TAP Vol 3 Issue 12 by Harborside Press LLC

Novel Agents in Lymphocytic Leukemia 9 | Differentiated Thyroid Cancer

VOLUME 3, ISSUE 12

| Pseudoprogression in Glioblastoma 31

AUGUST 15, 2012

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

JCO Spotlight

Study Shows Routine CT Surveillance Overused in Pediatric Hodgkin Lymphoma

ASCOPost.com

Maintenance of Certification: One Size Should Not Fit All

By Matthew Stenger

he value of routine CT surveillance monitoring of pediatric patients for recurrence of Hodgkin lymphoma has been unclear. A study of CT surveillance recently reported by Stephan D. Voss, MD, PhD, and colleagues from the ChilStephan D. Voss, MD, PhD dren’s Oncology Group (COG) in the Journal of Clinical Oncology showed that most relapses occurred early or were signaled by clinical changes and that detection of infrequent late relapses by surveillance imaging did not appear to affect survival. In this study, Dr. Voss and colleagues analyzed data from 216 patients aged ≤ 21 years who were See Page 86 enrolled in the COG Pediatric On-

cology Group 9425 trial between 1997 and 2001.1 All patients had biopsy-proven classical Hodgkin lymphoma and intermediate-risk (25%) or high-risk (75%) disease, and all had responded to ABVE-PC therapy (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) followed by radiation therapy. Patients were followed with surveillance CT scans at 0, 6, 12, 24, and 30 months.

Most Relapses Signaled by Clinical Changes During a median follow-up of 7.4 years, 25 patients (12%) experienced relapse. Relapse was local in 23 patients. The median time to relapse was 7.6 months (range, 0.2-48.9 months). In 19 (76%) of the 25 patients with relapse, relapse was suspected on the basis of reported changes in physical symptoms, lab values, or physical examination findings. Symptoms and clinical findings in patients with relapse included palpable continued on page 3

Expert’s Corner

Rethinking the Role of PSA Screening in Public Health A Conversation with Richard J. Ablin, PhD, DSc (Hon)

By Andrew D. Seidman, MD

fter a conference call and having returned several phone calls, I again opened my ASCO Medical Oncology Self Evaluation Program (SEP) book hoping to steal an hour to reread the chapter on multiple myeloma, and begin digging deeper into head and neck cancer. It was March 2011, and my Maintenance of Certification examination was looming a mere 6 weeks away. While trying to parse the relative roles of thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade), I was interrupted by a call from my research study assistant asking for assistance in screening a patient for a breast cancer clinical trial. Somewhat ironically, as one who has enjoyed being immersed in breast cancer care continued on page 89

Dr. Seidman is a medical oncologist at Memorial SloanKettering Cancer Center, New York.

By Ronald Piana

opulation screening to identify preclinical disease is considered a central factor in the decades-long decrease in mortality seen in certain cancers. However, hope in the face of deadly disease can sometimes blind us to the scientific evidence. According to the recent U.S. Preventive Services Task Force recommendation,1 such might be the case with routine prostate-specific antigen (PSA) screening, the most widely used method in efforts

PSA is prostate-specific, not cancer-specific. It is present in the normal, the benign, and the malignant prostate and can be elevated by numerous benign factors. — Richard J. Ablin, PhD, DSc (Hon)

to detect early prostate cancer. To add clarity to this ongoing debate, The ASCO Post recently spoke with Richard J. Ablin, PhD, DSc (Hon), Professor of Pathology at the University of Arizona College of Medicine, The Arizona Cancer Center, and the BIO5 Institute, Tucson, and the discoverer of PSA.

Discovering PSA What were the salient events leading up to your discovery of PSA? In 1968, after completing a postdoctoral fellowship in the Bacteriology and Immunology (currently Microbiology) Department at the University of Buffalo Medical School, I joined two urologists at the Millard Fillmore Hospital in Buffalo, who had developed cryosurgery (or cryoablation) for the treatment of prostate cancer. Several of the patients treated cryosurgically had advanced metastatic disease (T4, M1), for example, to the lungs and cervical vertebrae. Remarkably, postoperative radiologic evidence revealed that their

MORE IN THIS ISSUE 2012 ASCO Annual Meeting Hematology �� 9 GIST �� 23 Breast Cancer ��44, 50, 57 Renal Cell Carcinoma �� 51 Non–Small Cell Lung Cancer �� 52 MASCC/ISOO International Symposium �� 12, 58 AACR/Personalized Medicine Coalition �� 74 George W. Sledge, MD, on Genomics vs Cancer Site �� 84

continued on page 10

A Harborside Press® Publication

The ASCO Post | AUGUST 15, 2012

PAGE 2

FDA Update

FDA Approves Ziv-aflibercept for Metastatic Colorectal Cancer

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

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

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

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

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

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

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

Michael P. Link, MD Stanford University Medical Center

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

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

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

Harborside Press® Publishing Staff

he FDA has approved ziv-aflibercept (Zaltrap) for use in combination with a FOLFIRI (leucovorin, fluorouracil, irinotecan) chemotherapy regimen to treat adults with colorectal cancer. Ziv-aflibercept is an angiogenesis inhibitor that inhibits the blood supply to tumors. It is intended for patients whose cancer has become metastatic and whose tumors are resistant to or progressed after an oxaliplatin-containing chemotherapy regimen.

Clinical Trial Ziv-aflibercept’s safety and effectiveness was evaluated in a randomized clinical study of 1,226 patients with metastatic colorectal cancer whose cancer grew while receiving oxaliplatin-based combination chemotherapy, or whose cancer was removed by surgery but returned within 6 months after receiving oxaliplatin-based combination chemotherapy for adjuvant treatment. Participants received treatment until their cancer progressed or side effects became unacceptable. The study was designed to measure overall survival, or the length of time a patient lived. Patients who were assigned to receive the ziv-aflibercept– plus-FOLFIRI combination lived an average of 13.5 months compared to an

average of 12 months for those receiving FOLFIRI plus placebo. A reduction in tumor size occurred in 20% of patients receiving the zivaflibercept–plus-FOLFIRI combination vs 11% for those receiving FOLFIRI plus placebo. In addition, the clinical trial demonstrated an improvement in progressionfree survival, or the time a patient lived without the cancer progressing. The progression-free survival for patients receiving ziv-aflibercept plus FOLFIRI was 6.9 months compared with 4.7 months for those receiving FOLFIRI plus placebo.

Adverse Events Ziv-aflibercept is being approved with a Boxed Warning stating that the drug can cause severe and sometimes fatal bleeding, including gastrointestinal bleeding, and the development of holes in the gastrointestinal tract. The new agent can also make it more difficult for wounds to heal. The most common side effects observed in patients receiving ziv-aflibercept plus FOLFIRI were decreased white blood cell count, diarrhea, mouth ulcers, fatigue, high blood pressure, increased amount of protein in the urine, weight loss, decreased appetite, abdominal pain, and headache.

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

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ASCOPost.com | AUGUST 15, 2012

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JCO Spotlight

CT Surveillance in Hodgkin Lymphoma continued from page 1

lymphadenopathy in eight patients, recurrent ‘B’ symptoms in two, and combinations of pain, weight loss, adenopathy, and abnormal lab findings in eight.

Relapse Rates

vestigators defined rapid early response as “≥ 50% reduction in the sum of the products of the perpendicular diameters of measurable lesions and negative gallium scan after three chemotherapy cycles.” Failure to achieve rapid early response was considered slow early response. Relapses occurred across all Hodgkin lymphoma histologies and did not occur more frequently in patients with bulk disease. The median time to relapse was significantly longer in patients with rapid early response vs those with slow early response (11.5 vs 2.2 months, P = .044).

Six patients (24%) with no symptoms at the time of relapse had relapse detected by routine imaging. In these patients, relapses were detected by CT alone (n = 3), gallium scintigraphy alone (n = 1), CT and gallium scintigraphy (n = 1), or Most Relapses Occurred gallium scintigraphy, magnetic resonance in First Year imaging, and positron emission tomograOverall, 16 (64%) of the 25 relapses phy (PET; n = 1). An additional patient occurred within the first year after the end had relapse detected by CT performed as of treatment. Most patients with relapse part of a workup for potential pneumowere successfully treated with salvage nia. Two of the six patients had relapse detherapy, with 5-year event-free survival tected within the first year after completof 84% and 5-year ing therapy, and four overall survival of (16% of patients CT is overutilized for 95% reported in the with relapse) had the routine surveillance entire patient popurelapse detected by lation. Six patients surveillance imagof [Hodgkin lymphoma], died from relapsed ing later than 1 year with little impact on disease, with all of after treatment—ie, these patients havafter the period duroverall outcome in ing relapse within 1 ing which risk of repatients who do not year of completing lapse is highest. The treatment. There late asymptomatic experience an early were no deaths in relapses occurred relapse. patients with relapse both in patients detected after 1 year, with intermediateirrespective of how relapse was detected. stage disease (n = 1) and in those with Although the numbers of patients inadvanced-stage disease (n = 3). volved in the analysis of overall survival The majority of relapses occurred at in patients with relapse was small, overall previously involved sites or at both previsurvival was significantly greater in paously involved and new sites, with relapse tients with relapse after 1 year compared at only new sites occurring in two patients with patients having relapse within 1 year (8%). Relapses occurred with similar (P = .04). Due to small sample sizes, there frequency in patients with intermediatewere no significant differences between stage and advanced-stage disease (11% overall survival in patients with relapse and 12%) and among patients with slow during the first year (detected either by early response (9 of 77, 12%) and rapid imaging or by clinical change) and overearly response (16 of 132, 12%). The in-

Detecting Relapse in Hodgkin Lymphoma ■■ New data reveal that most relapses in children with Hodgkin lymphoma occur within the first year after treatment or are detected based on change in clinical status.

■■ Detection of late relapse, either by imaging or by clinical change, does not affect overall survival in this setting.

■■ These findings suggest that CT is overused for routine surveillance of Hodgkin lymphoma patients.

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

EXPERT POINT OF VIEW

n an accompanying editorial entitled “Who Benefits From Surveillance Imaging?” James O. Armitage, MD, University of Nebraska Medical Center, Omaha, noted that data on surveillance imaging (CT or PET/CT) indicate a general absence of survival benefit in adults with lymphomas, while pointing out that the utility of such imaging may be dependent on prevalence of relapse in particular populations and may vary among different types of James O. Armitage, MD lymphoma.1 He emphasized that any program of surveillance imaging must be concerned with the costs and potential risks of imaging—including the risk associated with biopsies to document relapse and the potential anxiety and fear associated with imaging, as well as risk of second cancers related to radiation dose.

To Image or Not? Returning to the question, “Who benefits from surveillance imaging?” Dr. Armitage concluded, “The report by Voss et al … suggests the answer is not children with Hodgkin’s lymphoma who achieve remission. However, it is still possible that in high-risk patients (ie, where the higher chance of relapse would increase the positive predictive value of an abnormal image) for whom potentially curative salvage therapy is available, these images might improve survival. One [such subgroup] is younger adults with high-risk diffuse large B-cell lymphoma. A clinical trial in this group of patients comparing routine follow-up using history, physical examination, and laboratory studies with the same evaluation plus surveillance imaging could have an important impact on practice—either to make surveillance routine or to decrease its use. Until such a trial is completed, surveillance imaging for patients with lymphoma in remission should not be routinely performed.”

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Disclosure: Dr. Armitage has served as a consultant or advisor for Ziopharm, Seattle Genetics, Genentech, Allos, and Roche.

Reference 1. Armitage JO: Who benefits from surveillance imaging? J Clin Oncol. June 11, 2012 (early release online).

all survival in patients with relapse after 1 year detected by clinical change or overall survival in patients with relapse after 1 year detected by imaging. The study thus showed that approximately 1,080 CT scans (five planned scans per patient) were performed off therapy to detect four late asymptomatic relapses and indicated that the use of surveillance imaging to detect these relapses did not have an impact on overall survival. There is concern that CT scanning in children, even with optimized dosing, may increase risk of cancers later in life. Some data on diagnostic imaging in pediatric patients with cancer indicate that those with neuroblastoma and lymphoma have the highest cumulative radiation doses, primarily from

CT scans and nuclear medicine examinations. The authors noted that due to the high curability of Hodgkin lymphoma with current treatment, there has been a renewed emphasis on limiting long-term treatment-related morbidity, including morbidity associated with diagnostic imaging. Surveillance CT scans are also expensive. The authors estimated that in the recently completed COG intermediate-risk Hodgkin lymphoma study AHOD0031, some 10,000 surveillance CT scans were scheduled, per protocol, to be performed after 1 year post-treatment in the more than 1,700 patients enrolled, with an aggregate cost to the health-care system of at least $3.48�� milcontinued on page 6

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

Indication VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other

medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a

cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group). • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases concentrations of VOTRIENT and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit juice. Concomitant use of strong CYP3A4 inducers (e.g., rifampin) should be avoided due to the potential to decrease concentrations of VOTRIENT. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of

concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions. The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs. 48%), diarrhea (59% vs. 15%), nausea (56% vs. 22%), decreased weight (48% vs. 15%), hypertension (42% vs. 6%), decreased appetite (40% vs. 19%), hair color changes (39% vs. 2%), vomiting (33% vs. 11%), tumor pain (29% vs. 21%), dysgeusia (28% vs. 3%), headache (23% vs. 8%), musculoskeletal pain (23% vs. 20%), myalgia (23% vs. 9%), gastrointestinal pain (23% vs. 9%), dyspnea (20% vs. 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in AST (51% vs. 22%), ALT (46% vs. 18%), glucose (45% vs. 35%), alkaline phosphatase (32% vs. 23%), total bilirubin (29% vs. 7%), and potassium (16% vs. 11%); decreases in albumin (34% vs. 21%) and sodium (31% vs. 20%); and leukopenia (44% vs. 15%), lymphocytopenia (43% vs. 36%), thrombocytopenia (36% vs. 6%), and neutropenia (33% vs. 7%). Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages. Reference: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.

VOTRIENT.com

The ASCO Post | AUGUST 15, 2012

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B:11.75”

JCO Spotlight

T:10.5” S:8.75”

CT Surveillance in Hodgkin Lymphoma continued from page 3

lion. This study is now closed to accrual but patients are still being monitored off therapy; an amendment to the original protocol has been submitted to reduce the number of follow-up surveillance imaging examinations required.

Conclusions As stated by the authors, “On the basis of these findings, it is our conclusion that CT is overutilized for the routine surveillance of [Hodgkin lymphoma], with little impact on overall outcome in patients who do not experience an early relapse…. This study … identifies an opportunity to reduce both unnecessary

medical expense and radiation exposure by decreasing the number of imaging studies being routinely performed on patients with [Hodgkin lymphoma]…. [W]e recommend reducing the routine use of CT surveillance imaging to the initial 12 months after therapy.”

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Disclosure: The authors of the COG study reported no potential conflicts of interest.

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.2% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be

Reference 1. Voss SD, Constine LS, Chauvenet A, et al: Surveillance computed tomography imaging and detection of relapse in intermediate- and advanced-stage pediatric Hodgkin’s lymphoma: A report from the Children’s Oncology Group. J Clin Oncol. June 11, 2012 (early release online).

used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10% compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. 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. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient, treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour

ASCOPost.com | AUGUST 15, 2012

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Senate Legislation Urges Federal Research Support to Improve Early Detection of Prostate Cancer

.S. Senator John F. Kerry (DMA) led unanimous passage of Senate Resolution 493 to recognize prostate cancer as an epidemic striking African American men dispropor-

tionately, with 250% higher mortality and 60% higher incidence. This bipartisan legislation urges federal agencies to support research for the advancement of diagnostic tools, including

urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache Musculoskeletal pain Myalgia Gastrointestinal pain Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorder b Skin hypopigmentation Stomatitis Chest pain a b

65 59 56 48 42 40 39 33 29 28 23 23 23 23 20 18 17 14 12 12 11 11 11 11 10

13 5 3 4 7 6 0 3 8 0 1 2 2 3 5 <1 <1 2 2 0 1 2 0 <1 2

1 0 0 0 0 0 0 0 0 0 0 0 0 0 <1 0 0 0 0 0 0 0 0 0 0

48 15 22 15 6 19 2 11 21 3 8 20 9 9 17 9 12 9 2 1 4 1 0 3 6

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

1 0 0 0 0 0 0 0 2 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), nail disorder (5% versus 0%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased

44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45

5 8 <1

3 2 0

22 18 35

2 2 2

0 1 0

Albumin decreased

Alkaline phosphatase increased Sodium decreased Total bilirubin increased Potassium increased a

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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American men. Senator Kerry said, “We need to stay focused on research and arm Americans with the tools to prevent, detect, cure, and treat this disease.

