in acute megakaryoblastic leukemia, RARS-T, and MDS with del(5q). Neither JAK2 nor MPL mutations are found in healthy people or those with secondary polycythemia, reactive thrombocytosis, lymphoid malignancies, or solid tumors.

2. Myeloproliferative neoplasms (MPN)

myelodysplastic syndromes (MDS), MDS/MPN overlap, and acute myeloid leukemia. These mutations are usually, but not always, absent in chronic myeloid leukemia.

ASCOPost.com | FEBRUARY 15, 2012

PAGE 45

Hematology for the Oncologist

megaly or leukocytosis). It is important to note that one does not require an abnormal blood count to consider JAK2V617F mutation screening in patients with splanchnic vein thrombosis. Results are the same regardless of whether JAK2V617F screening was performed using peripheral blood or bone marrow. JAK2 exon 12 and other exon mutations occur mostly in patients with JAK2V617F-negative polycythemia vera, and they are almost always associated with subnormal serum erythropoietin level. Therefore, their screening is warranted only when one suspects JAK2V617F-negative polycythemia vera and the serum erythropoietin level is subnormal. In other words, screening for JAK2 exon 12 mutations before screening for JAK2V617F or in the presence of normal or increased serum erythropoietin level is discouraged. The incidences of MPL mutations in MPN are too low to warrant their use in routine clinical practice. The reason I recommend JAK2 exon 12 mutation screening in special circumstances (see above) whereas I do not recommend MPL mutation screening in routine clinical practice is that the two techniques have a different impact on management: Detecting mutant MPL has no additional diagnostic value since morphology is adequate in diagnosing primary myelofibrosis or essential thrombocythemia, whereas the diagnosis of JAK2V617F-negative

polycythemia vera is therapeutically important.

Further Recommendations I prefer using cell-based quantitative assays for JAK2V617F mutation screening for a number of reasons: (1) diagnostic certainty is enhanced in

the presence of > 1% mutant allele burden and anything less than < 0.1% mutant allele burden should be considered negative until proven otherwise, (2) a ≥ 50% JAK2V617F allele burden suggests polycythemia vera or prefibrotic myelofibrosis as opposed to essential thrombocythemia, and (3) quantita-

ematology for the Oncologist is guest edited by Ayalew Tefferi, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. The series is intended to provide guidance in managing hematologic issues that may present in your patients with cancer.

2011 American Society of Hematology Annual Meeting San Diego, CA

2011 San Antonio Breast Cancer Symposium San Antonio, TX

In this supplement to The ASCO Post, you will find reports on a variety of subjects important to practicing clinicians, including: • HER2-positive Breast Cancer • Metastatic Breast Cancer • Tumor Molecular Profiling • Bisphosphonates in Early Breast Cancer

• Treatment and management of hematologic disease, including: – Lymphoma – Leukemia – Multiple Myeloma

Look for your copy packaged with this issue of The ASCO Post or read it online at ASCOPost.com Ayalew Tefferi, MD

continued on page 46

Read the Most Comprehensive Meeting Coverage in Oncology

Hematology for the Oncologist

tive measurements are more suitable for monitoring response to treatment known to affect mutant allele burden (eg, interferon-α) or assessing minimal residual disease after allogeneic stem cell transplantation. Neither the presence nor the burden of JAK2 or MPL

The ASCO Post | FEBRUARY 15, 2012

PAGE 46

Hematology for the Oncologist

JAK2 and MPL Mutation Screening continued from page 45

mutation is prognostically useful, and mutation screening should not be performed for this purpose. A positive result for either JAK2 or MPL mutation confirms the presence of a myeloproliferative neoplasm but does not distinguish one type from another. A JAK2 mutation accompanied by elevated hemoglobin is usually adequate for the diagnosis of polycythemia vera and one does not necessarily require a bone marrow examination or red cell mass measurement in addition. The absence of a JAK2 mutation and normal or elevated serum erythropoietin level makes the diagnosis of polycythemia vera very unlikely. The absence of JAK2 or MPL mutation does not exclude either essential thrombocythemia or primary myelofibrosis. Therefore, one needs to consult with an expert hematopathologist to establish an accurate diagnosis of essential thrombocythemia or pri-

Table 2: Indications to Test for JAK2 or MPL Mutations Screening Appropriate

Screening Inappropriate

JAK2V617F

■■ Erythrocytosis ■■ Thrombocytosis ■■ Bone marrow fibrosis ■■ BCR/ABL1-negative granulocytosis ■■ Unexplained monocytosis ■■ Unexplained splenomegaly ■■ Aquagenic pruritus ■■ Splanchnic vein thrombosis

■■ Disease prognostication ■■ Nonsplanchnic thrombosis

JAK2 exon 12 mutation

■■ JAK2V617F-negative erythrocytosis with low

■■ Before JAK2V617F screening ■■ In the presence of JAK2V617F ■■ In the presence of normal serum

serum erythropoietin

■■ High clinical suspicion for polycythemia vera despite absence of JAK2V617F

erythropoietin

■■ In the presence of increased serum erythropoietin

■■ For diagnosis of essential thrombocythemia or primary myelofibrosis

MPL mutation

■■ Research setting

mary myelofibrosis (including prefibrotic myelofibrosis) regardless of the results of the JAK2/MPL mutation screening.

■

■■ Routine clinical practice Disclosure: Dr. Tefferi reported no potential conflicts of interest.

Reference 1. Vardiman JW, Thiele J, Arber DA, et al:

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 114:937-951, 2009.