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6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebocontrolled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

novel biomarkers and imaging technologies. Improved diagnostic tools could save lives and ensure individualized, least invasive, and most costeffective patient care in millions of

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FDA Update

The ASCO Post | AUGUST 15, 2012

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Biokine Therapeutics Awarded FDA Orphan Drug Designation for Mobilization of Stem Cells in Patients with Cancer

iokine Therapeutics Ltd announced that it has received Orphan Drug designation from the FDA for BKT140, a highly selective chemokine receptor antagonist that induces

mobilization of hematopoietic stem cells from bone marrow into peripheral blood for collection and subsequent transplantation in patients with hematologic cancers.

• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, or severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

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FDA Approves Colon-cleansing Drug for Prep Prior to Colonoscopy

he FDA has approved sodium picosulfate, magnesium oxide, and citric acid (Prepopik) to help cleanse the colon in adults preparing for colonoscopy, Ferring Pharmaceuticals announced. The new solution is a low-volume, dual-acting stimulant and osmotic laxative. The FDA approval is based on data from two phase III studies, in which the regimen was as effective or superior to the control population in cleansing the colon. The most common side effects reported in adult patients taking the solution were nausea, headache, and vomiting. One dose of the solution consists of two packets of powder, each dissolved in cold water and taken at separate times. Patients should take the product the night before colonoscopy and the morning of colonoscopy (split-dose regimen). If this is not possible, patients may take it in the afternoon and evening before the colonoscopy (day-before regimen). As a condition of approval, studies must be conducted to determine if the drug can be used safely and effectively in children.

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:

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10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

utilizing BKT140. Biokine had previously completed a phase I/II clinical study that indicated both the drug’s safety and efficacy and its ability to shorten the number of treatment days and subsequent apheresis procedures. Laurence Shaw, MD, Chairman of Biokine’s board of directors, said, “In both preclinical and clinical studies BKT140 had shown that by targeting the chemokine receptor CXCR4, BKT140 also appears to have the potential to treat malignancies involving this key receptor.”

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In preclinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state C max and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

Earlier in 2012, Biokine received FDA approval to conduct a phase II clinical study for stem cell mobilization in patients with multiple nyeloma and non-Hodgkin lymphoma

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2012 ASCO Annual Meeting Hematology

Novel Agents Should Have Impact in Lymphocytic Leukemias By Caroline Helwick

gents with novel mechanisms of action may strongly impact outcomes in chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL), if data from early-phase studies presented at this year’s ASCO Annual Meeting are any indication.

Peter Hillmen, MBChB, PhD

There is a clear unmet need for more effective therapies in CLL, said Peter Hillmen, MBChB, PhD, of St. James University Hospital in Leeds, United Kingdom. An effective treatment should target the disease pathophysiologically, he said, as imatinib (Gleevec) does for See Page 86 chronic myelogenous

leukemia (CML). Therefore, much emphasis is being placed on understanding the molecular and cellular profiles of CLL, to guide drug development.

Ibrutinib Advances are also being made by exploring new targets. One such drug making news is the oral agent ibrutinib (PCI-32765), the first drug designed to target Bruton’s tyrosine kinase, a protein that is critical for B-cell receptor signaling in B lymphocytes and essential for CLL cell survival and proliferation. In a single-agent phase II study, ibrutinib produced high response rates in treatment-naive patients with CLL.1 The study included 31 patients previously untreated for CLL. The overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The rate of progression-free survival at 15 months was 96%. Investigators had previously reported on the cohort of treatmentrefractory patients, 70% of whom responded to the novel drug.2 “All subgroups responded equally well. Overall, the great majority of pa-

EXPERT POINT OF VIEW: CLL

he findings in chronic lymphocytic leukemia (CLL) were discussed by Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital in Melbourne, Australia, who observed, “There is a long list of novel agents in CLL. I think some of the most promising are those targeting the B-cell receptor pathway. This is a group of drugs that is going to completely change how we manage CLL.” The study of ibrutinib administered as first-line therapy—in which “virtually all patients benefited, Constantine S. Tam, MBBS, MD regardless of mutation status, and responses were durable”—represents a group of patients “we see in real life, older CLL patients,” Dr. Tam noted. “Older patients now have a real chance at a nonchemotherapy treatment that is easy to take, that they can take long term, that suppresses disease longterm and that, so far, appears not to be associated with mechanisms of resistance,” he said. “And in younger patients, I think we are looking at the prospect of a cure. Patients fail chemotherapy because we are not getting rid of disease in the bone marrow and lymph nodes, where cells are protected in the microenvironment. Now we can free those cells up and send them into the peripheral blood where they can be killed.” Dr. Tam further suggested that perhaps CLL should be managed more like chronic myelogenous leukemia, “with indefinite suppression of the disease with an oral agent.” Acknowledging that follow-up is still early, he concluded, “We have reached a crossroads in CLL treatment.”

■

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

EXPERT POINT OF VIEW: ALL

runo C. Medeiros, MD, of Stanford University School of Medicine, Palo Alto, commented, “It’s clear to say that new treatment strategies are needed for adults with [acute lymphocytic leukemia (ALL)] to improve outcomes of relapsed disease and to prevent relapses to begin with.” He noted that while 90% of ALL patients achieve a first remission, approximately 50% relapse, where 80% of these relapses occur within 2 years of diagnosis. Median overall survival for reBruno C. Medeiros, MD lapsed ALL ranges from 4 to 6 months and is minimally impacted by sex, age, time from diagnosis, or site of relapse, he said. Blinatumomab and inotuzumab ozogamycin both showed impressive single-agent activity in relapsed/refractory ALL, and both appear safe in the setting of prior stem cell transplant, according to Dr. Medeiros. What needs to be determined now is whether these monoclonal antibodies can be combined with chemotherapy or other monoclonal antibodies, and whether they have single-agent activity in the front-line setting.

■

Disclosure: Dr. Medeiros has served in a consulting or advisory role for Millennium, has received honoraria from Celgene and Millennium, and has received research funding from Celgene, Millennium, and Novartis.

tients gained benefit from this therapy,” said John C. Byrd, MD, of Ohio State University, Columbus. “This drug is like red wine—with time, it gets better. Responses increase, and many patients are still in follow-up. The continued daily dosing was well tolerated, which allows for extended treatment.” In a related study by the same investigators, ibrutinib was combined with ofatumumab, an anti-CD20 monoclonal antibody.3 Samantha Jaglowski, MD, also of Ohio State University, reported that the combination produced a 100% response rate in 24 patients with relapsed/ refractory CLL, prolymphocytic leukemia, and small lymphocytic leukemis.3 In three patients with Richter’s syndrome, the overall response rate was 67%. At 6.5 months follow-up, only two patients have shown disease progression. “The rapid onset of response, low relapse rate, and favorable safety profile make this noncytotoxic combination worthy of further study,” she said.

Blinatumomab Encouraging data are also building for the anti-CD19 bi-specific T-cell engager (BiTE) antibody blinatumomab. In a phase II study of 36 patients, blinatumomab produced responses (complete remission or “complete remission with only partial hematologic recov-

ery” [ie, < 5% blasts in the bone marrow, no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts]) in 72% of patients with relapsed/ refractory B-precursor ALL.4 BiTE antibodies are designed to direct the body’s cytotoxic T cells against tumor cells, enabling T cells to recognize and attack tumor cells in much the same manner as naturally occurring T cells. Blinatumomab targets CD19, which is expressed by 100% of leukemia cells. Patients received 5 µg/m2/d by continuous infusion during week 1, then 15 µg/m2/d thereafter. A complete remission (or complete remission with partial hematologic recovery) was observed in 72% of all patients and 74% of those receiving the optimal dose. All but two responders achieved a molecular response. Median overall survival in this heavily pretreated population was 9.0 months, and the median duration of hematologic complete response was 8.9 months, reported Max Topp, MD, of the University of Wuerzburg in Germany. “There was a high remission rate in all patient subgroups, including those with prior allogeneic stem cell transplant and multiple relapses,” Dr. Topp said. Fully reversible central nervous system events continued on page 10

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PAGE 10

2012 ASCO Annual Meeting Lymphocytic Leukemias continued from page 9

leading to treatment interruptions were observed in six patients, including three with seizures and three with encephalopathy; all six patients continued treatment at a lower dose.

The drug has very high single-agent activity, likely the highest activity of a single agent in the ALL refractory setting.

Inotuzumab Ozogamycin Other investigators reported encouraging results with inotuzumab ozogamycin, an anti-CD22 monoclonal antibody conjugated to calecheamicin. In a modified weekly treatment schedule, inotuzumab (1.8 mg/m2 every 3–4 weeks) was associated with a 52% overall response rate in patients with relapsed/refractory ALL.5 Median overall survival was 7 months. Most drug side effects, including

— Elias Jabbour, MD

liver function abnormalities, were grade 1 or 2 and reversible. Of 27 evaluable patients, 8 underwent allogeneic stem cell transplant after inotuzumab, and none of these patients developed veno-occlusive disease. “The drug has very high single-

Novel Agents for Chronic/Acute Lymphocytic Leukemia ■■ In a phase II study of previously untreated patients with chronic

lymphocytic leukemia (CLL), daily dosing with the oral Bruton’s tyrosine kinase inhibitor ibrutinib was associated with a 75% response rate and a 96% rate of progression-free survival at 15 months.

■■ Ibrutinib plus ofatumumab produced a 100% response rate in patients

with relapsed/refractory CLL; at 6.5 months follow-up, only two patients had disease progression.

■■ In a phase II study of relapsed/refractory acute lymphocytic leukemia

(ALL) patients, the anti-CD19 antibody blinatumomab produced hematologic responses in 72%, and a median duration of response of almost 9 months.

■■ The anti-CD22–calecheamicin conjugate inotuzumab ozogamycin produced a 52% response rate in relapsed/refractory ALL.

Role of PSA continued from page 1

distant metastases had regressed or disappeared. Naturally, people wanted to know why freezing of the primary prostatic cancer was destroying distant metastasis. In concert with cryosurgical studies in laboratory animals that developed an immune response to antigens (proteins) of the frozen tissue, I hypothesized that in patients with prostate cancer who had a remission of their metastases, the frozen-tissue destruction might have liberated a prostate cancer–specific antigen (or antigens) that was in turn responsible for the cryoimmunotherapeutic effect. Therefore, I initiated a series of immunologic studies of normal, benign, and malignant human prostatic tissues to ascertain whether a tumor-specific antigen was at work. I couldn’t find one—we are still looking—but I did discover a prostate tissue/organ–specific antigen, ergo, PSA, which was present in

normal, benign, and malignant tissue. Following these striking immune responses to freezing (for which I coined the term “cryoimmunotherapy”) and the identification of PSA, I took a cursory look at the possible clinical relevance of the tissue-spec-

agent activity, likely the highest activity of a single agent in the ALL refractory setting,” commented Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center, Houston. He noted that plans for further research include a pivotal trial of weekly inotuzumab vs standard of care in relapsed/refractory ALL and an ongoing study of inotuzumab combined with low-intensity chemotherapy in older patients (> 60 years) with the disease.

■

Disclosure: Dr. Hillman has served in a consulting or advisory role for Celgene, Gilead Sciences, Pharmacyclics, and Roche, has received honoraria from Celgene, Genzyme, GlaxoSmithKline, and Roche, and has received research funding from Genzyme, GlaxoSmithKline, and Roche. Dr. Byrd has received research funding from Pharmacyclics. Dr. Jaglowski reported no potential conflicts of interest. Dr. Topp has served in a consulting or advisory role for Micromet. Dr. Jabbour has served in a consulting or advisory role for Pfizer.

reduced or absent related to the treatment. In patients who had a clinical recurrence of disease, the previously reduced or absent area was increased. This empirically suggested that PSA could possibly be used, following further studies, for prognosis. I dropped this line

Prostate cancer is an age-related cancer. If a group of asymptomatic men between the ages of 60 to 69 years undergo a prostatic biopsy, more than 65% of them would have prostate cancer. — Richard J. Ablin, PhD, DSc (Hon)

ificity of PSA. For this purpose and by way of example, I electrophoretically analyzed serum specimens from patients with prostate cancer prior to and following treatment. I observed an elevated area based on the electrophoretic mobility of PSA in the pretreatment specimens, which was markedly

of inquiry, which perhaps in hindsight was not the best choice, as I wanted to continue my investigations for a possible prostate cancer–specific antigen.

‘Four Cruxes’ In several prominent editorials you argue uneaquivocally that population

References 1. Byrd JC, Furman RR, Coutre SE, et al: The Bruton’s tyrosine kinase inhibitor PCI-32765 in treatment-naive chronic lymphocytic leukemia patients: Interim results of a phase Ib/II study. 2012 ASCO Annual Meeting. Abstract 6507. Presented June 4, 2012. 2. O’Brien S, Burger JA, Blum KA, et al: The Bruton’s tyrosine kinase inhibitor PCI-32765 induces durable responses in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Follow-up of a phase Ib/II study. 53rd American Society of Hematology Annual Meeting. Abstract 983. Presented December 13, 2011. 3. Jaglowski SM, Jones JA, Flynn JM, et al: A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and related diseases. 2012 ASCO Annual Meeting. Abstract 6508. Presented June 4, 2012. 4. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012. 5. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamycin, a CD22 monoclonal antibody conjugated to calecheamicin, given weekly, for refractory-relapse acute lymphocytic leukemia. 2012 ASCO Annual Meeting. Abstract 6501. Presented June 4, 2012.

screening for prostate cancer is bad public health policy. Please explain why. Because PSA cannot diagnose prostate cancer. To that end, I’ve shaped my reasoning into what I call the “four cruxes.” First, PSA, the protein I identified in 1970, is prostate-specific, not cancer-specific. It is present in the normal, the benign, and the malignant prostate and can be elevated by numerous benign factors. Second, there is no dichotomy in the level of PSA as a diagnostic tool for prostate cancer. In other words, a man can have a PSA of 0.5 ng/mL and have prostate cancer, while another man can have a PSA of 11 ng/mL and not have cancer. Third, the PSA test cannot distinguish an indolent cancer from an aggressive cancer. Prostate cancer is akin to a “turtle” and a “rabbit” in an open box. The turtle is the indolent, nonaggressive cancer; it wanders around inside the box and goes nowhere. The continued on page 18

Stimulating Possibilities

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

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

STIMULATES

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

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

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

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

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

The ASCO Post | AUGUST 15, 2012

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2012 MASCC/ISOO International Symposium Supportive Care Research Runs the Gamut from Genetic Markers of Treatment Side Effects to Neuropathic Pain Therapies By Alice Goodman

ttendees from around the world gathered for the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held June 28–30 in New York. Below are highlights from the meeting, representing progress in some areas and the need for further advances in others.

Genomics in Predicting Treatment Side Effects Using a Bayesian method to analyze the millions of single nucleotide polymorphisms (SNPs) from an individual patient with cancer can reliably identify a cluster or network of such variations that predict treatment-related side effects, according to a presentation by Stephen Sonis, MD, Brigham and Women’s Hospital, Boston. Citing data from two unpublished studies using this method, Dr. Sonis showed that the accuracy of this approach was greater than 95%. “We believe this [method] will be a game changer and will let us prospectively evaluate and understand who is at risk for side effects from cancer therapy. This can have a major impact on how we address side effects and how we optimize outcomes for our patients,” he stated. Dr. Sonis commented that the ability to preselect which patients are at risk for specific side effects can save money by optimizing resources and also will enable smaller, faster clinical trials. Single nucleotide polymorphisms are the most common variation in the genome, he explained. There are about 25,000 genes, but over 10�� million single nucleotide polymorphisms. “Unlike genes, [single nucleotide polymorphisms] may or may not be associated with function. This means we are not restricted to looking at genes only involved in coding,” he said.

Old vs New Paradigm “The old paradigm [ie, using a single gene to find an association] was a bit arrogant in that it presumed that we already knew what we were looking for. Findings using the new paradigm are more robust and much more likely to be valid,” Dr. Sonis stated. The

Bayesian method analyzes 1 to 2�� mil�� lion individual single nucleotide polymorphisms and their interactions to pick “team players.” This type of analysis does not predetermine the number of “players,” he explained. A retrospective study at DanaFarber Cancer Institute used Bayesian networks to identify 82 single nucleotide polymorphisms that could predict which patients would develop mucositis with an accuracy of 99.3%. The investigators examined charts of myeloma and lymphoma patients slated for transplant from 2006 to 2001, identified 153 subjects, and classified them as oral mucositis (OM)–negative (102 patients) or OM–positive

At the MASCC/ISOO meeting, Dr. Sonis shared preliminary data from the OnPART development study—data that were generated the day before his presentation. In a subset of patients with breast cancer (N = 30) treated with dose-dense doxorubicin/cyclophosphamide plus paclitaxel (Taxol), the side effects were as follows: nausea/vomiting, 42%; oral mucositis, 38%; diarrhea, 23%; fatigue, 58%; cognitive dysfunction, 23%; and peripheral neuropathy, 16%. In this preliminary analysis, the Bayesian network predicted which patients would develop chemotherapy-induced diarrhea with an accuracy of 96.7%.