CancerConnect Offers Online Alternative Networking for Patients

Social Media

By Caroline Helwick

ocial networking sites like Facebook and Twitter are rapidly growing, giving patients with cancer a place to connect with others. But an alternative networking website claims to be a more comprehensive, responsible, “commercial-free” alternative. Over 10,000 patients with cancer have registered at CancerConnect (www.CancerConnect.com), which was launched in 2010 to enrich the patient’s experience. At a single online destination, patients with cancer can find over 50 disease-specific communities as well as groups focused on caregiving, health and wellness, stem cell transplant, chemotherapy, and nutrition. They can learn about clinical trials, shop the “store,” and tap into other resources relevant to cancer survivorship. The website promises patients with cancer a place to “learn about cancer, share information, and find inspiration, hope, and support.”

Scope Is Both Local and Universal CancerConnect is a “local strategy with a national tie-in,” explained Charles H. Weaver, MD, an oncologist who is CEO of OmniHealth, the

CancerConnect is a HIPAAcompliant, safe, and secure nonadvertising environment… This is primarily patients supporting patients. —Charles H. Weaver, MD

multimedia corporation that developed the site. CancerConnect is licensed to hospitals and cancer clinics to enhance their websites and provide local information and resources. “But once patients step into the ‘disease communities,’ they are sharing on a national level,” he said. A Georgia resident with a rare cancer can connect with a person sharing that experience in Seattle. Its private label aspect has made CancerConnect the largest and fastest growing social media platform dedicated to serving patients and their providers, according to Dr. Weaver. OmniHealth Media now manages the CancerConnect platform for Vanderbilt University Hospital,

Memorial Sloan-Kettering Cancer Center, Roswell Park Cancer Institute, the Dana-Farber Cancer Center, the Seattle Cancer Care Alliance, and others. According to Dr. Weaver, the 10,000 registered users visit the site for “information, validation, and support.

Follow The ASCO Post on Twitter

This is primarily patients supporting patients,” he said.

Reputable Online Environment While there are other online destinations where patients with cancer might seek these things, CancerConnect is a “HIPAA-compliant, safe, and secure nonadvertising environment. We don’t share your profile, and we don’t allow target marketing,” he noted. “We also moderate all our communities,” Dr. Weaver added. “If a user posts information that is not supported by data, we call them out. We have strict rules of engagement that make the platform more credible.”

■

Disclosure: Dr. Weaver is the CEO of OmniHealth Media and editor of CancerConnect.

twitter.com/ascopost

The Latest Addition to an Established Line of Indications for SCCHN

AP N PR OW OV ED

erbitux: now approved new indication

for the First-Line Treatment of Recurrent Locoregional or Metastatic SCCHN in Combination With Platinum-Based Therapy With 5-FU ERBITUX Indications

new

■ ERBITUX® (cetuximab) is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck ■ ERBITUX, in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration SCCHN=squamous cell carcinoma of the head and neck.

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Scan QR code for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Important Safety Information Including Boxed WARNINGS Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients — Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. In the squamous cell carcinoma of the head and neck study in combination with platinumbased therapy with 5-FU, there was an increased incidence of hypomagnesemia in subjects who received

Important Safety Information Including Boxed WARNINGS Important (continued)Safety Information Including Boxed WARNINGS (continued)

concomitant EU-approved cetuximab and cisplatin therapy with 5-FU compared to cisplatin with 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX (cetuximab) therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean halflife of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) vs CT alone (n=215) (incidence ≥40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) vs CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US11AB07106

11/11

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4), in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer: Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Pharmacology (12.1), Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 4, and 5 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 4, and 5. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 4 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

Erbitux1111PBSwip3.indd 1

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1,3,4, and 5, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 4) or Phase 2 (Studies 3 and 5) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck: Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high 38 1 24 1 Aspartate Transaminase, highc c 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse events in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

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Table 2:

Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU Alone 5-FU (n=215) (n=219) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations b 44 11 27 8 Infection Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders c 70 9 2 0 Acneiform Rash Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer: Erbitux Monotherapy — Table 3 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 4. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 3:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinomaa Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Grades Any Grades Body System Any b 3 and 4 Grades 3 and 4 Preferred Term Grades % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 20 5 Infusion Reactionsc Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1 a Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. b Adverse events were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion-related. BSC = best supportive care Erbitux in Combination with Irinotecan — The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/ malaise (16%), and acneiform rash (14%).

Erbitux1111PBSwip3.indd 2

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux (cetuximab) has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. Geriatric Use: Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

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Oncologists Examine Promise vs Reality of Personalized Medicine By Caroline Helwick

ersonalized medicine: It’s a phrase that reverberates across all cancer meetings. “Matching the right drug to the right patient” will be accomplished, in the not too distant future, through genomic sequencing of the tumor and targeted, less toxic therapy. This much has been established—or has it? The journey has begun, but there are roadblocks that could stall progress, said Gordon Mills, MD, of the Zayed Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center, Houston. Dr. Mills was asked to present the challenges to implementation of personalized medicine in a discussion at the 2011 European Multidisciplinary Cancer Congress.1 “We are coming closer to having a scientific underpinning for what we want to do but integrating this remains a challenge,” he said. “Can we achieve personalized therapy? Is it even doable?” For the discussion, Dr. Mills was joined by José Baselga, MD, PhD, Associate Director of the Massachusetts General Hospital Cancer Center, Boston, who provided a more optimistic perspective on personalized medicine.2

José Baselga, MD, PhD

‘A Watershed Moment’ “There is a sea change in the treatment of patients with cancer. This is a watershed moment in cancer history,” Dr. Baselga began. Understanding the genetics of each tumor will change how researchers test new drugs and clinicians use them. The challenge is to establish the technology to support the necessary clinical research. Comprehensive genetic characterization of tumors will encompass DNA epigenetics, mutations, and chromosomal alterations; proteomics; and messenger RNA and micro-RNA profiling. It is important, he said, to genotype in real time for known and clinically significant mutations that

can be targeted, and then—after testing for drug sensitivity—to monitor serially during treatment (with circulating tumor cells, functional imaging). “We cannot continue to start chemotherapy and wait 2 months for the CT scan to tell us if the patient is responding,” he said.

Need to Study Drugs Earlier, in Smaller Trials To have a major impact, technologic advances and novel treatments must be applied in early disease, and clinical trials condensed. “Smaller, smarter clinical trials will provide answers,” Dr. Baselga predicted. “We can’t afford to do clinical trials with thousands of patients now.” For example, an analysis of the Neo-ALTTO study presented at the meeting3 showed that FDG-PET/ CT metabolic responders, vs nonresponders, were twice as likely to achieve a pathologic complete response after neoadjuvant dual HER2 blockade. If clinical outcomes prove similar between the 450-patient NeoALTTO trial and the 8,000-patient ALTTO adjuvant trial, “we can propose that neoadjuvant studies might answer our [efficacy] questions,” he said. Success in personalized medicine will also require effective combinations to address the compensatory pathways that form the escape routes for tumors. The recognition of crosstalk between mTOR and the estrogen receptor led to the discovery that everolimus (Afinitor) given with an aromatase inhibitor can reverse the resistance to hormonal therapies (as in the BOLERO-2 study). “Studies of resistance will be key,” he said. Dr. Baselga concluded that in addition to sophisticated technology platforms, novel trial design, and tolerable drugs that will hit the mark, bringing personalized medicine forward will also require recruiting “the best pool of physician scientists into a culture of teamwork.”

An ‘N of One’ Problem Dr. Mills added a sobering note. While personalized medicine is “clearly in our future,” he questioned whether “we are overpromising our patients.” “The biggest problem is the ‘N of one,’” he said, pointing out that small, homogeneous patient groups unified

Personalized Medicine Reconsidered ■■ Although the concept of personalized medicine is now widely accepted and vaunted, its implementation remains challenging in most cancer settings.

■■ One of the biggest problems is the fact that some disease subgroups are so small it may be impossible to implement clinical trials with sufficient power.

■■ Other problems include the need for multiple biopsies and the

difficulty of distinguishing mutations that are targetable drivers from those that are passengers.

by discreet tumor genetic profiles will turn cancer into “an orphan disease.… Some subgroups will be so small it will be impossible to implement clinical trials with sufficient power,” Dr. Mills noted.

Gordon Mills, MD

While remarkable responses have been observed in individual patients whose tumors seem matched to the optimal drug, only subpopulations of patients benefit, resistance develops, and their responses are not durable. “We have to figure out how to make durable, combinatorial therapy to improve outcomes,” he said.

Increasing Recognition of Tumor Complexity As the uniqueness of individual tumors becomes clear, concerns are growing that even combinations of the right drugs will fall short due to intratumoral heterogeneity. Studies have found up to 40% discordance between the primary and recurrent lesions, and discordant cases have significantly worse outcomes. Personalized medicine will require multiple biopsies. As Dr. Baselga noted, the goal is to replace biopsies with molecular imaging and characterization of circulating tumor cells or DNA, but this “remains a dream,” Dr. Mills maintained. Further, science must be able to distinguish mutations that are drivers, and therefore targetable, from

those that are mere passengers. Tumors will need to be sequenced in depth to capture important subclones, he said. “We are finding hundreds if not thousands of mutations. How will we integrate this information to find drivers that can be targeted for each patient? Not all mutations are created equal. And for the actionable aberrations, we have a limited number of drugs,” he pointed out. Cost will certainly be an issue. While the price of sequencing is dropping, the cost of handling the sequencing is not. “The cost of $10,000 for a human genome does not include the costs of bioinformatics analysis of data storage and handling. Indeed, it has been estimated that even the eventual $1,000 genome will cost $100,000 to manage and interpret,” he said, and the cost will rise in parallel with the depth of sequencing demanded. Fewer than 5% of companies now reimburse for genomic testing. There are also ethical, regulatory, laboratory, and educational issues.

MD Anderson Program Forging ahead, The University of Texas MD Anderson Cancer Center has begun a research program to deliver on the promise. “We are finding actionable mutations and doing ‘N of one’ clinical trials in an efficient manner to determine which populations could benefit from a particular drug,” Dr. Mills reported. “We are seeing very exciting results,” he said. For example, they have found high response rates among patients with PI3K mutations treated with PI3K-targeted therapies, especially those with endometrial or ovarian cancer, although the responses are not long-term.

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Perspective

Altogether, however, the initial results in the first 1,000 patients have, in general, been “surprising and disappointing,” he noted. Only about 40% have had aberrations, and only 25% had actionable mutations. Dr. Mills assumes that patients who are cured of their cancer tend to have low-grade tumors that are “chock full” of actionable targets— they respond to standard treatments. Clinical trials, on the other hand, are more likely filled with patients who have high-grade tumors with p53 mutations “that we don’t know what to do with,” driven by genomic instability, he suggested. “Thus, while there is incredible excitement about the potential implementation of personalized cancer therapy, it is easy to contend that the spectacular press and excitement is massively overblown,” Dr. Mill maintained. “The number of successes—and in most cases, these are found only in small subpopulations of patients and are transient— are far outnumbered by spectacular

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com. Treating pNET 22

Biosimilars in cancer treatment 37

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I thought he had Hodgkin disease, so I arranged a lymph node biopsy. I remember looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematologic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that others could not. To my surprise, he said this pathology was something he’d never seen before.