Several new well-designed studies published since the last update allowed panel members to develop evidencebased informed guidelines, which will hopefully improve clinical practice. — Rachel Gibson, PhD

published on or before December 20, 2010. A total of 146 papers were included in the final analysis. For prevention of chemotherapyand radiation-induced diarrhea in patients with pelvic malignancies, use of Lactobacilllus spp–containing probiotics was deemed a “suggested guideline” based on overwhelmingly positive evidence. Amifostine was suggested to reduce chemotherapyand radiation-induced esophagitis in patients with NSCLC. For patients undergoing standarddose radiation therapy, the panel recommended against using mesalamine or olsalazine (Dipentum) for prevention of GI mucositis. Because of conflicting data, the panel was not able to strongly recommend or suggest that circadian rhythm (ie, giving radiation in the morning vs evening) could protect patients from radiation-induced GI mucositis or grade 3/4 diarrhea. The evidence to date suggested that giving radiation in the evening could reduce mucositis and grade 3 or 4 diarrhea, but this was based on only one trial.

Recommendations (51 patients), with positivity defined as 2 consecutive days of WHO grade > 2 OM. After extracting DNA from patient saliva specimens, the researchers were able to identify 82 SNPs that predicted the OM-positive patients with a high degree of accuracy.

Ongoing Study The Oncology Preferences and Risk of Toxicity (OnPART™) development study, currently being conducted at the West Clinic in Memphis, seeks to determine whether this method is applicable in a broader range of sold tumors and patients receiving other treatments. The tumors being studied include breast cancer, colorectal cancer, ovarian cancer, and non–small cell lung cancer (NSCLC, in patients treated with at least three cycles of chemotherapy. The chemotherapy-related side effects that are being analyzed include nausea/vomiting, mucositis, fatigue, diarrhea, peripheral neuropathy, and cognitive dysfunction. These were classified as none or mild vs moderate to severe.

“These findings are remarkably consistent with the first study at Dana-Farber in transplant patients with myeloma,” Dr. Sonis stated.

Updated Guidelines for GI Mucositis MASCC’s updated guidelines for management of gastrointestinal (GI) mucositis incorporated new evidence that led to few changes from the version issued in 2007. “Regimen-related mucosal injury is a clinical and economic challenge to oncology practice. It is important to continue to update the clinical guidelines for the prevention and treatment of GI mucositis. Several new well designed studies published since the last update allowed panel members to develop evidence-based informed guidelines, which will hopefully improve clinical practice,” explained Rachel Gibson, PhD, University of Adelaide, Australia. A team of experts from Australia, The Netherlands, and the United States reviewed 1,536 relevant papers

The panel recommended that intravenous amifostine be given prior to radiotherapy to prevent radiationinduced proctitis and recommended against use of misoprostol suppositories and oral sucralfate for prevention of radiation-induced side effects. However, sucralfate enemas were suggested for management of chronic radiation-induced proctitis in patients with rectal bleeding. Oral sulfasalazine at 500 mg three times daily was suggested for reducing the incidence and severity of radiation-induced enteropathy in patients receiving external-beam radiation to the pelvis. Hyperbaric oxygen was suggested as a potentially effective treatment for proctitis and GI mucositis in patients undergoing radiation, but the cost may be prohibitive, Dr. Gibson commented. Octreotide was recommended at a subcutaneous dose of at least 100 mg three times daily for treatment of diarrhea uncontrolled by loperamide in patients on standard- and high-dose

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2012 MASCC/ISOO International Symposium chemotherapy for stem cell transplant.

Cardiotoxicity of Molecularly Targeted Agents vs Anthracyclines Molecularly targeted agents are associated with less risk of cardiotoxocity than anthracyclines. Cardiac damage occurring with molecularly targeted agents is caused by cellular dysfunction and is usually reversible, whereas anthracycline-induced cardiac damage is caused by cell death and is irreversible, explained Michael S. Ewer, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Michael S. Ewer, MD

The risk of cardiac dysfunction with either molecularly targeted agents or anthracyclines is related to prior damage. Risk factors for cardiac injury include prior chemotherapy and prior radiation, and include “anything that has previously damaged the heart, makes it more susceptible to ongoing damage, or leads to vascular or ischemic injury,” he stated. Patients on molecularly targeted therapy need cardiac monitoring, but extensive monitoring and aggressive treatment of left-ventricular ejection fraction may not be necessary as it is in the case of anthracyclines, Dr. Ewer continued. “Many patients [who develop decreased left-ventricular ejection fraction and incipient heart failure] can be treated with standard heart failure drugs, given a rest from targeted therapy, and then have the targeted agent restarted safely,” he stated. Other targeted therapies such as bevacizumab (Avastin), sunitinib (Sutent), and imatinib (Gleevec) can cause hypertension, fluid retention, and thromboembolic phenomenon. In the case of trastuzumab (Herceptin), studies involving more than 10,000 patients with breast cancer treated with adjuvant trastuzumab therapy found that the risk of heart failure and decline in left-ventricular ejection fraction was increased, but

only two cardiac deaths were reported, Dr. Ewer said. The risk of cardiac toxicity is increased when anthracyclines are given together with trastuzumab. Timing is important, and separating the administration of these agents reduces the cardiac effects, he advised. Sunitinib increases the risk of hypertension in clinical trials, yet hypertension is associated with longer survival. Both symptomatic and asymptomatic changes in left-ventricular ejection fraction are seen more frequently on sunitinib and then plateau over time. “This suggests that sunitinib does not destroy myocytes,” Dr. Ewer stated. Many patients who develop hypertension on sunitinib can continue to receive the drug if they are treated with blood pressure–lowering medications. The incidence of cardiovascular death is low on sunitinib, he noted. Bevacizumab also causes hypertension, which should be managed aggressively. If malignant hypertension develops, bevacizumab should be withdrawn. Lapatinib (Tykerb) may cause a decrease in left-ventricular ejection fraction as well, but from the cardiac standpoint the drug is generally safe, and long-term use and use in combinations is feasible, Dr. Ewer said.

Few Effective Interventions for Cachexia The presence of cachexia is strongly prognostic, but there are currently no good treatments for the syndrome. Many studies have shown that feeding patients is of no benefit, and appetite stimulants are only minimally helpful. It is important to educate patients and their families about this cancer-associated disorder.

tients who lose greater than 5% from premorbid weight have a worse prognosis. The predominant loss in patients with cancer is of muscle mass, she continued. Weight loss and cachexia can occur with standard chemotherapy and with targeted agents. Neither parenteral nor enteral nutrition are helpful for cachexia in patients with refractory cancers. “These forms of nutrition should be used only in patients where there is a potential for cure. They are not helpful in patients with refractory cancers,” noted Dr. Jatoi. “The general consensus is that routine use of total parenteral nutrition should be discouraged in patients undergoing chemotherapy, and a recent meta-analysis found that enteral nutrition had no advantage,” she said. “Feeding is not the way to manage patients with incurable refractory cancers,” she continued. “Education is the most important thing we can do for our patients. Cancer is the driving process, and an evolving literature shows that this syndrome can cause family strife and grief. Having a long discussion about the syndrome and its causes with the patient and family is very important.” Appetite stimulants such as megesterol acetate or corticosteroids may improve appetite, but have no survival benefit and do not improve quality of life. “Only about 20% to 30% of patients will have some improvement in appetite with megesterol acetate independent of a placebo effect,” Dr. Jatoi explained. “The bottom line is that we need better interventions to help patients with this syndrome,” she stated. Agents being studied in clinical trials for treatment of cancer-associated weight loss include selective androgen receptor modulators, antimyostatin agents, and JAK inhibitors. She cautioned that when interpreting clinical trials, one should consider dropouts and the placebo effect. “Beware of basing clinical practice on preliminary phase I or II studies,” she said.

Treatment of Neuropathic Pain: Work in Progress Aminah Jatoi, MD

“Cachexia is not starvation. It is weight loss and anorexia in the setting of incurable cancer,” said Aminah Jatoi, MD, Mayo Clinic, Rochester, Minnesota. It is well known that patients with good appetites live longer, and that pa-

“Virtually all the treatments we use to treat neuropathic pain are off-label,” said Charles Loprinzi, MD, Mayo Clinic. “There is a glimmer of hope that new treatments, such as Scrambler Therapy and menthol, may prove helpful.” The antidepressants duloxetine (Cymbalta) and venlafaxine—both

Charles Loprinzi, MD

serotonin norepinpehrine reuptake inhibitors—are sometimes used to treat chemotherapy-induced peripheral neuropathy. At this year’s ASCO Annual Meeting, a randomized trial showed that about one-third of patients with chemotherapy-induced peripheral neuropathy due to oxaliplatin or taxanes had clinically meaningful pain relief with duloxetine.6 While not universally effective, this is an important finding, Dr. Loprinzi noted. Fewer side effects were seen with duloxetine than previously reported, and Dr. Loprinzi attributed this to starting at a lower dose than on the package insert. He noted that venlafaxine should also be started at a lower dose. Reports and anecdotal experience suggest that venlafaxine decreases neuropathic pain. “Small studies suggest that there is some effect with venlafaxine given prior to chemotherapy,” he noted. “Both duloxetine and venlafaxine appear to have some effect on [chemotherapy-induced peripheral neuropathy], but nearly as great an effect as we would like,” he stated. More work is needed to further substantiate this apparent benefit. A small placebo-controlled study by Debra Barton, PhD, AOCN, FAAN, RN, and others supported the use of topical baclofen/amitriptyline/ ketamine to improve some aspects of chemotherapy-induced peripheral neuropathy, but not others.7 That study used a lower dose of this topical treatment than the investigators wanted to use, and Dr. Loprinzi said that the topical preparation should be studied at a higher dose. Another small study from China reported, in abstract format at the 2012 ASCO Annual Meeting, that acetylL-carnitine may improve peripheral neuropathy symptoms, but another abstract at the same meeting reported that this same agent increased taxane neuropathy. “The bottom line is that continued on page 17

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

APPROVED FOR SUBCUTANEOUS ADMINISTRATION*

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

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

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

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

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

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

Living Proof

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

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

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

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2012 MASCC/ISOO International Symposium Supportive Care Research continued from page 13

the jury is still out on acetyl-L-carnitine,” he said. Scrambler Therapy—a proprietary technique developed by Competitive Technologies, Inc—is an innovative form of percutaneous electrical stimulation applied to painful areas of the body that was developed for neuropathic pain.8 The technique is different from traditional transcutaneous electrical nerve stimulation (TENS), which works primarily with musculoskeletal pain, Dr. Loprinzi said. “At first I was skeptical, but we have obtained a machine, and our early experience at Mayo is positive,” he stated.

Although gabapentin and pregabalin are commonly used to treat chemotherapy-induced peripheral neuropathy, there has been no published evidence of any benefit. A small phase II trial found that topical menthol may be helpful in patients with severe chemotherapyinduced peripheral neuropathy. “This is an exciting new area, and there may be something effective here,” he said. Future studies are planned.

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Disclosure: Dr. Sonis is a founder of InformGenomics, the study’s sponsor. Drs. Gibson and Ewer reported no potential conflicts of interest. Dr. Loprinzi disclosed that Competitive Technologies provided a Scrambler machine to the Mayo Clinic for clinical studies.

References 1. Sonis S: Molecular predictors in supportive care. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 30, 2012. 2. Gibson R: Updated clinical practice guidelines for GI mucositis. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 29, 2012. 3. Ewer M: Cardiac issues and targeted agents. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 29, 2012. 4. Jatoi A: Cachexia. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 30, 2012. 5. Loprinzi C: Treatment of established chemotherapy neuropathy: Completed and ongoing studies. MASCC/ISOO Interna-

tional Symposium on Supportive Care in Cancer. Presented June 30, 2012. 6. Smith EM, Pang H, Cirrincione C, et al: CALGB 170601: A phase III doubleblind trial of duloxetine to treat chemotherapy-induced peripheral neuropathy. 2012 ASCO Annual Meeting. Abstract CRA9013. Presented June 5, 2012. 7. Barton D: A double-blind, placebocontrolled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 19:833-841, 2011. 8. Pachman DR, Linquist BM, Barton DL, et al: Pilot study of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy. 2012 ASCO Annual Meeting. Abstract 9075. Presented June 2, 2012.

‘Young and Strong’ Program Addresses Multiple Needs of Women in 40s and Younger Diagnosed with Breast Cancer By Charlotte Bath

“Y

oung and Strong” is an exportable model of a program developed at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston to address the significant challenges facing young women with breast cancer. The new model has been designed to “serve young women with breast cancer who are receiving care outside of the comprehensive cancer setting, particularly in places where resources are limited,” according to an article by the program’s designers and leaders in the Journal of Oncology Practice.1 Founded in 2005, the Program for Young Women With Breast Cancer “helps patients and providers to address issues that are more common among young women with breast cancer, including concerns about fertility and reproductive options, genetics, psychosocial matters, and other treatment and survivorship issues,” the authors noted. Over the years, the program has served more than 1,600 women aged 42 and younger in clinics and hundreds more through See Page 86 patient education

woman to access optimal comprehensive care in an environment that provides extra support, enhanced medical services (eg, easily available genetics and fertility preservation consultations), and education,” the authors stated.

Exportable Version Ann H. Partridge, MD, MPH

and support programs. Comprehensive Program “To our knowledge, this is the first such comprehensive program developed to target the multiple and complex issues associated with a breast cancer diagnosis in young women,” the authors wrote. The lead author, Ann H. Partridge, MD, MPH, serves as the program’s Director, and the multidisciplinary advisory group is composed of patient advocates; providers from medical oncology, breast surgery, radiation oncology, nursing, and social work; and translational, psychosocial, and population-based investigators. “From a clinical perspective, the program serves as an umbrella for all young patients with breast cancer and their providers, helping each

The new exportable version, which was being pilot tested when the article was being written, will “provide Web- and print-based materials to patients and the oncologists who care for them,” the authors explained. After diagnosis, patients receive a booklet addressing the unique issues facing young women with breast cancer and access to a comprehensive website that offers additional information, videos, questions to ask their doctors, and a list of resources. “Clinicians are provided baseline and follow-up care checklists and disease management algorithms; written clinical care descriptions; and video presentations on fertility, early menopause, pregnancy after breast cancer, psychosocial concerns (eg, coping with anxiety, dating, and dealing with young children), ge-

netic factors, body image, and sexual functioning,” the authors continued. “Our intervention materials incorporate information about these issues and how to help manage them, as well as how improved doctor-patient communication may promote better quality of care. A dedicated e-mail address is included so that oncologists who focus on the care of young women with breast cancer at our center can respond on a daily basis to case queries, requests for additional support, and questions about the latest data regarding the care of this population. By targeting both the patient and provider, we hope to optimize the care of young women with breast cancer.”

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Disclosure: This effort has been supported by an Improving Cancer Care Grant from ASCO, funded by Susan G. Komen for the Cure. Program staff members also work closely with the Survivorship Program and the Lance Armstrong Foundation Center of Excellence at DanaFarber Cancer Institute.

Reference 1. Partridge AH, Ruddy KJ, Kennedy J, et al: Model program to improve care for a unique cancer population: Young women with breast cancer. J Oncol Practice, May 22, 2012 (early release online).

The ASCO Post | AUGUST 15, 2012

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Expert’s Corner

Role of PSA continued from page 10

rabbit is the aggressive cancer; it hops around and might even jump out of the box at anytime and metastasize. We can’t tell the difference between the turtle and the rabbit. And fourth, prostate cancer is an agerelated cancer. If a group of asymptomatic men between the ages of 60 to 69 years undergo a prostatic biopsy, more than 65% of them would have prostate cancer. Therefore, a PSA-prompted biopsy may or may not, related to the individual’s age, find cancer. However, unable to determine among these men which are the turtles and which are the rabbits, results in a huge amount of unnecessary procedures and possibly associated morbidities. Again, the central problem is that we can’t differentiate between indolent and aggressive cancers of the prostate. It’s like flipping a coin.

Mass Screening Origins How did your discovery make the leap from a couple of papers to a mass screening juggernaut? Nine years after my identification of PSA in 1970, some other researchers rediscovered my work and subsequently developed what we know as the PSA test. FDA approved the PSA test in 1986, as a prognostic assay to monitor patients with prostate cancer following treatment, ie, as a “harbinger” for the recurrence of disease. Even though it was not approved for screening asymptomatic men, the impetus of a noninvasive test—albeit not cancer-specific—in concert with the uncertainties of a digital rectal exam (DRE) prompted the urologic community to begin using PSA as a screening tool. Then in 1987, Thomas Stamey, MD, and colleagues wrote a New England Journal of Medicine paper extolling the benefits of PSA screening,2 setting off a medical tsunami. For instance, from 1986 to 1991, there was an 82% increase in the diagnosis of prostate cancer. From 1989 to 1992, radical prostatectomies almost tripled, soaring from

Visit

78 men per 100,000 to 206 per 100,000, in a few years. In the same period, radical prostatectomies for men over 75 years of age doubled, going from 44 men per 100,000 to 89 per 100,000. We now have 30 million American men per year undergoing routine PSA screening, leading to mountains of unnecessary biopsies and treatments. Truth be told, 15 years after his influential publication Dr. Stamey recanted his original position, indicating it was predominantly benign prostatic hypertrophy (BPH) that was associated with an increased PSA. In reference to conducting radical prostatectomies, he commented, “We originally thought we were doing the right thing.”

FDA’s Role When did FDA approval change from prognostic to diagnostic? In 1994, FDA compounded the problem by approving PSA testing in

we doubled the incidence of this disease, but the mortality rate has had a minute uptick. I’m not suggesting that prostate cancer should be ignored; it’s a deadly disease that kills about 30�� thousand American men a year. The problem is that this test is being hyped in the media as a tool to detect cancer, which it isn’t. Prostate cancer–surviving celebrities tour the country chanting, “get screened, get treated, and get cured.” Unfortunately, it’s not that neat a package.

Risk Stratification What about PSA as a risk-stratification tool? It’s an excellent approach if it’s handled correctly. However, given the inherent flaws of the test, you would need to do population screening to identify men with “elevated” PSA levels who could possibly be stratified into various risk categories. But, with the heteroge-

A decrease in mortality—and particularly prostate cancer–specific mortality—is a good thing, but don’t jump to the conclusion that it’s the result of PSA testing. — Richard J. Ablin, PhD, DSc (Hon)

conjunction with DRE as a diagnostic method for prostate cancer, in spite of having knowledge of three of the four “cruxes” I mentioned earlier. The FDA also never considered the risks vs benefits equation in PSA screening. Consequently, more than 1�� million American men have been overdiagnosed and overtreated. For example, in 1985, prior to PSA testing, the risk of a man developing prostate cancer during his lifetime was about 8.5 %; mortality was 2.5 %. Fastforward to the latest data in 2005—the 8.5% incidence ballooned to 18%, but the mortality only increased to 3%. So

neous nature of prostate cancer and no dichotomy in the level of PSA, what is an “elevated” level? Once you establish baseline PSA levels, you could follow them in intervals of 6 months to a year. This is particularly applicable to men with a family history of prostate cancer. However, for that approach to work, the medical community would need to reshape its biopsy-treatment profitdriven model and recognize that the test is also detecting abnormalities such as prostatitis and BPH. Then, using serial PSA follow-ups in concert with other diagnostic tests could possibly produce health benefits.

Declining Mortality What about the argument of decreasing mortality? A decrease in mortality—and particularly prostate cancer–specific mortality—is a good thing, but don’t jump to the conclusion that it’s the result of PSA testing. In looking, for example, at the impact of PSA screening in Seattle and Connecticut over 15 years, where the intensity of screening and treatment was higher in Seattle, the prostate cancer–specific mortality was virtually identical. There are more examples like that. Improvement in surgical techniques and treatment modalities along with healthier patients with increased life expectancies have had an impact on survival; it’s just harder to quantify those factors. In fact, recent data show a decrease in mortality in most cancers, save for a few.

Closing Thoughts Any last words on PSA? Ancient alchemists attempted to turn common metals into gold and silver—thus far, it has not been possible. PSA was developed as a prognostic marker to follow a man with prostate cancer and perhaps help tailor his future treatments, not as a diagnostic tool in asymptomatic men. The manner in which the PSA test has been employed for screening doesn’t work, and to use it that way on such a mass scale is nothing short of criminal— lest we forget the dictum Primum non nocere: “First, do no harm.”

Disclosure: Dr. Albin potential conflicts of interest.

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reported

Reference 1. U.S. Preventive Services Task Force: Screening for prostate cancer: Current recommendation. May 2012. Available at www.uspreventiveservicestaskforce.org/ prostatecancerscreening.htm. Accessed June 18, 2012. 2. Stamey TA, Yang N, Hay AR, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987.

website at ASCOPost.com

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS.

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib

Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7

months (95% CI: 6.3, 8.6) [43% longer median PFS]

0.8 0.7

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.4, 3.0) All responses were partial responses per RECIST criteria INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3, in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

0.6 0.5 0.4 0.3

sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers. The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST. Please see brief summary on the following pages.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. 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 is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU471611

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. 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. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, 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 INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

June 2012

ASCOPost.com | AUGUST 15, 2012

PAGE 21

Expert’s Corner

Differentiated Thyroid Cancer: Who, When, and How to Treat? A Conversation with Manisha H. Shah, MD By Caroline Helwick dolent and highly curable, when it recurs, the therapeutic plan is not always straightforward. The ASCO Post asked thyroid cancer specialist Manisha H. Shah, MD, Associate Professor of Internal Medicine at The Ohio State University Comprehensive Cancer Center, Columbus, for guidance.

Primary Concerns and Standard Treatment Manisha H. Shah, MD

ifferentiated thyroid cancer—papillary, follicular, and H�� ü�� rthle cell carcinomas—has historically been managed by endocrinologists, surgeons, and radiation oncologists, but recent progress in the field has led to greater involvement by medical oncologists, especially in the care of patients with advanced disease. While differentiated thyroid cancer is typically in-

Since the vast majority of patients with differentiated thyroid cancer can be cured, what are the concerns for oncologists treating these patients? For patients who develop distant metastasis, differentiated thyroid cancer is potentially fatal, with a 5-year disease-specific survival rate of less than 50%. You first establish whether the goal of treatment is curative or palliative. Even lung metastases are potentially curable. The management of these patients can be

complex, and should be multidisciplinary. Medical oncologists should be familiar with all forms of treatment. What is standard treatment for newly diagnosed patients? Upon initial diagnosis, treatment for the majority of patients includes total thyroidectomy, thyroid-stimulating hormone (TSH) suppression, and radioactive iodine. For high-risk patients, you can consider externalbeam radiation therapy to the neck. In the adjuvant setting, there is no role for cytotoxic chemotherapy or tyrosine kinase inhibitors.

Recurrence and Metastases When patients develop recurrence, what is your first consideration? Not all patients with differentiated thyroid cancer need treatment upon the diagnosis of metastatic disease. The oncologist should determine the

need to initiate treatment based on an assessment of clinical symptoms, tumor histology, radioiodine avidity status, and disease staging with serum thyroglobulin and thyroglobulin antibody, TSH, CT of the neck and chest (with or without CT of the abdomen/ pelvis and head), or PET scans. Treatment may be warranted at diagnosis in the presence of symptoms or aggressive histology, such as tall-cell, insular variant, or poorly differentiated papillary carcinoma. We offer treatment (surgery or radioactive iodine but never a tyrosine kinase inhibitor) for patients with metastatic differentiated thyroid cancer who are radioiodine-avid and asymptomatic but have rising serum thyroglobulin or a positive wholebody iodine scan. In other cases, we watch and wait, with staging studies done every 3 to 6 months, for patients who are radioiodine-refractory and continued on page 22

Molecularly Targeted Treatment of Thyroid Cancer Rapidly Evolving By Caroline Helwick

ecent advances in understanding the pathogenesis and altered signaling pathways in thyroid cancer are improving treatment options for this malignancy, especially for the subset of patients with medullary thyroid cancer and those with differentiated thyroid cancer that has metastasized, according to Keith Bible, MD, PhD, of the Mayo Clinic, Rochester, Minnesota. Dr. Bible discussed these molecular targets at an educational session at the 2012 ASCO Annual Meeting. Keith Bible, MD, PhD “There are numerous potential molecular targets in thyroid cancer, and for most of them, we have the means of pharmacologic inhibition. We are entering a whole new realm of thyroid cancer treatment,” Dr. Bible said. The tyrosine kinase inhibitor vandetanib (Caprelsa) was approved in 2011 for advanced, progressive medullary thyroid cancer, whose activating RET mutations can be inhibited by vandetanib. At this year’s ASCO meeting, the EXAM trial of cabozantinib also met its primary endpoint as a medullary thyroid cancer treatment option, showing median progression-free survival to be 11.2 months with cabozantinib vs 4.0 months with placebo.1 A new drug application under the FDA’s fast track designation has been submitted for the drug, which was granted orphan drug status in January 2011.

Key Molecular Target The fact that RET is also upregulated in some differentiated thyroid cancers triggered interest in evaluating tyrosine kinase inhibitors in this cancer as well, with the discovery that tyrosine kinase inhibitors are also highly active in this setting, particularly those targeting the vascular endothelial growth factor receptor (VEGF-R).

“VEGF-R, in particular, has emerged as apparently the most important therapeutic molecular target in [differentiated thyroid cancer],” he noted. “Fortuitously, sunitinib [Sutent], sorafenib [Nexavar], pazopanib [Votrient], and axitinib [Inlyta] all target VEGF-R, and all also have clinical activity in [differentiated thyroid cancer].” In a phase II trial of pazopanib led by Dr. Bible, 18 of 37 patients had confirmed partial responses (49%), “and these responses were remarkably durable, most lasting more than a year,” he said.2 Responses were more frequent and more durable in follicular vs papillary subtypes. “Perhaps histologic differences in mutation carriers can help us individualize therapy with these agents,” he suggested, adding that pharmacogenomics and pharmacokinetics may someday further refine patient selection. The role of BRAF mutations in papillary thyroid cancer is also of interest, since mutant BRAF is associated with resistance to anti-VEGF therapies. “This gives us a hint that perhaps we can begin to individualize therapy based on mutational status linking to histology,” he said. Unfortunately, tyrosine kinase inhibitors have been disappointing in the highly aggressive anaplastic thyroid cancer.

■

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

References 1. Schoffski P, Elisei R, Müller S, et al: An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib in medullary thyroid carcinoma patients with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012. 2. Bible KC, Suman VJ, Molina JR, et al: Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol 11:962-972, 2010.

The ASCO Post | AUGUST 15, 2012

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Expert’s Corner

Thyroid Cancer continued from page 21

asymptomatic with a stable or slowly progressing tumor or minor tumor burden, or who have favorable histology or genotype. We offer a tyrosine kinase inhibitor or clinical trial protocol to radioiodine-refractory patients who are symptomatic or have any of the following indications: bulky tumor burden, moderate-to-rapid progression of disease, disease in an unsafe location, or unfavorable histology or genotype. We do not base treatment with a tyrosine kinase inhibitor simply on a rising thyroglobulin, even in the setting of established measurable disease. Once you decide to treat metastatic disease, how do you proceed? Patients can receive the same treatment as for initial disease (surgery, levothyroxine, radioiodine). If the patient has radioiodine-refractory disease, you can consider palliative surgery and/or local radiotherapy. Again, there is no role for cytotoxic chemotherapy, but depending upon resectability and risk related to radiation, you could consider a clinical trial protocol or a tyrosine kinase inhibitor.

the potential for side effects, including atrial fibrillation and osteoporosis. Lifetime replacement therapy is necessary, not only because we have removed the thyroid gland but also because levothyroxine suppresses the growth of cancer.

Radioiodine Treatment Considerations What is the optimal use of radioiodine therapy? Radioactive iodine can be used in the adjuvant or metastatic setting, but the majority of patients receive it as adjuvant treatment after thyroidectomy. In the metastatic setting, radioiodine is often given to patients with rising serum thyroglobulin levels (velocity, or absolute increase > 10 ng/ mL) or evidence of iodine-avid evaluable metastases, but the selection of patients for radioiodine is not always clear. Some clinicians advocate treat-

thyroglobulin response or objective response to radioiodine treatment, and receipt of a cumulative radioiodine dose > 600 mCi. Because of the inverse relationship between FDGPET avidity and radioiodine uptake, some clinicians consider a positive FDG-PET scan itself as a definition of radioiodine-refractory disease.

Roles of Surgery and Radiation Is there a role for surgery in metastatic disease? In the setting of metastatic disease, we can treat the primary and metastatic tumors with surgery, external-beam radiation therapy, or ethanol ablation. Metastatic differentiated thyroid cancer is one of the few solid tumors where resection of the primary tumor is done even in stage IV disease. The goals of total thyroidectomy are to prevent local complications, facilitate monitoring (al-

There is no role for cytotoxic chemotherapy in metastatic disease, but depending upon resectability and risk related to radiation, you could consider a clinical trial protocol or a tyrosine kinase inhibitor. — Manisha H. Shah, MD

TSH Suppression What is the optimal approach to TSH suppression? TSH suppression with levothyroxine is critical, and oncologists may need help from an expert endocrinologist in terms of maintaining the optimal dose and achieving efficacy. Proper dosing is critical, as is periodic long-term monitoring. For patients with known recurrent differentiated thyroid cancer (vs those treated in the adjuvant setting), the target TSH level is <�� 0.1 �� mU/L. The typical levothyroxine dose necessary to achieve suppression is > 1.6 µg/kg/d. When patients request a higher dose, this should prompt discussion about

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ing most patients with thyroglobulin levels > 10 ng/mL, whereas others support using radioiodine primarily for patients believed to be at high risk for clinically relevant sequellae due to progressive disease. How do you determine whether the patient is refractory to radioactive iodine treatment? The oncologist should confirm that the patient is radioiodine-refractory. It is generally agreed that disease is radioiodine-refractory if there is a negative whole-body iodine scan following radioiodine administration, lack of

low interpretation of thyroglobulin and whole-body iodine scan), and increase the effectiveness of radioiodine. Resection of metastases can be considered for lymph nodes in the neck or mediastinum or for isolated lung or bony lesions. With resection, some of these patients can be cured. Can you elaborate on the role of radiation? Since these are radiosensitive tumors, we can offer external-beam radiotherapy to the thyroid bed and bilateral neck nodes in an adjuvant setting for high-risk patients or for

patients with locoregionally recurrent disease following thyroidectomy and radioiodine. External-beam or stereotactic radiation can also be delivered for spinal cord compression or symptomatic bony lesions, impending fractures, or lytic lesions in the long bones. When treating the high-risk patient with curative intent, the radiation dose is 6,000 to 7,000 cGy over 6 to 7 weeks. This is a toxic regimen, and patients need preparation and counseling, and possibly percutaneous endoscopic gastrostomy (PEG) tubes. In the palliative setting, lower doses—2,000 to 3,000 cGy over 2 to 3 weeks—are well tolerated. If the patient has had prior radiation to the neck, subsequent surgery will be difficult, and this should be kept in mind when considering the use of adjuvant external-beam radiation.

Role of Chemotherapy Is there ever a role for cytotoxic chemotherapy, and where do tyrosine kinase inhibitors fit in? There is no role for cytotoxic chemotherapy in the treatment of radioiodine-refractory thyroid cancer. There are hints, however, that the combination of gemcitabine plus oxaliplatin might be active, based on a 57% response rate shown in a small study.1 Tyrosine kinase inhibitors, on the other hand—especially antiangiogenic agents—have an emerging role [see sidebar, “Molecularly Targeted Treatment of Thyroid Cancer Rapidly Evolving”], but they should be used in selected cases by experienced physicians.

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Disclosure: Dr. Shah has served as a consultant or in an advisory role for Bayer and has received research funding from Daiichi Sankyo, Eisai, and Exelixis.

Reference 1. Spano JP, Vano Y, Vignot S, et al: GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma. Medical Oncology. September 25, 2011 (early release online).

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ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ignite a meaningful response

WARNING - NEUTROPENIA • ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

B:17

T:16.

S:15.3

For metastatic breast cancer patients failing combination chemotherapy or relapsing within 6 months of adjuvant therapy; prior therapy should have included an anthracycline unless clinically contraindicated.

Rely on evidence

from a phase III trial vs an established regimen Inclusion criteria1

ABRAXANE® 260 mg/m2 IV

• Females at least 18 years of age

30-minute infusion q3w (n=233) No standard premedication

• Measurable metastatic breast cancer • ECOG performance status 0 to 2 • No prior taxane therapy for metastatic disease N=460 ECOG=Eastern Cooperative Oncology Group.