A small piece of information or a major breakthrough in one scientific discipline can translate valuable information into another scientific area.

—Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

continued on page 20

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failures.” “There are still many patients who will benefit, but in terms of delivering ‘personalized medicine’ to all patients,” Dr. Mills concluded, “we are way below the desired numbers.”

■

Disclosure: Drs. Mills and Baselga reported no potential conflicts of interest.

References 1. Mills GB: Challenges to impelementation of personalised cancer therapy. 2011 European Multidisciplinary Cancer Congress. Abstract 3. Presented September 24, 2011. 2. Baselga J: Personalised medicine: Are we hunting the Holy Grail? Personalised medicine is the future. 2011 European Multidisciplinary Cancer Congress.

Abstract 2. Presented September 24, 2011. 3. Gamez C, Flamen P, Holmes E, et al: FDG-PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer patients: the Neo-ALTTO study results. 2011 European Multidisciplinary Cancer Congress. Abstract 5013. Presented September 24, 2011.

The ASCO Post | FEBRUARY 15, 2012

PAGE 54

Calendar

2012 Oncology Meetings FEBRUARY 12th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting February 22-25 • Santa Monica, California For more information: http://iaslc.org 16th Annual International Congress on

ACCC 38th Annual National Meeting March 12–14 • Baltimore, Maryland For more information: http://accc-cancer.org EPI2K12 March 12-14 • Sydney, Australia For more information: http://epi2K12.org

Hematologic Malignancies February 23-26 • Snowbird, Utah For more information: cancerlearning.onclive.com Fifth Annual Symposium on

February 25 • Orlando, Florida For more information: www.bmli.com International Conference on Translational Research in Radio-Oncology and Physics for Health in Europe February 27-March 2 • Geneva, Switzerland For more information: http://ictr-phe12.web.cern.ch

MARCH ACR 5th Annual PET/CT Symposium March 1-4 • Stowe, Vermont For more information: www.acr.org

NCCN 17th Annual Conference March 14-18 • Hollywood, Florida For more information: www.nccn.org

3rd European Lung Cancer Conference April 18-21 • Geneva, Switzerland For more information: www.esmo.org

Hematology/Oncology Pharmacy Association 8th Annual Meeting March 21-24 • Orlando, Florida For more information: www.hoparx.org 65th Society of Surgical Oncology Annual Meeting March 21-24 • Orlando, Florida For more information: www.surgonc.org Society of Interventional Radiology 37th Annual Meeting March 24-29.San Francisco, California For more information: www.sirmeeting.org

4th ESMO Sarcoma and GIST Conference March 9-10 • Milan, Italy For more information: www.esmo.org Society for Thoracic Radiology Thoracic Imaging Meeting March 11-14 • Huntington Beach, California For more information: www.thoracicrad.org

American Radium Society Annual Meeting April 28-May 2 • Las Vegas, Nevada For more information: www. americanradiumsociety.org American Roentgen Ray Society Annual Meeting April 29-May 4 • Vancouver, Canada For more information: www.arrs.org

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

9th International Symposium on Ovarian Cancer and Other Gynecologic Malignancies March 30-31 • New York, New York For more information: http:// cancerlearning.onclive.com 5th Annual Interdisciplinary Prostate Cancer Congress March 31 • New York, New York For more information: http:// cancerlearning.onclive.com

JUNE ASCO Annual ’12 Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org

ASTRO Spring Refresher Course April 13-15 • Chicago, Illinois For more information: www.astro.org 35th National Conference on Breast Cancer April 13-15 • Hollywood, Florida For more information: www.acr.org

3rd Asian Breast Cancer Congress March 3-4 • Bangalore, India For more information: http://abcconline.net TAT 2012 (International Congress on Targeted AntiCancer Therapies) March 8-10 • Amsterdam, The Netherlands For more information: www.tatcongress.org

APRIL

29th Annual Miami Breast Cancer Conference March 14-17 • Miami, Florida For more information: cancerlearning.onclive.com

Personalized Therapies and Best Clinical Practices for Breast Cancer

AACR 103rd Annual Meeting March 31-April 4 • Chicago, Illinois For more information: www.aacr.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 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

ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org

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/panpacififlymphoma 13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 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

ASCOPost.com | FEBRUARY 15, 2012

PAGE 55

Calendar

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

SEPTEMBER Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

OCTOBER ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer 32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

Chemotherapy Foundation

17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com

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

RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com

DECEMBER 35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org

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

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org 9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com

Pan Pacific

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Lymphoma Conference

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July 17-20, 2012

ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

NOVEMBER 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

Hyatt Regency Maui Resort & Spa Lahaina, Maui, Hawaii

A comprehensive conference by internationally recognized speakers presenting the most recent developments in lymphoma and transplantation.