RANDOMIZATION Paclitaxel injection 175 mg/m2 IV 3-hour infusion q3w (n=227) Standard steroid premedication required

The ABRAXANE approved indication is the same as that of paclitaxel injection for metastatic breast cancer2 efficacy end point assessed was reconciled target lesion response rate (recTLRR) • The primary efficacy — recTLRR was based on independent radiologic assessment of tumor responses — recTLRR was reconciled with investigator-reported responses and includes only responses achieved in first 6 cycles of therapy the first efficacy end points included overall response rate, time to disease progression, and overall • Secondary efficacy survival, among other measures1

Important Risk Information Important Risk Information WARNING - NEUTROPENIA 3 ABRAXANE should not be baseline neutrophil counts are , oradministered rechallengedif in patients who experience • ABRAXANE should not be if baseline neutrophil than 1500 cells/mm • ABRAXANE therapy should notadministered be administered to patients withcounts are• less 3 , orand rechallenged in patients who experience less than 1500 cells/mm severe hypersensitivity. Dose reduce for moderate or severe hepatic impairment, severe neutropenia, severe sensory neuropathy. ABRAXANE metastatic breast cancer who have baseline neutrophil counts severe hypersensitivity. Dose reduce for moderate or severe hepatic cause fetal harm 3. In order to monitor the occurrence of lesscan than 1,500 cells/mm impairment, severe neutropenia, and severe sensory neuropathy. of bone marrow suppression, primarily neutropenia, which may ABRAXANE can cause fetal harm be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients Please see Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING regarding receiving ABRAXANE. neutropenia, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

7.25”

.75”

375”

Illuminate

a superior tumor response (recTLRR) recTLRR (PRIMARY END POINT) VS PACLITAXEL INJECTION FOR ALL RANDOMIZED PATIENTS IN THE PHASE III TRIAL IN METASTATIC BREAST CANCER

ABRAXANE®

21.5% (50/233) 95% CI: 16.19%-26.73%

n=233

Paclitaxel injection

11.1%

n=227

(25/227) 95% CI: 6.94%-15.09% P=0.003*

100

recTLRR (%)

* From Cochran-Mantel-Haenszel test stratified by first-line vs >first-line therapy.

• Prior therapy included an anthracycline unless clinically contraindicated To learn more about ABRAXANE, contact your local Celgene sales representative or go to www.abraxane.com.

Important Dosing Information • Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment • ABRAXANE contains albumin (human), a derivative of human blood • ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE • Men should be advised to not father a child while receiving ABRAXANE Please see Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING regarding neutropenia, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages.

B:11.625”

• There was no statistically signiﬁ cant difference in overall survival between the 2 study arms significant

S:10”

• recTLRR was the prospectively defi ned, protocol-specifi c end point, based on independent radiologic defined, protocol-specific assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the fi rst 6 cycles of therapy. The recTLRR was lower than the investigator-reported response rates, which are first based on all cycles of therapy

T:11.125”

• ABRAXANE demonstrated superior recTLRR (primary end point) of 21.5% vs 11.1% for paclitaxel injection in all randomized patients (P=0.003)

Visible results

in a challenging patient population recTLRR (PRIMARY END POINT) VS PACLITAXEL INJECTION FOR PATIENTS WHO FAILED COMBINATION CHEMOTHERAPY OR RELAPSED WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY

ABRAXANE®

15.5% (20/129) 95% CI: 9.26%-21.75%

n=129

Paclitaxel injection n=143

8.4% 10

(12/143) 95% CI: 3.85%-12.94%

recTLRR (%)

• ABRAXANE demonstrated recTLRR of 15.5% vs 8.4% for paclitaxel injection in patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy • recTLRR was the prospectively defined, protocol-specific end point, based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. The recTLRR was lower than the investigator-reported response rates, which are based on all cycles of therapy • Prior therapy included an anthracycline unless clinically contraindicated

Patients treated with ABRAXANE received a median of 6 cycles of therapy (range: 1-18)1

Important Risk Information • During postmarketing surveillance, reports of congestive heart failure and left ventricular dysfunction were observed, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • Severe hypersensitivity reactions have also been reported during postmarketing surveillance • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration References: 1. Data on file. Celgene Corporation. 2. Taxol [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company. Rev April 2011.

100

Important Safety Information WARNING - NEUTROPENIA • ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophils counts of < 1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity • In order to monitor the occurrence of myelotoxicity, perform frequent peripheral blood cell counts • Retreat with subsequent cycles of ABRAXANE after neutrophils recover to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more), during a course of ABRAXANE therapy, dose reduce for subsequent courses of therapy Nervous System • Sensory neuropathy occurs frequently with ABRAXANE • The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification • If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate and severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men: • Men should be advised to not father a child while receiving ABRAXANE

ADVERSE REACTIONS - Randomized Metastatic Breast Cancer Study • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported • In the randomized metastatic breast cancer study, the most common adverse events (≥20%) were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%, patients with normal baseline 35%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST (SGOT) elevations (any 39%), alkaline phosphatase elevations (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%). Other adverse events of note include vomiting (any 18%; severe 4%), and mucositis (any 7%; severe <1%). 3% (7 of 229) of patients discontinued the use of ABRAXANE due to sensory neuropathy. • Other adverse events have included ocular/visual disturbances (any 13%; severe 1%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). Dehydration and pyrexia were also reported. Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations • Severe hypersensitivity reactions have also been reported with ABRAXANE • During postmarketing surveillance, reports of congestive heart failure and left ventricular dysfunction were observed, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs like anthracyclines • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS: • No drug interaction studies have been conducted with ABRAXANE • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers: • It is not known whether paclitaxel is excreted in human milk • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric: • The safety and efficacy of ABRAXANE in pediatric patients have not been evaluated Geriatric: • No toxicities occurred notably more frequently among patients ≥ 65 years of age who received ABRAXANE Renal Impairment: • The use of ABRAXANE has not been studied in patients with renal impairment • Patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine > 2 mg/dL DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE

Please see accompanying Brief Summary for ABRAXANE, including Boxed WARNING regarding neutropenia, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages. ABRAXANE® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 07/12 US-ABR120055

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Rx Only

The following is a brief summary; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 2 DOSAGE AND ADMINISTRATION 2.1 General After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE a Levels Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 Moderate < 10 x ULN AND 1.26 to 2.0 x ULN 200 mg/m2 Severe < 10 x ULN 2.01 to 5.0 x ULN 130 mg/m2 b > 10 x ULN OR > 5.0 x ULN not eligible a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. 2.3 Dose Reduction: in Case of Severe Neutropenia or Severe Sensory Neuropathy Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1 and 5.2) and Adverse Reactions (6.1)]. 4 CONTRAINDICATIONS ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, perform frequent peripheral blood cell counts. Retreat with subsequent cycles of ABRAXANE after neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3

for seven days or more) during a course of ABRAXANE therapy, dose reduce for subsequent courses of therapy. [see Dosage and Administration (2.3)]. 5.2 Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.3)]. 5.3 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.4 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.5 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.6 Use in Men Men should be advised not to father a child while receiving ABRAXANE. [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, diarrhea. 6.1 Clinical Trials Experience The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 2: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients Paclitaxel Injection ABRAXANE® 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia 2 3 < 100 x 109/L < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 (continued)

Table 2: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients Paclitaxel Injection ABRAXANE速 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsd 3 <1 Vomiting Any symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection pts received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients.. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported as has autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculo-papular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.3 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. Patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. • Abraxane injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. • Men should be advised not to father a child while receiving Abraxane [see Warnings and Precautions (5.6)]. • Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction. • Patients must be informed that sensory neuropathy occurs frequently with Abraxane and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia,fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. For full Prescribing Information go to www.abraxane.com Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2011 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; and RE41,884 ABRBS.001 02/12

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2012 ASCO Annual Meeting Gastrointestinal Oncology

Striking Activity Shown for Regorafenib in Advanced GIST By Caroline Helwick

egorafenib, an orally administered investigational tyrosine kinase inhibitor that has shown activity in chemorefractory metastatic colorectal cancer, markedly delayed disease progression in patients with treatmentrefractory metastatic gastrointestinal stromal tumor (GIST) in the phase III GRID trial, presented at the ASCO Annual Meeting in Chicago.1

George D. Demetri, MD

“Although imatinib [Gleevec] and sunitinb [Sutent] have revolutionized the management of GIST, drug resistance remains a challenge. GIST that is refractory to tyrosine kinase inhibitors is a life-threatening unmet medical need,” said George D. Demetri, MD, of the Dana-Farber Cancer Institute, Boston, who presented the results.

The Gist of GRID “This randomized international phase III trial showed that regorafenib significantly increases progression-free survival vs placebo in patients with metastatic GIST that is progressing despite prior therapy with at least the only two standard drugs available,” he said. “We feel that regoSee Page 86 rafenib has the potential to fulfill an unmet need for advanced GIST patients and potentially represents a new standard of care for this patient population.” The GRID trial (GIST–Regorafenib

in Progressive Disease) rapidly accrued 236 patients with metastatic or unresectable GIST whose disease progressed after treatment with both imatinib and sunitinib, as well as in nearly half the patients following treatment with other unapproved agents such as other kinase inhibitors. Patients were randomized 2:1 to oral regorafenib at 160 mg/d plus best supportive care for repeating 4-week cycles, given 3 weeks on, 1 week off, or to best supportive care and matching placebo. The placebo group was allowed to cross over to open-label regorafenib upon disease progression, which 85% did. Regorafenib was associated with a median progression-free survival of 4.8 months, compared with 0.9 months with placebo—a 73% reduc< .0001). Disease contion in risk (P �� trol (response or stable disease ≥ 12 weeks) was achieved by 52.6% vs 9.1%, respectively, Dr. Demetri reported. Benefit was observed across all the prespecified subgroups. “It was immaterial whether patients were on thirdline treatment, or fourth, or greater,” he said, “the hazard ratios were quite similar: 0.23 and 0.31, respectively.” Median overall survival has not been reached in either arm. “Because of the crossover design, the lack of statistical significance between study arms in terms of overall survival was not unexpected, since the vast majority of placebo patients rapidly crossed over to receive unblinded regorafenib. Nevertheless, there is a trend for [an overall survival benefit with] regorafenib, with a hazard ratio of 0.77 (P = .199),” he noted.

Further Analysis Interestingly, an exploratory analysis after crossover showed that placebo patients who later received regorafenib had a median progression-free survival of 5 months (by investigator assess-

Regorafenib in GIST ■■ Regorafenib, an oral agent that targets multiple tyrosine kinases,

reduced the risk of disease progression by 73% in patients with metastatic or unresectable gastrointestinal stromal tumors resistant to both imatinib and sunitinib.

■■ Median progression-free survival was 4.8 months with regorafenib,

compared with 0.9 months with best supportive care alone (P < .0001).

■■ Disease control was achieved in 52.6% and 9.1% of patients on the regorafenib and best supportive care arms, respectively.

EXPERT POINT OF VIEW

rant McArthur, MB, BS, PhD, Head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre in Melbourne, Australia, congratulated the investigators on a rapidly accrued, well-conducted, and ethical study that encouraged crossover to the active arm. He noted that regorafenib is an “extremely interesting” inhibitor of a broad range of KIT mutants, showing impressive activity across all gasGrant McArthur, MB, BS, PhD trointestinal stromal tumor (GIST) genotypes. Regorafenib can also inhibit other kinases that may be relevant in the GIST cells themselves and in the microenvironment, “which may be why we are seeing third-line activity,” he proposed. “This was a randomized study against a standard of care,” Dr. McArthur noted, suggesting that it may have been more informative to compare regorafenib to an active treatment, as was done in a recent German trial of thirdline nilotinib (Tasigna).1 In the control arm of that study, patients could receive (continue on, or switch to) sunitinib (Sutent) or imatinib (Gleevec), or could receive placebo. Median progression-free survival was 3.7 months for nilotinib (similar to the control arms), whereas it was 4.8 months with regorafenib in the GRID trial. “We must be cautious comparing different studies, but this gets to the point of whether placebo was the best control arm for the study,” Dr. McArthur said. “Clearly this is a positive study, and no doubt regorafenib is a viable third-line option. However, best supportive care as the comparator is one previous standard of care; the alternative is continuation of KIT inhibitors at progression, and that may have been an alternative comparator for this study.”

■

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

Reference 1. Reichardt P, Blay JY, Gelderblom H, et al: Phase III study of nilotinib versus beset supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. February 21, 2012 (early release online).

ment), not much different from those originally randomized to regorafenib (7.4 months, as assessed by investigators), he pointed out. As expected with this class of drugs in disease already resistant to other kinase inhibiors, the objective response rate was low at 4.5%, vs 1.5% with placebo. Adverse events have occurred in 21.8% of the regorafenib arm and 25.6% of those on placebo. Regorafenib was well tolerated. The most significant toxicities of at least grade 3, for regorafenib vs placebo, were handfoot skin reactions (19.7% vs 1.5%), hypertension (22.7% vs 3.0%), and diarrhea (5.3% vs 0%), but these did not lead to excess study discontinuations (6.1% vs 7.6%). “Patients were able to stay on study with appropriate

dose modifications,” he said. Data on genotype were available for approximately half the patients. Analyses showedyvirtually identical benefits with regorafenib in patients with the KIT exon 11 mutation (HR = 0.21) and exon 9 mutation (HR = 0.239), in terms of progression-free survival.

■

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

Reference 1. Demetri GD, Reichardt P, Kang Y, et al: Randomized phase III trial of regorafenib in patients with metastatic and/ or unresectable gastrointestinal stromal tumor progressing despite prior treatment with at least imatinib and sunitinib: GRID trial. 2012 ASCO Annual Meeting. Abstract LBA10008. Presented June 4, 2012.

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PAGE 24

Perspective Health-care Policy

As Conflicting Guidelines Evolve, Experts Continue to Debate the Merits of Cancer Screening Population-wide tests to catch early cancers are leading to overdiagnosis, unnecessary surgery, and even death, some say. By Jo Cavallo

“I

n the 1930s and 1940s, when the American Cancer Society [ACS] first brought forth the message that early cancer detection saves lives, it was a broad brushstroke and an appropriate message. The problem now is that new technology enables us to find [tumors that would never progress to invasive cancers], and suddenly the message isn’t so simple anymore,” said Otis W. Brawley, MD, Chief Medical Officer and Executive Vice President, Research and Cancer Control Science at the American Cancer Society and Professor of Hematology, Medical Oncology, Medicine, and Epidemiology at Emory University, Atlanta.

Otis W. Brawley, MD

Series of Controversies The value of using populationwide screening tests on asymptomatic people to detect cancer early, when it is presumably easier to cure, has come into question and ignited a fierce debate among physicians—and confusion among the public. The first controversy erupted in 2008, when a draft report from the U.S. Preventive Services Task Force (USPSTF) of an analysis of data on the prostatespecific antigen (PSA) test—the most common screening tool—showed that PSA testing in asymptomatic men is not necessary. The following year, the USPSTF advised that healthy women get routine breast cancer screenings biannually beginning at age 50 and stopping at age 74, instead of its previous recommendation that mammograms should be obtained annually and begin at age 40. According to the Task Force findings, to save the life of one woman in her 40s, 1,904 would have to undergo annual screening, which would result in a number of false-positives, psychological distress,

and unnecessary surgery. In May, the Task Force issued its final recommendations against regular prostate cancer screenings for men of all ages, saying that in this test, too, the collateral damage from overscreening far outweighs the potential benefit. According to the Task Force, one man in every 1,000 screened may avoid death as a result of the PSA test, while one man in every 3,000 tested will die as a result of complications from prostate cancer surgery and dozens more will suffer from erectile dysfunction, incontinence, pain, infection, and emotional distress.

Evolving Concept “The conceptual model of cancer screening is super-compelling: Find the cancer early and cure it; don’t find the cancer and the person dies. But with the possible exception of the Pap test, cancer screening is not that simple,” said Peter B. Bach, MD, Director of the Center for Health Policy and Outcomes at Memorial Sloan-Kettering Cancer Center. What is proving to be more advantageous are screenings for people at increased risk for cancer. A review of 21 studies on the benefits and harms of low-dose computed tomography screening for lung cancer recently published in the Journal of the American Medical Association found that such screening does benefit individuals at high risk for lung cancer due to smoking.1 However, the review also found a relatively high risk of false-positives, with approximately 20% of the people screened requiring further testing, including biopsies, but only 1% had lung cancer. Still, said Dr. Bach, the lead author of the JAMA report, the evidence shows that when screening is done in high-risk individuals such as smokers, “the risk/benefit tradeoff does seem to favor benefit.”

What Is Cancer? Even when abnormal cell growth is found during routine screenings, it doesn’t mean that a cancer will become invasive and lead to death. “An overwhelming issue here is our definition of what cancer is,” said Dr.