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PAGE 57

In the News

Depression Is Dangerous among Patients with Cancer, but Talking and Pharmacologic Treatments Can Be Effective By Charlotte Bath

“D

epression is a very dangerous problem in oncology settings,” stated Mary Jane Massie, MD, Attending Psychiatrist at Memorial Sloan-Kettering Cancer Center in New York. “We know that depressed people do less well in the oncology setting, probably in large part because they feel so bad, they don’t fill their prescriptions. They don’t think it is useful to take their medicines. They’re missing appointments. They’re less compliant.” Dr. Massie specializes in the psychological treatment of people with breast cancer and their families and also counsels women at high risk of breast cancer who are considering risk-reducing options. She told The ASCO Post, “we have come a long way in 30 years” in terms of being able to talk about depression. “We know how common anxiety and depressive disorders are,” she said, agreeing that about 25% of patients with cancer experience depression at some time. “We fortunately see—around the country and around the world—that there is so much more openness about mental health issues in general and acceptance of having trained mental health professionals to work with patients with cancer and other medical illnesses,” she said. That work can include talking treatments through individual counseling and emotional support groups or pharmacologic treatment with antidepressants.

Actual and Virtual Emotional Support Comprehensive cancer centers “are required to have emotional support services for patients,” Dr. Massie said, and Memorial Sloan-Kettering has many of them. “Given the numerous talented, well-trained, highly experienced people and the large volume of

patients we get, we can really tailor our groups,” Dr. Massie stated. “In a place like Memorial, because we are so big, and sadly, we have so many women with breast cancer, we can have groups for newly diagnosed patients; groups for women with metastatic disease; and still other groups for people of different ages. A woman in her late 70s often doesn’t feel she has much in common with someone who is 25. So we can sometimes offer groups for more mature patients and have the same kind of group for younger patients,” she explained. “But out in the heartland of America, there may be just one support group each week. Men with prostate cancer, people with lung cancer, and women with breast cancer are all in the same group. I think you do the best you can with what you have available to you.” She noted that the “Look Good… Feel Better” program can also be very helpful for patients with cancer. “Look Good…Feel Better” is a nationwide program that offers free workshops and educational resources aimed at improving the self-esteem and quality of life of people undergoing treatment for cancer.1 Another newer option is a virtual group or online support group, “because it isn’t so easy when you are really sick to get into the cancer center or get into the psychiatrist’s office,” Dr. Massie noted. Social media, such as Facebook, can be used to develop emotional connections and support systems, as described in an article by

Expect Questions from Your Patients

hen patients and family members have concerns about depression, they often bring them up with the staff, not with the treating oncologist. “I think that people with cancer don’t want to distract their medical oncologist or their surgeon by talking about their mood,” Dr. Massie noted. “Some people are frankly embarrassed because they feel that having depression, low mood, or Mary Jane Massie, MD anxiety means that they are a lesser person.” Or they may assume that other patients with cancer are coping just fine, although sadness and anxiety are so common in patients with cancer, Dr. Massie said. “Patients want their oncologists to focus on the cancer,” she continued. Just as patients don’t expect oncologists to spend time talking about finances or scheduling difficulties, they often don’t expect oncologists to spend time talking about emotions.

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.

Spur and Refer Staff members can spur conversation and refer patients to support groups. “We would hope the oncologist’s nurse or social worker can say to patients, ‘Let’s talk about your mood or your spirits. Has this been emotionally difficult for you? How are you holding up?’” Dr. Massie said. Staff members could reassure patients that they are not alone in experiencing anxiety and depression and need not be alone in addressing these issues. Patients can be referred to emotional support groups or to a psychiatrist for individual counseling and/or antidepressant medication. Dr. Massie suggested that the treating oncologist consider starting the patient on an antidepressant, especially if there will be a wait to see a psychiatrist.

■

groups. In those cases, Dr. Massie said, oncologists should consider initiating a discussion about depression and perhaps prescribing an antidepressant, then referring the patient to a psychiatrist for follow-up, and maybe having a

Depressed people do less well in the oncology setting, probably in large part because they feel so bad, they don’t fill their prescriptions. They don’t think it is useful to take their medicines. They’re missing appointments. They’re less compliant. —Mary Jane Massie, MD

a Miami Herald columnist chronicling her own experiences with breast cancer.2

Prescribing Antidepressants Not all patients are willing to acknowledge changing moods and depression and sign up for support

staff member try to arrange an appointment the same day or soon after. If it takes a while to get an appointment, the patient can start the antidepressant in the interim. In other cases, patients themselves may ask about medication for depression. Patients are often started on one

of the selective serotonin-reuptake inhibitors, with escitalopram (Lexapro) being among the most common. “I think that a good oncologist has some understanding about how to approach the problem pharmacologically,” Dr. Massie commented. “If what they try first works, great. But if it doesn’t, then what? I think that’s when it gets a little trickier. That is why, hopefully, oncologists cultivate relationships with mental health people in their geographic area, so they can make good referrals,” she said. “There are a lot of antidepressants available,” Dr. Massie said. “For different people, different drugs are better. Some antidepressants are more energizing; some are more sedating. So if a person needs a ‘picker-upper,’ we might consider one of the more energizing drugs. If a person is quite anxious, having trouble sleeping, and depressed, you wouldn’t want to prescribe an energizing drug.” continued on page 58

The ASCO Post | FEBRUARY 15, 2012

PAGE 58

In the News

Depression in Cancer continued from page 57

Avoiding Drug Interactions Decisions about which medication to prescribe should also take into account concerns about drug interactions. “There certainly has been concern about the use of tamoxifen with some antidepressants, and I

think many people today feel that venlafaxine might be the safest drug to take when a person is taking tamoxifen,” Dr. Massie said. “It appears that some antidepressants may render tamoxifen less effective,” Dr Massie explained. In general, however, antidepressants can be safely used with

cancer treatments. “Patients with cancer already have so many effects from their cancer therapy, so we are grateful that antidepressants with relatively few side effects can be useful,” Dr. Massie stated. Nevertheless, more needs to be known about potential drug interactions, she added.