Peter B. Bach, MD

Brawley. Rudolf Virchow, a mid-19th century physician and pathologist who discovered that leukemia was caused by the rapid proliferation of abnormal white cells, was the first person to define cancer as a process in which healthy cells mutate and then reproduce. This definition led to the notion that early detection of these mutating cells leads to cure. But Dr. Virchow could never have imagined the advancements in medicine that now make it possible to detect tiny cancers at such early stages, noted Dr. Brawley. “Virchow never saw cancer on an x-ray, CT, or MRI scan or diagnosed it with a fine-needle biopsy, but pathologists today still use the same hematoxylin and eosin (H&E) stains he used to diagnose cancer. Now, for example, we may see cells that look like breast cancer, but does that mean that those cells are genomically programmed to grow, spread, and metastasize? No, it doesn’t. In fact, we know that between 10% and 30% of localized breast cancers found on mammograms will not progress,” said Dr. Brawley.

Other Groups Weigh In A host of medical organizations, including the ACS, the American College of Radiology, the American Society of Breast Disease, and the American Medical Association, have all come out against the new mammography screening guidelines from the USPSTF. These groups all support mammography screening beginning at age 40. There is slightly more support for the USPSTF recommendations on PSA screening, with the ACS, the American Urological Association (AUA), and the American College of Preventive Medicine agreeing that

there is insufficient evidence to recommend routine PSA screening for average-risk men in any age group. However, the ACS advises that average-risk men with at least a 10-year life expectancy receive information on screening and have the opportunity to make an informed decision beginning at age 50. The AUA recommends that screening information be conveyed to men aged 40 and older who have a life expectancy of more than 10 years. In July, ASCO released a new evidence-based provisional clinical opinion (PCO) on the use of PSA screenings, which recommends that physicians discuss the benefits and risks of PSA testing with asymptomatic patients who have life expectancies greater than 10 years.2 The PCO notes that the risks of testing outweigh the benefits for men with shorter life expectancies.

Interpreting Cancer-screening Statistics All the publicity surrounding the debate over the benefits and risks associated with cancer screenings has failed to dissuade people from seeking them. A study published in the April 25, 2012, issue of JAMA found that despite the 2008 USPSTF recommendation against prostate cancer screening in men aged 75 or older, PSA screening rates did not change.3 One reason for the consistency in screening rates may be that physicians do not understand cancer-screening statistics, and as a consequence, provide misleading information to their patients. A study published earlier this year in the Annals of Internal Medicine, which included a survey of over 400 primary care physicians in the United States, found that the majority of respondents could not distinguish between relevant and irrelevant or even misleading information when it comes to cancer screenings and whether they save lives.4 According to the findings, 47% of physicians incorrectly said that finding more cases of cancer in screened as opposed to unscreened populations “proves that screening saves lives.” And 76% said that better survival rates prove that screening saves lives.

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PAGE 25

Perspective

Refining the Message “The role of screening is clear in individuals who are at high risk for developing cancer based on either their genetics or family histories,” said Frank L. Meyskens, Jr, MD, Director, Chao Family Comprehensive Cancer Center at the University of California, Irvine, and Chair-Elect of ASCO’s Cancer Prevention Committee. “Once you go beyond that to an asymptomatic general population, it becomes difficult

Disclosure: Drs. Bach, Brawley, and Meyskens, Jr, reported no potential conflicts of interest.

References 1. Bach PB, Mirkin JN, Oliver TK, et al: Benefits and harms of CT screening for lung cancer: A systematic review.

JAMA 307:2418-2429, 2012. 2. Basch E, Oliver TK, Vickers A, et al: Screening for prostate cancer with prostate-specific antigen testing: American Society of Clinical Oncology provisional clinical opinion. J Clin Oncol. July 16, 2012 (early release online). 3. Prasad SM, Drazer MW, Huo D, et al:

2008 US Preventive Services Task Force recommendations and prostate cancer screening rates. JAMA 307:1692-1694, 2012. 4. Wegwarth O, Schwartz LM, Woloshin S, et al: Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med 156:340-349, 2012.

AMG 386: Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

Frank L. Meyskens, Jr, MD

to justify, because either during the risk phase where there are no pathologic changes or even when there are early pathologic changes, it’s very difficult to predict who is going to go on to develop cancer and who isn’t. Once cancer is invasive, it’s easy to make recommendations about what to do, but up until then, it’s difficult. Progress in validating genomic and nongenomic biomarkers may help refine screening and early detection recommendations, but we are not there yet.” According to Dr. Bach, improving the public’s understanding of the role of cancer screenings and changing physicians’ reliance on them will take time, but progress is being made. “Reports in the media on the benefits and risks of screening tests are starting to be more balanced. An important part of the messaging to the public is that cancer screening tests themselves don’t make you healthier—they just have the potential to make you healthier—and that they only make sense if you are meaningfully at risk of cancer.” Shifting physicians’ attitudes may take longer. “There’s a cognitive dissonance between the practice of evidence-based medicine and how we train doctors to make clinical decisions. And they are fundamentally different,” said Dr. Bach. “I think that this is going to be a generational change. As we shift to doctors who are brought up more on the ability to evaluate and utilize comparative effectiveness research when making clinical decisions, rather than relying on personal experience or intuition, the use of cancer screening tests will become more strategic.”

■

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

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of AMG 386 With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free ee survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel IV QW (3 on/1 off)

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

AMG 386 IV QW Monotherapy

Primary

PFS

2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Placebo IV QW Monotherapy

Key Secondary

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

AMG 386 is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information:: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com Trials.com (20090508) T • www.ClinicalTrials.gov Trials.gov (NCT01204749) T

AMG 386 is an investigatio i tigational agent that at has not been approved ed by the FDA for the use se underr investigatio tigation forr this ttrrial.

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

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PAGE 26

FDA Update

FDA Grants Accelerated Approval to Carfilzomib for Multiple Myeloma

nyx Pharmaceuticals announced that the FDA has granted accelerated approval to carfilzomib (Kyprolis) for the treatment of patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib (Velcade) and an immunomodulatory therapy, and have demonstrated disease progression on or within 60 days of completion of the last therapy. The indication for carfilzomib is based on response rate; no data are available for carfilzomib that demonstrate an improvement in progressionfree survival or overall survival. “The approval of [carfilzomib] provides a treatment option to patients with multiple myeloma whose disease has progressed despite use of available therapies,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “We are encouraged by the continued progress in the development of drugs for multiple myeloma over the past decade, offering improved treatment of this disease.”

Study Design The safety and effectiveness of carfilzomib, which is administered intravenously, was evaluated in a study of 266 patients with relapsed multiple myeloma who had received at least two

prior therapies, including bortezomib and thalidomide (Thalomid). The study was designed to measure the percentage of patients who experienced complete or partial disappearance of tumor after treatment (overall response rate). The overall response rate was 23%. The median duration of response was 7.8 months. The most common side effects observed in more than 30% of the study participants were fatigue, low blood cell count and blood platelet levels, shortness of breath, diarrhea, and fever. Serious side effects seen with carfilzomib included heart failure and shortness of breath. Patients should be monitored closely and treatment withheld if these serious side effects occur.

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Everolimus Approved for Advanced Breast Cancer

he FDA has approved everolimus tablets (Afinitor) for use in combination with exemestane to treat postmenopausal women with advanced hormone receptor–positive, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole. The approval was based on a randomized, double-blind, multicenter trial conducted in 724 postmenopausal women with estrogen receptor–positive, HER2-negative, advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Patients were randomly allo-

cated to everolimus 10 mg/d plus exemestane 25 mg/d (n = 485) or to placebo plus exemestane 25 mg/d (n = 239). Patients were not permitted to cross over to everolimus at the time of disease progression.

Study Results The median progression-free survival at the time of final analysis was 7.8 and 3.2 months in the everolimus and placebo arms, respectively (HR 0.45 [95% CI: 0.38, 0.54], P < .0001). The objective response rates were 12.6% and 1.7% in the everolimus and placebo arms, respectively. An interim analysis of overall survival conducted at 46% of expected events was not statistically significant (HR 0.77 [95% CI: 0.57, 1.04]). The final analysis of overall survival is expected to be performed in June 2014. The most common side effects observed in patients were mouth ulcers, infections, rash, fatigue, diarrhea, and decreased appetite. Patients aged 65 years and older should be monitored closely as these patients experience a higher rate of serious side effects than younger patients receiving the treatment. Forty percent of patients on the everolimus arm were aged 65 years and older, and 15% were aged 75 years and older. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last everolimus dose was 6% in patients aged 65 years and older compared to 2% in patients younger than 65 years of age. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions, and contrain-

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dications is available at: http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/022334s016lbl.pdf

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Enzalutamide Gets Priority Review for Castrate-resistant Prostate Cancer

edivation, Inc, and Astellas Pharma, Inc, announced that the FDA has accepted for filing the New Drug Application (NDA) for enzalutamide (formerly MDV3100) for the potential treatment of men with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy and granted Priority Review Designation. Enzalutamide is an oral, oncedaily androgen receptor signaling inhibitor. The investigational agent inhibits androgen receptor signaling in three distinct ways: it inhibits (1) testosterone binding to androgen receptors; (2) nuclear translocation of androgen receptors; and (3) DNA binding and activation by androgen receptors. In the phase III AFFIRM trial, common side effects observed more frequently in enzalutamide- compared with placebo-treated patients included fatigue, diarrhea, and hot flush. Seizure was reported in less than 1% of enzalutamide-treated patients. Serious adverse events, adverse events causing patients to stop treatment, and adverse events causing death all were lower in the enzalutamide group than in the placebo group.

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Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

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

DECODE

metastatic melanoma

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

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

EXTEND

survival

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

P<0.0001

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

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

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

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

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

zelboraf.com

The ASCO Post | AUGUST 15, 2012

PAGE 30

Journal Spotlight Genitourinary Oncology

Radiotracer Targeting of Free Prostate-specific Antigen By Matthew Stenger

erum levels of prostate-specific antigen (PSA) are widely used as a biomarker for prostate cancer, although they often do not distinguish between normal tissue and cancer and

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.

converted to an inactive form, Ulmert and colleagues from Memorial SloanKettering Cancer Center in New York developed a radiolabeled monoclonal antibody (89Zr–labeled 5A10) that

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.

selectively targets the initially produced active, “free” form of PSA.1 This selectivity potentially allows a See Page 86 more accurate, imaging-based clinical assessment of advanced prostate cancer.

Visualization of Lesions The 89Zr–5A10 radiotracer was shown to localize in an androgen receptor–dependent manner in vivo in models of castration-resistant prostate cancer. The radiotracer was specifically taken up into tumor tissue of mice with subcutaneous PSA-positive prostate cancer xenografts and allowed measurement of changes in PSA production induced by testosterone or androgen receptor inhibition. Further, the radiotracer specifically localized to tumor-bearing mouse hind limbs, but not to sites of fracture and bone repair, thus overcoming the imitations of current bone scans that fail to distinguish between malignant and nonmalignant signals. These findings indicate that a radiotracer that allows quantitation of androgen receptor–dependent changes in PSA expression levels at tumor lesions can selectively and noninvasively detect and permit visualization of primary and metastatic prostate tumors and measure responses to antiandrogen treatment. As stated by the investigators, “[T]he molecular imaging tool presented here could have near-term clinical impact, particularly because the dosimetry of other 89Zr-labeled monoclonal antibodies has been determined to be favorable for humans and will soon be examined in clinical trials.” 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

do not always accurately reflect clinical outcome. In order to overcome the fact that the small proportion of tumorassociated PSA that is released into Safety:7" circulation is rapidly and irreversibly

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Reference 1. Ulmert D, Evans MJ, Holland JP, et al: Imaging androgen receptor signaling with a radiotracer targeting free prostate-specific antigen. Cancer Discov 2:320-327, 2012.

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PAGE 31

Pearls in Neuro-oncology

Understanding and Managing Pseudoprogression in Glioblastoma Patients By Tracy Batchelor, MD

Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of NeuroOncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer.

ncologists play a critical role in the interpretation of radiographic studies in glioblastoma patients, within an evolving therapeutic landscape. Integration of tumor molecular pathology, knowledge of radiation treatment plans, and an understanding of drug mechanisms of action are critical for accurate radiologic interpretation and patient management. One important issue that may arise in interpreting such images is the phenomenon of tumor “pseudoprogression”; oncologists need to be able to distinguish this effect from true disease progression.

A follow-up contrast-enhanced, cranial MRI is typically obtained 4 to 6 weeks from the conclusion of concurrent chemoradiation and prior to the start of additional chemotherapy. Interpretation of this first postchemoradiation MRI can be challenging. It is not uncommon to observe increased contrast-enhancement and surrounding T2/FLAIR (fluid-attenuated inversion recovery) hyperintensity within the radiation treatment field on this scan compared to the prechemoradiation scan. While these radiographic findings raise the possibility of tumor progression, they may also reflect the biologic effect of chemoradiation on the tumor and the tumor microenvironment, typically referred to as “treat-

Month 14

a. Pre-operative MRI

b. Post-operative MRI

e. MRI 6 months post-chemoradiation

rent radiation and temozolomide, and a particular glioblastoma subtype may be more susceptible to tumor pseudoprogression. The incidence of tumor pseudoprogression ranges from 28% to 66% in all glioblastoma patients undergoing chemoradiation and typically occurs within 3 months after the completion of concurrent radiation and temozolomide.1 Glioblastoma patients with promoter methylation of the repair enzyme 06-methyl guanine DNA methyltransferase (MGMT) may be at a higher risk of tumor pseudoprogression, with 91% (21 of 23 patients) of such patients developing early radiographic changes in one study.2

Month 16

Month 18

c. MRI 8 weeks postchemoradiation

f. MRI 12 months post-chemoradiation

d. FDG-PET 8 weeks post-chemoradiation

g. MRI 16 months post-chemoradiation

Fig. 1: Radiologic studies in a glioblastoma patient with tumor pseudoprogression. (a) preoperative MRI demonstrates nodular enhancement in the left occipital lobe; (b) postoperative MRI shows subtotal resection; pathologic diagnosis was MGMT-methylated glioblastoma; (c) MRI 2 months after completion of chemoradiation shows increased enhancement concerning for progressive tumor; (d) FDG-PET shows hypometabolism in region of enhancement; (e–g) Gradual resolution of enhancement consistent with tumor pseudoprogression. Images courtesy of Tracy Batchelor, MD. Panels (c) and (f) from Batchelor TT, Sorenson AG, Louis DN: Case 17-2012—A 54-year-old man with visual-field loss and a mass in the brain. N Engl J Med 366:2116, 2012. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission.

Treating Glioblastoma The standard of care for newly diagnosed glioblastoma patients consists of surgery followed by chemoradiation. Radiation is typically administered over 30 fractions (6 weeks) to a total tumor dose of 55 to 60 Gy in combination with daily temozolomide, an oral methylating agent, at 75 mg/ m2/d. Subsequently, temozolomide (150–200 mg/m2) is administered 5 days each month for an additional 6 months. This approach is associated with superior progression-free and overall survival vs radiation alone.

ment effect” or tumor “pseudoprogression.” However, development of new contrast enhancement outside the radiation treatment field represents tumor progression and should be treated accordingly.

Pseudoprogression Incidence and Findings Tumor pseudoprogression was recognized in the era prior to the approval of temozolomide for glioblastoma. However, the incidence may have increased in the modern era of concur-

The radiographic findings typically consist of an increased area of contrast enhancement and enlargement of noncontrast T2/FLAIR hyperintense signal surrounding the enhancement. These radiographic changes range from mild to dramatic and may or may not result in neurologic symptoms. Unfortunately, other imaging techniques such as MRI-based perfusion and spectroscopy or brain FDG-PET scans cannot reliably distinguish tumor progression from pseudoprogression. Depending on the brain location

or degree of mass effect, tumor pseudoprogression may result in exacerbation of existing neurologic symptoms and signs or the appearance of new impairments.

Management and Prognosis Approximately one-third of patients are symptomatic from tumor pseudoprogression and may require treatment with corticosteroids. Bevacizumab (Avastin), a humanized, monoclonal antibody against the vascular endothelial growth factor (VEGF)-A ligand might be efSee Page 86 ficacious in the treatment of radiation-related brain necrosis but has not been adequately studied or established as an effective therapy for symptomatic tumor pseudoprogression.3 Although preliminary evidence suggests that concurrent treatment of newly diagnosed glioblastoma patients with chemoradiation and an inhibitor of VEGF may reduce the incidence of pseudoprogression, no VEGF inhibitor is yet approved for newly diagnosed glioblastoma, and follow-up studies are required.4 Asymptomatic patients with presumed pseudoprogression do not require any therapy, although shortinterval brain MRI scans (every 6–8 weeks) are usually necessary to monitor the evolution of these changes and to exclude the possibility of tumor progression. Typically, the contrast enhancement and T2/FLAIR hyperintensity gradually diminish on serial MRI scans in patients with tumor pseudoprogression (Fig. 1). While tumor pseudoprogression may become symptomatic and require corticosteroid treatment, it appears to confer a favorable prognosis, with a median survival of 38 months in one report of 32 glioblastoma patients with established tumor pseudoprogression.