It’s Not Too Late— Participate in QOPI® This Spring Demonstrate Your Commitment to Deliver Quality Care

QOPI : THE QUALITY ONCOLOGY PRACTICE INITIATIVE ®

QOPI® is a practice-based quality assessment program, developed by practicing oncologists, to promote excellence in cancer care. Through QOPI, you compare the care your practice delivers to published, evidencebased guideline recommendations, established measures for quality oncology care, and to care delivered by other oncology practices throughout the U.S. You will gain key information to identify areas to target for your quality improvement efforts, and be able to demonstrate to your patients, payors, and colleagues your commitment to deliver the best care to every patient. Additional benefits of data collection include: • Reports which are the only ABIM-approved oncology-specific data source for use towards MOC Part IV-Practice Improvement requirements • CME credit • Fellowship program quality assessment experience • Initial step towards earning QOPI® Certification, a designation that recognizes practices that consistently achieve the highest standards of care

The spring 2012 QOPI data collection starts March 22nd. Practices new to QOPI are encouraged to register to participate by February 22nd. Visit qopi.asco.org for more information.

Late-occurring Depression Dr. Massie often sees patients at the time they are diagnosed. “But another time that people are referred to me is at the end of treatment or 1 year after the end of treatment,” she said. “Some people hold it together” throughout diagnosis and treatment, Dr. Massie said, “but then lose it when treatment is completed.” The aftermath of treatment can be “kind of scary,” Dr. Massie noted. During treatment, the patient usually is surrounded by knowledgeable and supportive health professionals. “Then all of a sudden, you’re done with your treatment and back in the real world, where people are sick of hearing about your breast cancer. They don’t want to talk about it anymore. They want you to get back to your desk and get your job done,” Dr. Massie said. “And family members often are worn out and no longer want to talk about it either.” Specially tailored counseling may be needed by women with breast cancer who are receiving palliative care and are near the end of their lives. This might include discussions about dying, how to talk about death with children, and who will take care of the children. For these women, a combination of individual and group counseling might be most appropriate. Some may not be well enough to attend support group sessions, but even for those who can attend, “Group leaders may want them to have private sessions, too, to help them work through their issues, and probably medications would be very helpful.” Dr. Massie said. “Often, as people are getting more ill, they are getting more home visits,” Dr. Massie said. This allows visiting health professionals a chance to observe the patient in her own environment and to make recommendations for medications and other care. She added that hospice workers “are really tuned in” to the emotional and other needs of patients and “are extraordinary helpful.”

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

References 1. Look Good…Feel Better: Helping Women with Cancer. Available at lookgoodfeelbetter.org. Accessed January 20, 2012. 2. Torres A: Facebook, medication help breast cancer patient deal with depression. Miami Herald, January 3, 2012.

ASCOPost.com | FEBRUARY 15, 2012

PAGE 59

Lab Notes

Ongoing Molecular Research in the Science of Oncology DRUG RESISTANCE Targeting AKT/mTOR May Improve Response to Monoclonal Antibodies in Some Cancers The insulin-like growth factor (IGF) network plays a central role in regulating tumor cell growth and differentiation, tumor angiogenesis, metastasis, apoptosis, and multidrug resistance. Increased IGF-1 receptor (IGF-1R) expression and circulating IGF-1 are associated with increased risk for development of disease and more rapid disease progression in a number of cancers, including head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC). Although IGF-1R inactivation has antitumor effects, a number of clinical trials of anti– IGF-1R monoclonal antibodies have shown only modest efficacy, with the mechanisms involved in drug resistance remaining undefined.

Korean Study Shin and colleagues at the College of Pharmacy at Seoul National University, Republic of Korea, recently showed that tumor cells resistant to the anti-IGF-1R monoclonal antibody cixutumumab become sensitive to the drug after suppression of mTOR-mediated protein synthesis or inactivation of the epidermal growth factor receptor (EGFR).1 On the hypothesis that cooperation between EGFR and IGF-1R could cause resistance to inhibitors of a number of individual receptor tyrosine kinases, these investigators assessed the involvement of EGFR signaling in IGF1R monoclonal antibody resistance. Treatment of cixutumumab-resistant HNSCC and NSCLC cells with cixutumumab induced activation of Akt and mTOR, resulting in synthesis of EGFR, Akt1, and (antiapoptotic) survivin proteins as well as activation of the EGFR pathway. Targeting of the mTOR pathway with rapamycin or targeting of the EGFR pathway with the anti-EGFR monoclonal antibody cetuximab (Erbitux) resulted in prevention of cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects with cixutumumab in vitro and in vivo. As stated by the authors, “These data show that resistance to IGF-1R inhibition by [a monoclonal antibody] is associated with Akt/mTOR-directed

enhanced synthesis of EGFR, Akt1, and survivin … [and] suggest that Akt/ mTOR might be effective targets to overcome the resistance to IGF-1R monoclonal antibodies in HNSCC and NSCLC.”

Shin DH, et al: Mol Cancer Ther 10:2437-2448, 2011.