Clinical Trial Criteria The recognition of tumor pseudoprogression in newly diagnosed glioblastoma patients has prompted a revision to radiographic response criteria and to eligibility criteria for clinical trials in this population.5 continued on page 32

The ASCO Post | AUGUST 15, 2012

PAGE 32

Pearls in Neuro-oncology

Pseudoprogression in Glioblastoma continued from page 31

Patients with radiographic progres� sion within 3 months of completion of concurrent chemoradiation are typically excluded from enrollment into an experimental trial unless the progression is outside the radia� tion treatment field or radiographic change within the radiation treat� ment field is confirmed as tumor progression by biopsy or resection.

Recommendations In a glioblastoma patient who manifests increased contrast enhance� ment within the radiation treatment field on a cranial MRI scan within

3�� months of completion of concur� rent chemoradiation, I typically con� tinue the standard, postradiation te� mozolomide course with follow-up MRI scans every 6 to 8 weeks. Corti� costeroids are administered only if the radiographic changes result in new symptoms or an exacerbation of exist� ing symptoms. If the contrast contin� ues to expand at 6 months or beyond, a stereotactic biopsy is advised. If the contrast enhancement stabilizes or di� minishes, a diagnosis of tumor pseu� doprogression is likely and the patient should complete a standard course of temozolomide.

■

Disclosure: Dr. Batchelor is a consultant for Roche, Spectrum, Kirin Pharmaceuticals, Champions Biotechnology, and Advance

Medical; receives research funding from Pfizer, AstraZeneca, Millennium, and National Institutes of Health; and receives CME lectures/contributions from Educational Concepts Group, Imedex, Robert Michael Educations Institute, UpToDate Inc., Research To Practice, and Oakstone Medical Publishing.

References 1. Fink J, Born D, Chamberlain MC: Pseudoprogression: Relevance with re� spect to treatment of high-grade gliomas. Curr Treat Options Oncol 12:240-252, 2011. 2. Brandes AA, Franceschi E, Tosoni A, et al: MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant ra� diochemotherapy in newly diagnosed glio� blastoma patients. J Clin Oncol 26:2192-

2197, 2008. 3. Levin VA, Bidaut L, Hou P, et al: Ran� domized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79:1487-1495, 2011. 4. Pinho MC, Polaskova P, Jennings D, et al: Impact of adjuvant anti-VEGF therapy on treatment-related pseudopro� gression in patients with newly diagnosed glioblastoma receiving chemoradiation with or without anti-VEGF therapy. 2012 ASCO Annual Meeting. Abstract 2025. Presented June 1, 2012. 5. Wen PY, Macdonald DR, Reardon DA, et al: Updated response assessment criteria for high-grade gliomas: Re� sponse assessment in neuro-oncology working group. J Clin Oncol 28: 19631972, 2010.

Adding Bevacizumab to Chemotherapy Improves Progression-free Survival in Platinum-sensitive Recurrent Ovarian Cancer By Charlotte Bath

he addition of bevacizumab (Avastin) to gemcitabine and carboplatin, followed by bevaci� zumab until disease progression, resulted in significantly improved progression-free survival compared to gemcitabine and carboplatin plus placebo among women with plati� num-sensitive recurrent ovarian, pri� mary periotoneal, or fallopian tube cancer. Results from the phase III OCEANS (Ovarian Cancer Study Comparing the Efficacy and Safety of Chemotherapy and Anti-Angio� genic Therapy in Platinum-Sensitive Recurrent Disease) trial were pub� See Page 86 lished in the Jour� nal of Clinical Oncology.1 The study was sponsored by Genentech, which manufactures bevacizumab.

Analysis of Progression-free Survival Both treatment groups consisted of 242 patients with histologically confirmed disease progression and ≥ 6 months after completion of front-line platinum-based chemo� therapy. “At the time of the final [progression-free survival] analysis (338 events), the median follow-up was 24 months,” the authors report� ed. The median [progression-free survival] was 12.4 months for pa� tients receiving bevacizumab vs 8.4

months for those receiving placebo (P < .0001). “As ovarian cancer becomes a chronic illness, treatments that prolong [progression-free sur� vival], and therefore time without cytotoxic chemotherapy, become increasingly relevant,” the authors noted.

Other Key Data The overall response rate was also significantly improved in patients receiving bevacizumab—78.5% vs 57.4% in the placebo group (P < .0001). The duration of response was 10.4 months for patients receiving bevacizumab vs 7.4 months for pa� tients receiving placebo. The median overall survival data remain immature, but the most re� cent analysis put survival at 35.2 months among patients receiving placebo vs 33.3 months for those receiving bevacizumab. The ma� jority of the 235 deaths (48.6% of patients) resulted from disease pro� gression. ‘‘The [overall survival] data from OCEANS are not yet ma� ture, and the percentage of patients receiving subsequent therapy with chemotherapy and with bevacizum� ab or other antiangiogenic therapy is being observed for subsequent analysis,” the researchers stated. “The National Comprehensive Cancer Network Compendium lists bevacizumab as a therapeutic op�

tion for [recurrent ovarian cancer], making subsequent therapy with bevacizumab an available choice for many women with [this disease] in the United States,” the authors added. “All patients in both arms expe� rienced at least one adverse event,” the researchers reported. Serious adverse events occurred in 34.8% of patients receiving bevacizumab and 24.9% of patients receiving placebo. Grade�� 3 or higher hyper� tension and proteinuria occurred more frequently in patients receiv� ing bevacizumab. “The rates of neutropenia and febrile neutrope� nia were similar in both arms,” the authors wrote. No gastrointestinal

perforations occurred during study treatment or within the 30-day safety-reporting period.

■

Disclosure: The Ovarian Cancer Study Comparing the Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS) study was sponsored by Genentech.

Reference 1. Aghajanian C, Blank SV, Goff BA, et al: OCEANS: A randomized, dou� ble-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinumsensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30:2039-2045, 2012.

The ASCO Post

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

Now Enrolling

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

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

Randomization

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

N=~544

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

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

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

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

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

• Immunogenicity of ramucirumab

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

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

The ASCO Post | AUGUST 15, 2012

PAGE 34

Journal Spotlight Thoracic Oncology

No Improvement in Overall Survival, Worse Toxicity with Motesanib Added to Chemotherapy in Non–Small Cell Lung Cancer By Matthew Stenger

wo trials (E4599 and AVAiL) have suggested a benefit to add� ing the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy in patients with ad� vanced nonsquamous non–small cell lung cancer (NSCLC). Bevacizumab acts by binding directly to circulat� ing VEGF and preventing interaction of VEGF with its receptors. It has been believed that small-molecule tyrosine kinase inhibitors that tar� get multiple angiogenesis pathways would offer advantages over singletarget agents. Motesanib inhibits multiple an� giogenic pathways by inhibiting VEGF receptors 1, 2, and 3, plate� let-derived growth factor recep� tor, and Kit tyrosine kinases. The agent was shown to have antitumor activity alone and in combination regimens in early-phase trials. How� ever, the multinational randomized, double-blind, placebo-controlled MONET1 trial, recently reported by Giorgio V. Scagliotti, MD, Uni� versity of Turin, Torino, Italy, and colleagues in the Journal of Clini� cal Oncology, showed that adding motesanib to carboplatin/paclitaxel resulted in no improvement in over� all survival and an excess of serious toxicities.1

histology. Thereafter, only patients with nonsquamous histology were enrolled. In total, 1,090 patients with stage�� IIIB/IV or recurrent nonsqua� mous NSCLC received carboplatin (area under the curve 6 mg/mL × min) and paclitaxel (200 mg/m2) for up to six 3-week cycles plus daily placebo (n = 549) or motesanib 125 mg (n = 541). Patients had no prior therapy for advanced disease. Median age was 60 years in both groups, and similar proportions of motesanib patients vs control group patients were former smok� ers (72%), male (62% vs 61%), and white (67% vs 64%) and had ECOG performance status ≥ 1 (65% vs

MONET Trial Results ■■ Motesanib plus carboplatin/paclitaxel failed to significantly improve

overall survival over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the subset of patients with adenocarcinoma.

■■ The study results underscore the need for better understanding of

the mechanisms involved in the angiogenesis pathways, and for the development of molecular markers to enable better treatment decisions on the basis of the probability of response.

62%), histology of adenocarcinoma (83% vs 81%), stage IV/recurrent disease (87% vs 86%), and measure� able disease (97% vs 96%). Two percent of patients in both groups had received prior adjuvant chemo� therapy.

No Overall Survival Improvement

Giorgio V. Scagliotti, MD

Enrollment of Squamous Histology Stopped MONET1 initially enrolled pa� tients with advanced squamous or nonsquamous NSCLC. However, a planned independent data monitor� ing committee review after enroll� ment of 600 patients, including 223 with squamous histology, showed higher early mortality and a higher incidence of gross hemoptysis among motesanib recipients with squamous

outside the United States/Canada/ Australia/European Union (n = 414, HR = 0.77, 95% CI = 0.61–0.98); most of these patients were Asian. Median progression-free survival was significantly but modestly pro� longed in the motesanib group (5.6 vs 5.4 months, HR = 0.79, 95% CI = 0.68–0.90, P < .001), with a similar outcome in patients with adenocar� cinoma. Objective response rate was sig� nificantly higher with motesanib < .001), with a simi� (40% vs 26%, P �� lar outcome in patients with adeno� carcinoma. Earlier motesanib stud� ies suggested a relationship between increased levels of placental growth factor and efficacy outcomes in

Patients in both groups were treat� ed for a median of 4.1 months. There was no difference in median over� all survival between the motesanib group and the control group (13.0 vs 11.0 months, hazard ratio [HR] = 0.90, 95% confidence interval [CI] = 0.78–1.04, P = .14). There was also no difference between groups when only patients with adenocarcinoma were considered (n = 448 vs 442, 13.5 vs 11.0 months, HR = 0.88, 95% CI = 0.75–1.03, P = .11). Prespecified subgroup analyses suggested prolonged survival with motesanib in nonwhite patients (n = 375, HR = 0.76, 95% CI = 0.59–0.97) and patients enrolled

motesanib treatment, but no associa� tion between placental growth factor and response rate or survival was ob� served in the current study.

Increased Toxicity Discontinuation of study treat� ment occurred in 31% of motesanib recipients vs 15% of the control group. Numerous adverse events occurred with at least 5% greater frequency in motesanib patients, including diar� rhea, nausea, vomiting, abdominal pain, hypertension, pneumonia, and gallbladder-related disorders (eg, cho� lecystitis, cholelithiasis, gallbladder enlargement). Motesanib patients had higher rates of serious adverse events (49% vs 34%), grade 4 adverse events (21% vs 14%), and serious grade 3 or higher adverse events, including neutropenia (5% vs 2%), diarrhea (5% vs <1%), pneumonia (4% vs 1%), and dehydra� tion (4% vs < 1%). Among adverse events typically associated with VEGF inhibition, frequencies were higher in the motesanib group for hypertension

Roy S. Herbst, MD, PhD

(any grade 26% vs 6%) and grade 3 or higher arterial thromboembolic (2% vs < 1%) and hemorrhagic (3% vs 1%) events. Hemorrhagic events con� sisted of gastrointestinal hemorrhage (1 vs 0), pulmonary hemorrhage (2 vs 1), and hemoptysis (3 vs 1). Death due to adverse events with� in 30 days of completing treatment occurred more frequently in mote� sanib patients (14% vs 9%). Adverse events leading to death that oc� curred in at least four patients in ei� ther treatment group were pneumo� nia (7 vs 0), general physical health deterioration (6 vs 1), respiratory failure (5 vs 2), pulmonary embo� lism (3 vs 6), and cardiorespiratory arrest (1 vs 4).

Lack of Validated Predictive Markers As stated in an accompanying editorial by Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD, of Yale Comprehensive Cancer Center, New Haven, Connecticut, the MONET1 trial adds to a grow� ing list of trials that have shown no benefit of adding multitargeted ty� rosine kinase inhibitors to chemo� therapy in advanced NSCLC, in� cluding phase III trials of sorafenib (Nexavar) in first-line treatment and vandetanib (Caprelsa) in secondline treatment.2 This phenomenon has also been observed with the ad� dition of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (eg, gefitinib [Iressa, dis� continued in the U.S.] and erlotinib [Tarceva]) to chemotherapy, where� as results have been mixed with the addition of the anti-EGFR monoclo� nal antibody cetuximab (Erbitux) to chemotherapy. The reasons that tyrosine kinase inhibitors have failed to improve sur�

ASCOPost.com | AUGUST 15, 2012

PAGE 35

Journal Spotlight

vival when added to chemotherapy are unclear. However, a potential mecha� nism for the lack See Page 86 of synergy between these agents and chemotherapy may be G1 phase cell-cycle arrest caused by tyrosine kinase inhibitors, which may interfere with the cycle-depen� dent cytotoxicity of chemotherapy. Drs. Morgensztern and Herbst ob� served that in addition to not improv� ing survival in NSCLC, multitargeted antiangiogenic tyrosine kinase inhibi� tors have been associated with signifi� cant additional toxicity; meta-analyses have shown that the VEGF receptor tyrosine kinase inhibitors sorafenib

and sunitinib (Sutent) are associ� ated with two- to threefold increased risks for bleeding, arterial thrombotic events, and treatment-related mortali� ty. The commentators noted, “It seems likely that, similarly to EGFR [tyrosine kinase inhibitors], combination with chemotherapy might not be the best setting for the use of multitargeted an� giogenesis inhibitors.” As concluded by Drs. Morgen� sztern and Herbst, “One of the pri� mary problems with antiangiogenic therapy is the lack of validated pre� dictive markers. Because there are no trials that show a benefit from the addition of antiangiogenic [ty� rosine kinase inhibitors] to chemo� therapy, additional studies using this

unselected approach are not recom� mended. Therefore, there is a definite need for an improved understanding of the complex mechanisms that are involved in the angiogenesis path� ways, and for the development of molecular markers to allow a better treatment decision on the basis of the probability of response. This would also help avoid the unnecessary use of potentially toxic drugs in patients with known resistance and would fa� cilitate the discovery of new targets and drugs on the basis of the resis� tance mechanisms.”

■

Disclosure: Dr. Scagliotti has served in a consulting or advisory role for Eli Lilly, Keunchil Park, and Amgen, and has received honoraria from AstraZeneca, Eli Lilly, Pfizer, and Roche. Dr. Morgensztern has served in a

consulting or advisory role for Genentech. Dr. Herbst has served as consultant or advisor for Amgen.

References 1. Scagliotti GV, Vynnychenko I, Park K, et al: International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/ paclitaxel in patients with advanced non� squamous non-small-cell lung cancer: MONET1. J Clin Oncol. July 2, 2012 (ear� ly release online). 2. Morgensztern D, Herbst RS: Mul� titargeted tyrosine kinase inhibitors in unselected patients with advanced nonsmall-cell lung cancer (NSCLC): Im� pressions from MONET (the Motesanib NSCLC Efficacy and Tolerability study). J Clin Oncol. July 2, 2012 (early release online).

Rush’s New Hospital Building Listed as One of the Most Innovative Infrastructure Projects in the World

he new hospital at Rush Univer� sity Medical Center, Chicago, has been listed in KPMG’s recent second edition of Infrastructure 100: World Cities Edition, a report show� casing 100 of the most innovative and inspiring urban infrastructure projects from around the world. Rush is one of only 10 health-care projects listed. Only two health-care projects in the United States were in� cluded. The report by KPMG, a world� wide consulting firm, is designed to provide insight into the infrastruc� ture projects that make great cities, with a particular focus on the inno� vations that make them “Cities of the Future.” According to KPMG, the development of sustainable urban infrastructure is one of the greatest challenges of the 21st cen� tury. More than half of the global population is already squeezed into cities that, collectively, make up less than 2% of the planet’s land. Of the 100 projects identified by the re� gional judging panels, 10 were se� lected by a global judging panel as being the most noteworthy within each project category.

The ‘Rush Transformation’ The new Rush hospital build� ing, referred to as the Tower, is the centerpiece of the 10-year “Rush

Transformation” that also includes a new orthopedics building, a new parking garage and central power plant, renovations of selected exist� ing buildings, and demolition of ob� solete buildings. The entire 10-year project was designed and built to conserve energy and water, reduce waste, and use sustainable building materials. The Tower is the largest new con� struction health-care project in the world to be LEED Gold-certified for energy use, lighting, water, and ma� terial use, as well as incorporating a variety of other sustainable strate� gies. LEED stands for Leadership in Energy and Environmental Design. The 14-floor, 806,000-square-foot hospital building opened in Janu� ary 2012 and is recognized as one of Chicago’s most distinctive new buildings.