GENE PROFILING Impact of p53 Status on Cancer Treatment Selection Wild-type p53 emerges from a latent state and becomes stabilized and activated in response to genotoxic and cellular stress signals, resulting in the transcriptional modulation of multiple genes involved in regulating cell-cycle progression, senescence, and apoptosis. More than 50% of human tumors carry p53 mutations. Most of these are missense mutations that result in loss of tumor-suppressing activities and gain of oncogenic activities, termed ‘gain of function.’ Mutant p53 protein enhances proliferation and survival in cells and tumorigenesis in mice when compared with cells or mice that are p53-deficient. Suh and colleagues from The University of Texas MD Anderson Cancer Center recently studied the effects of stress signals known to stabilize wildtype p53—oncogene activation, DNA damage, and oxidative stress caused by reactive oxygen species (ROS)—on mutant p53 in mice.1 They found that activation of oncogenes in mice with mutant p53 stabilized the mutant p53.

Stabilization and Survival This stabilization resulted in more potent tumor phenotypes compared with mice harboring the p53 mutation without oncogene activation, although these phenotypes did not result in reduced survival. However, doxorubicin, a DNA-damaging agent, resulted in stabilization of mutant p53 and decreased survival compared with untreated p53 homozygous mice. Further, γ-irradiation resulted in increased stabilization of mutant p53, multiple tumors, and decreased survival compared with irradiated mice with wild-type p53. The use of an ROS scavenger to reduce ROS levels (which are increased, for example, by radiation therapy) resulted in reduced levels of mutant p53 protein. These findings are of potentially great importance in terms of selecting treatments for patients with mutant p53. They suggest that outcomes of clinical trials should be analyzed according to p53

status of patients receiving such DNA damaging treatments as doxorubicin and radiation therapy. The results also indicate that the “gain of function” phenotype resulting from stabilized mutant p53 may be overcome by inhibiting ROS-mediated DNA damage and suggest that management of ROS levels may be warranted in patients with mutant p53. As stated by the authors, “These data suggest that direct knowledge of the p53 status of a patient may be critical in preventing unintended consequences when determining therapeutic strategies. This study also emphasizes the need for individually tailored treatment for cancer patients depending upon their p53 mutation status.” Suh Y-A, et al: Cancer Res 71:71687175, 2011.

RISK ASSESSMENT Overexpression of p16 Does Not Indicate Increased Risk of Breast Cancer in Women with Atypical Hyperplasia Women diagnosed with atypical hyperplasia have a substantial risk of subsequent development of breast cancer, with a cumulative incidence of approximately 30% at 25 years. Atypical hyperplasia is considered to be a precursor to ductal carcinoma in situ (DCIS). p16 (a nuclear protein encoded by the p16INK4a gene) plays an important role in cellcycle regulation, and a number of studies have shown that expression of p16 in biopsies of patients with DCIS is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki-67 (proliferation marker) and COX-2 (inflammatory/invasive marker). In a recent study, Radisky and colleagues from the Mayo Clinic Department of Cancer Biology in Jacksonville, Florida, found no association of increased p16 expression and risk for development of breast cancer in women with atypical hyperplasia.1 The investigators assessed expression of p16, Ki-67, and COX-2 in archived sections from 233 women with atypical hyperplasia diagnosed at the Mayo Clinic. With a median follow-up of 14.5 years, 47 patients (20%) developed breast cancer. Expression of p16 was significantly increased in older patients compared with younger patients. Joint overexpression of Ki-67 and COX-2 was found to convey significantly greater risk of breast

cancer in the first 10 years after diagnosis, compared with overexpression of only one of these markers. SEE PAGE 59 However, the addition of p16 expression levels to the analysis did not strengthen the association of Ki67 and COX-2 with cancer risk. As stated by the authors, “p16 overexpression, either alone or in combination with COX-2 and Ki-67, does not significantly stratify breast cancer risk in women with [atypical hyperplasia].” The finding of an increased proportion of p16-positive lesions in older women is consistent with other studies showing age-related increases of p16 in other tissues. The authors noted that “Determining whether the increased abundance of p16-positive cells in [atypical hyperplasia] of older women is associated with tumor protective or promoting effects of senescence activation will require further investigation.”

■

Radisky DC, et al: Cancer Prev Res 4:1953-1960, 2011. “Lab Notes” is compiled and written for The ASCO Post by Matthew Stenger.

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PAGE 61

In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Risk of Sexual and Continence Problems No Lower with Robotic than with Open Surgery Although robotic-assisted laparoscopic radical prostatectomy “is eclipsing open radical prostatectomy among men with clinically localized prostate cancer,” the risks of problems with sexual functioning and continence are no lower with robotic than open surgery, according to a study in the Journal of Clinical Oncology. The study compared continence and sexual function among a random sample of Medicare enrollees who had hospital and physician claims for radical prostatectomy and diagnostic codes for prostate cancer, and reported receiving treatment with either robotic-assisted laparoscopic radical prostatectomy or open retropubic radical prostatectomy. Surveys mailed to the men included self-ratings for problems related to continence and sexual function at a median of 14 months postoperatively. “The main focus of this survey was the quality of the decision-making process leading to surgery, but items related to bother of adverse effects were also included,” the investigators noted. “For the analyses in this article, the two key outcome questions were ‘Since this prostate surgery, how much of a problem have you had with leaking or dripping urine?’ and ‘Since this prostate surgery, how much

of a problem have you had with sexual functioning, such as problems with erections?’ Possible responses,” the investigators explained, “were ‘No problem,’ ‘A very small problem,’ ‘A small problem,’ ‘A moderate problem,’ and ‘A big problem.’”

Final Sample Surveys were returned by 685 men, but some did not answer all of the questions. The final sample size was 406 men assumed to have had the robotic-assisted laparoscopic procedure and 220 assumed to have had open surgery. Overall, 189 (31.1%) of 607 men reported having a moderate or big problem with continence, and 522 (88.0%) of 593 men reported having a moderate or big problem with sexual function. “In logistic regression models predicting the log odds of a moderate or big problem with postoperative continence and adjusting for age and educational level, robotic prostatectomy was associated with a nonsignificant trend toward greater problems with continence,” the investigators reported. “Robotic prostatectomy was not associated with greater problems with sexual function,” they added. “Medicare-age men with clinically localized prostate cancer should understand that risks of problems with continence and sexual function remain high in the recent national surgical experience regardless of whether they choose [robotic or open prostatectomy], and they should not be led to expect fewer bothersome adverse effects following

[robotic-assisted surgery],” the researchers concluded. “The apparent lack of better outcomes associated with [roboticassisted surgery] also calls into question whether Medicare should pay more for this procedure until prospective largescale outcome studies from the typical sites performing these procedures demonstrate better results in terms of adverse effects and cancer control.”

Barry MJ, et al: J Clin Oncol. January 3, 2012 (early release online).

LUNG CANCER High EGFR Expression Can Predict Survival Benefit from Cetuximab plus First-line Chemotherapy in NSCLC High expression of epidermal growth factor receptor (EGFR) can predict survival benefit from cetuximab (Erbitux) added to first-line chemotherapy in patients with advanced non–small cell lung cancer (NSCLC). The identification of high EGFR expression as a tumor biomarker follows findings from the phase III First-Line ErbituX in Lung Cancer (FLEX) study that showed adding cetuximab to cisplatin and vinorelbine significantly improved overall survival compared to chemotherapy alone. Tumor cell expression of EGFR was an eligibility criterion for the FLEX study, and the current analysis used FLEX data on the intensity and frequency of membrane immunohistochemistry staining to generate EGFR scores of 0 to 300 for assessable patients. The selected threshold was 200, with scores < 200 considered low and > 200 high.

Data Breakdown

Tumor EGFR immunohistochemistry data were available for 1,121 (99.6%) of 1,125 patients from the FLEX study intention-to-treat population. “High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients,” the investigators reported in The Lancet Oncology. For patients with high EGFR expression, overall survival was longer (median, 12.0 months) in the chemotherapy-plus-cetuximab group than in the chemotherapy-alone group (median, 9.6 months), “with no meaningful increase in side effects,” the authors noted. No corresponding survival benefit was found for patients with low EGFR expression. “A treatment interaction test assessing the difference in the [haz-

ard ratios] for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (P = .044),” the investigators stated. Based on their findings, the investigators believe that “high EGFR expression might now be applied clinically as a predictive biomarker to identify patients with advanced NSCLC who will benefit from the addition of cetuximab to first-line chemotherapy.” Merck KGaA provided funding for the study.

Pirker R, et al: Lancet Oncol 13:33-42, 2012.

THYROID CANCER Vandetanib Demonstrates Therapeutic Efficacy in Patients with Advanced Medullary Thyroid Cancer A phase III trial among patients with locally advanced or metastatic medullary thyroid cancer met its primary objective of progression-free survival prolongation among patients receiving vandetanib compared to placebo. The secondary efficacy endpoints of objective response rate, disease control rate, and biochemical response “also showed statistically significant benefit in the treatment group compared with the control group,” the investigators reported in the Journal of Clinical Oncology. Patients were recruited from 23 countries and randomly assigned on a 2:1 basis to vandetanib at 300 mg/d (231) or placebo (100). The mean age was 52 years. Most patients in both groups had sporadic medullary thyroid cancer and metastatic disease. Vandetanib—a oncedaily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling—had previously shown antitumor activity in a phase II study among patients with the hereditary type of medullary thyroid cancer. Patients with objective disease progression could elect to receive open-label vandetanib.

Estimated Survival At a median follow-up of 24 months, 37% of patients had shown disease progression and 15% had died. A final survival analysis is to take place when 50% of the patients have died. Median progression-free survival was 19.3 months in the placebo group, and although median progression-free survival was not yet reached continued on page 62

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The ASCO Post | FEBRUARY 15, 2012

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AVASTIN® (bevacizumab)

In the Literature

Emerging Clinical Data continued from page 61

in the vandetanib group, it was estimated at 30.5 months, an estimated prolongation of 11.2 months. “In this clinical study, vandetanib has shown efficacy in patients with locally advanced or metastatic [medullary thyroid cancer], a challenging group of patients for whom there has been no effective therapy,” the authors concluded. “Common adverse events (any grade)

Solution for intravenous infusion Initial U.S. Approval: 2004

occurred more frequently with vandetanib compared with placebo, including diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%),” the investigators reported.

■

Wells SA, et al: J Clin Oncol 30:134-141, 2012. “In the Literature” is compiled and written for The ASCO Post by Charlotte Bath

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WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2‑negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None.

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5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

AVASTIN® (bevacizumab) Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4024 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑88 years (median 59), 41% male and 85.1% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients

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AVASTIN® (bevacizumab)

receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 7, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL+Avastin vs. IFL)

were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n=84 or with Avastin (n=95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL + Placebo (n = 396) 74%

Arm 2 IFL + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4. Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥ 2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%). Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/ hypotension (2). Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥ 5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3. Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Body as a Whole Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Weight loss Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

24%

19%

25%

14%

18% 1%

27% 16%

75%

84%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

T:13"

Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%.

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients. Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. 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. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

AVA0000400601

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