Infrastructure–Healing Link According to the KPMG report, the changing nature of health-care means that in addition to patients relying on skilled doctors and new technology for recovery, providers are now acutely aware of the links between physical infrastructure, the built environment, psychology, and healing. Below is the list of the 10 most innovative health-care projects as chosen by a panel of independent

Lobby of new hospital at Rush University Medical Center, Chicago. Photo courtesy of Rush University.

industry professionals for the Infra� structure 100: World Cities Edition. ■■ The Royal London Hospital, Unit� ed Kingdom ■■ New Physical Medicine and Reha� bilitation Hospital, Kuwait ■■ Kayseri Integrated Health Cam� pus, Turkey ■■ Bahia Suburbio Hospital, Brazil ■■ Integrated Health and Water Man�

agement Project, Brazil ■■ Queen Mamohato Memorial Hos� pital, Lesotho ■■ Victorian Comprehensive Cancer Centre (VCCC), Australia ■■ IIUM Teaching Hospital, Malaysia ■■ Rush University Medical Center Transformation Project ■■ New University of Michigan C.S. Mott Children’s Hospital

■

PERJETA: for the first-line treatment of HER2+* metastatic breast cancer Indication

PERJETA™ (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity

• Exposure to PERJETA can result in embryofetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Additional Important Safety Information Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and trastuzumab and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further

6.1-Month Improvement in Median IRF†-Assessed PFS‡1 Placebo + trastuzumab + docetaxel

PERJETA + trastuzumab + docetaxel

100 90 80

18.5

MONTHS

60 PFS (%)

HR = 0.62 95% CI [0.51-0.75] P< 0.0001

12.4

40 30

MONTHS

20 10 0

P+T+D Pl+T+D

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk IRF = independent review facility. PFS = progression-free survival.

† ‡

Select Important Safety Information: Most Common Adverse Reactions

The most common adverse reactions (>30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.1 Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information. For more information, scan the QR code or visit www.PERJETA.com.

Reference: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. *HER2+ = human epidermal growth factor receptor 2 positive.

HER0000955000

Printed in USA.

(06/12)

PERJETA™ (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA™ (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

ASCOPost.com | AUGUST 15, 2012

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Direct from ASCO

Clinicians to Benefit from New JCO Initiatives

ournal of Clinical Oncology (JCO) has recently launched several new features for readers under the direction of Stephen A. Cannistra, MD, who began his tenure as Editor-in-Chief in June 2011. These initiatives include the creation of two new article types: Rap� id Communications (RC) and Under� standing the Pathway (UTP). RC papers are original reports with significant potential to become practice changing and are free access upon publication. UTP articles are written to accompany select original reports and explain the underlying pathway or biology presented in a study. The podcast program is a recent initiative that has now become a main� stay for many online users, providing key results from a clinically useful per� spective for those on the go. Also, the launch of the JCO app for commonly used mobile devices has further en� hanced the ability of readers to access timely and practice-changing infor� mation from virtually anywhere.

New Initiatives Bring Latest Research into Daily Practice As part of JCO’s ongoing com� mitment to help clinicians bring the latest research into daily practice, the Journal has now embarked on two additional initiatives. First, video in�

struction is being offered online with select original reports to illustrate important medical procedures (eg, laparoscopy). Articles with video content are identified in the print version with a video icon in the Table of Contents and include a QR code at the end of the article for quick ac� cess with a mobile device. The other initiative is the cre� ation of a third new article type, called Oncology Grand Rounds (OGR). These articles are written to accompany select original re� ports by leading experts, who dis� cuss common patient scenarios and then suggest the best management approaches based on the literature and their own clinical experience. “I have often felt that it is diffi� cult for busy practitioners to fully know how to integrate the findings

Fig. 1: Achieving thematic consistency in the Journal of Clinical Oncology. Figure was originally printed in Cannistra S: J Clin Oncol. July 2, 2012 (early release online). © American Society of Clinical Oncology. All rights reserved.

of original research into their own clinical practice, and my hope is that this new [OGR] section will help to accomplish this goal,” said

I have often felt that it is difficult for busy practitioners to fully know how to integrate the findings of original research into their own clinical practice, and my hope is that this new [OGR] section will help to accomplish this goal. —Stephen A. Cannistra, MD

Dr. Cannistra. “These articles are expected to be data-driven and rec� ognize all relevant literature ( JCO or otherwise), including ASCO Practice Guidelines and Provision� al Clinical Opinions where appro� priate.” JCO envisions that these initia� tives will help create a thematic con� sistency around high-profile origi� nal reports (Fig. 1), and will better enable its readership to take another step toward the ultimate goal of pro� viding better patient care.

■

ASCO University’s e-Seminars Offer a Stimulating Way to Stay on Top of Trends as Well as Meeting Highlights

id you miss one of the sympo� sia this year and need to quickly catch up on the highlights in small, digestible portions? No problem. ASCO University’s e-Seminar series now has you covered. Or, is there a new journal article that everyone’s talking about, and you need guidance on how to inter� pret it, preferably by the lead author? ASCO’s e-Seminars have you cov� ered there, too. Launched in 2011, e-Seminars are 1-hour live webinars on current issues in cancer care. Produced through ASCO University, they take place on the last Thursday of each month (ex� cept for July and August) and include

a 45-minute presentation by thought leaders in specific topics, followed by a 15-minute question-and-answer session. Presented live, the e-Semi� nars are recorded and then become available to watch at any time.

Live Format and Current Topics Meet Need With the pace of innovation moving fast, now was the time to offer education in this format to oncologists and others involved in cancer care, said Don S. Dizon, MD, Assistant in Medicine at Mas� sachusetts General Hospital, and Immediate Past Chair of ASCO’s Integrated Media and Technology

Committee, the plan� ning group that over� sees the e-Seminars and determines the webinar topics. “Even in just the last 10 years, there’s been a huge influx of informa� tion; the field is chang� ing so rapidly,” he said. “We felt there was a need, particularly for community health providers, but also for aca� demic clinicians, to have a stimu� lating way to stay on top of what’s happening in the field.” Attendance on the live webinars is growing as word about them spreads.

Don S. Dizon, MD

Heather M. Hylton, MS, PA-C

Aimed at All Oncology Professionals Heather M. Hylton, MS, PA-C—the lead physician assistant in the Department of Medicine at Memorial Sloan-Kettering Cancer continued on page 41

The ASCO Post | AUGUST 15, 2012

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Direct from ASCO

ASCO Responds to Supreme Court Ruling on Health-care Law

hen the Supreme Court up� held the Patient Protection and Affordable Care Act on June 28, ASCO released a statement by ASCO President Sandra M. Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center.

to provide coverage of pre� ventive screenings for cancer without charging copayments or coinsurance to individuals. This applies to private healthcare insurance, Medicare, and Medicaid. Promoting access to preventive screenings is an im� portant step that will save lives

ASCO will continue to work with policy makers to protect and retain these core patient safeguards that are critical to individuals who have cancer or who are at risk for cancer. — Sandra M. Swain, MD

able Care Act ensures that in� dividuals are not excluded from enrolling in a health insurance plan on the basis of preexisting conditions. ■■ Protections for patient access to clinical trials. The Afford� abe Care Act ensures that indi� viduals with cancer are covered under private insurance if they and their physicians determine enrollment in a clinical trial is their best option. This protec�

Volume 29, Issue 15

May 20, 2011

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

Critically Important Provisions In the statement, Dr. Swain highlighted some of the provisions contained in the Affordable Care Act “that are critically important to the treatment and screening of can� cer, and will help eliminate dispari� ties in patients with cancer.” These provisions, most of which have enjoyed significant bipartisan sup� port, include: ■■ Protections for patient access to preventive screening for cancer. The Affordable Care Act includes safeguards

and improve the quality of care through earlier diagnosis and better outcomes. ■■ Protections to help vulnerable individuals with cancer secure and retain access to healthcare insurance. The legislation requires insurers to allow indi� viduals to remain covered under their parents’ health insurance plan until at least age 26. The Act also eliminates lifetime caps on insurance coverage. ■■ Safeguards for individuals with cancer and other preexisting conditions. The Afford�

ASCO’s Guideline on Sentinel Lymph Node Biopsy for Melanoma

irect your patients to www. cancer.net/whattoknow so they can learn about ASCO’s re� cent guideline on sentinel lymph node biopsy for melanoma, in� cluding what it means for patients and a list of questions to ask the

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

www.jco.org

tion already exists for Medicare beneficiaries. “As the ongoing policy debate unfolds, ASCO will continue to work with policy makers to pro� tect and retain these core patient safeguards that are critical to in� dividuals who have cancer or who are at risk for cancer,” Dr. Swain said.

■

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

What’s Hot in

JCO

JCO.org Choosing the Best Trastuzumab-Based Adjuvant Chemotherapy Regimen: Should We Abandon Anthracyclines?

DNA Methylation As a Clinical Marker in Oncology

Adjuvant Therapy for Gastric Cancer: Revisiting the Past to Clarify the Future

Targeting the Notch Pathway: Twists and Turns on the Road to Rational Therapeutics

Brentuximab Vedotin and Panobinostat: New Drugs for Hodgkin’s Lymphoma—Can They Make One of Medical Oncology’s Chemotherapy Success Stories More Successful?

ASCOPost.com | AUGUST 15, 2012

PAGE 41

Direct from ASCO

ASCO University e-Seminars continued from page 39

Center and e-Seminar Work Group Leader for ASCO’s Integrated Media and Technology Committee—point� ed out the multidisciplinary nature of the e-Seminars. “They are an excellent resource for oncology professionals, includ� ing physician assistants and nurse practitioners,” she said. “They are based on current educational needs, but also current practice issues, and they provide information that oncology professionals need to im� prove not only their practice, but patient outcomes.”

inar planning group is now working with the Journal of Oncology Practice to create content addressing key is� sues that relate to running a practice. An e-Seminar slated to run in No� vember will focus on fostering team dynamics within practices that are using advanced practice providers.

Dr. Dizon pointed out that the eSeminar planners are always open to suggestions on new areas to tackle. “I recommend that folks review what’s available and then reach out to ASCO if there are any other top� ics they’d like to see covered,” he said. “We want them to bring it to

our attention so we can better serve them.” To submit potential topics for fu� ture e-Seminars via email, write to university@asco.org.

■

Offering Education beyond Traditional Formats Dr. Dizon added that learning on� line is a nice complement to keeping abreast of trends and advancements via printed materials such as journals. “Print is very important, but I be� lieve that having a stimulating, live seminar in which you listen to the thought leader in a certain topic and then get to ask questions also works really well in terms of teaching,” said Dr. Dizon. After the live presentation, the e-Seminar then becomes available along with slides and a bibliography. The cost is $53 per e-Seminar, with 20% off for ASCO members. Oncol� ogy fellows in training can access the e-Seminars for free. e-Seminars are available for pur� chase via the new ASCO Bookstore platform at www.asco.org/store. All current e-Seminar offerings are displayed at university.asco.org/elearning/seminars.

Practice-related Topics on the Horizon The Integrated Media and Tech� nology Committee and the e-Sem�

Recent e-Seminar Titles ■■ Use of Multigene Assays in Breast and GI Cancers

■■ Implementing an EHR into Oncology Practice

■■ Lymph Node Dissection in Breast Cancer

■■ Five Things Physicians and Patients Should Question

■■ Quality Improvement:

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

Getting Started

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The ASCO Post | AUGUST 15, 2012

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Direct from ASCO

Former Foundation Grantee Pays It Forward, Building a Legacy for the Next Generation

undreds of investigators, Designed to extend the impact of such as 2008 Young Inves� the Foundation’s investment, the tigator Award and 2010 Career YIA provides funding for an ear� ly-career investigator to conduct Development Award recipient an innovative research project Richard Carvajal, MD, have re� under the men� ceived seed fund� torship of a for� ing from ASCO’s You, too, have the mer Foundation Conquer Cancer grantee like Dr. Foundation early ability to expand the Carvajal. in their careers— horizon of cancer The Leader� funding that sup� research and leave your ship to Legacy ported their pro� campaign, sup� fessional growth legacy in oncology ported entirely and helped lay by supporting the by ASCO Mem� the foundation bers and oncolo� for their develop� Foundation’s 2012 gy professionals, ment into today’s Leadership to Legacy raised enough oncology lead� funding to sup� ers. Committed campaign. port a $50,000 to improving the YIA in 2011 lives of people and 2012. The 2012 Leadership with cancer now and in the future, to Legacy YIA recipient is James many of these past grantees are Harding, MD, an outstanding re� now mentoring the next genera� searcher at Memorial Sloan-Ket� tion of researchers. They are ex� tering Cancer Center. Dr. Hard� ponentially increasing the impact ing’s award supports his project, of the Foundation’s initial invest� “A Phase 2 Trial of Vorinostat in ment by imparting their expertise Patients with Metastatic Uveal and insight to eager young scien� Melanoma: Exploring the Molec� tists. ular Effects and Therapeutic Im� plications of Histone Deacetylase Inhibition in Uveal Melanomas,” which he will conduct under Dr. Carvajal’s professional guidance and mentorship.

Expanding the Horizon of Cancer Research Richard Carvajal, MD

Foundation Lauches Leadership to Legacy Campaign The number of research pro� posals the Foundation receives annually far surpasses its funding capacity. In 2010, to provide even more young investigators with the opportunity to pursue their pas� sion, the Foundation launched the Leadership to Legacy™ cam� paign to raise support for a unique Young Investigator Award (YIA).

Both the YIA and Dr. Carvajal’s mentoring will allow Dr. Harding to gain invaluable clinical research experience and help build the groundwork for his future in on� cology. You, too, have the ability to expand the horizon of cancer research and leave your legacy in oncology by supporting the Foun� dation’s 2012 Leadership to Legacy campaign. Help jump-start the career of a passionate young re� searcher and make it possible for the Foundation to fund the 2013 Leadership to Legacy YIA. To make a gift, visit www.conquercancer�

foundation.org/donate today. Be sure to specify “Leadership to Legacy” in the comments field.

■

Volume 7, Issue 3

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

www.jop.ascopubs.org

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

What’s Hot in

JOP

JCO.org Socioeconomic and Physician Supply Determinants of Racial Disparities in Colorectal Cancer Screening

Health Care Costs for Patients With Cancer at the End of Life

Health Policy Conflict of Interest Disclosure in Off-Label Oncology Clinical Trials

Use of a Urine Anastrozole Assay to Determine Treatment Discontinuation Among Women With Hormone-Sensitive Breast Cancer: A Pilot Study

Ethics of Ongoing Cancer Care for Patients Making Risky Decisions

Allen S. Lichter, MD 2006-Present ASCO Chief Executive Officer

Sandra M. Swain, MD 2012-2013 ASCO President

David H. Johnson, MD

Shape Your Future and Ours

2012-2013 Leadership Development Program, Immediate Past Chair

Join ASCO’s Leadership Development Program Apply today at www.asco.org/leadership

ASCO Member Since 1980

ASCO Member Since 1986

ASCO Member Since 1984

Join ASCO’s Leaders of Tomorrow. Today If you completed your final subspecialty training between 2003 and 2008 and are interested in becoming a future leader in ASCO, our Leadership Development Program is for you. Participants in this year-long program will learn valuable leadership skills and gain exposure to the roles and mission of ASCO and the Society’s powerful place in developing the future of cancer care.

This program requires a time commitment for travel and training. If selected you will: • Network with and receive mentorship from ASCO leadership • Interact with ASCO committees and government research agencies • Enhance leadership skills through interactive sessions • Receive first-hand advocacy experience on Capitol Hill

To apply today or view the full eligibility requirements for ASCO’s Leadership Development Program, visit www.asco.org/leadership. Applications must be received by September 19, 2012.

“The ASCO Leadership Development Program strives to teach its participants how to build a team and then lead that team to greatness. As participants in this program, we have been challenged to define a strategic issue and work together to reach a desired outcome. I see this program as a springboard for future leadership opportunities in my clinic and oncology” Melissa Dillmon, MD, FACP, Harbin Clinic

The ASCO Post | AUGUST 15, 2012

PAGE 44

2012 ASCO Annual Meeting Lapatinib Shows Value Similar to Trastuzumab in Neoadjuvant Regimens for Breast Cancer, but with Greater Toxicity By Caroline Helwick

apatinib (Tykerb) proved valu� able as a component of neoad� juvant chemotherapy for HER2positive operable breast cancer in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 trial presented at the 2012 ASCO Annual Meeting by Andre Robidoux, MD, of the NSABP and the University of Montreal Hospital Center in Canada.1

Similar Complete Response Rates “Substitution of lapatinib for trastuzumab [Herceptin] in com� bination with the chemotherapy program employed in this study re� sulted in similar high percentages of pathologic complete responses in both hormone receptor–positive and hormone receptor–negative cohorts. Combined HER2-targeted thera� py produced a numerically higher [pathologic complete response] percentage than single-agent HER2directed therapy, but the difference was not statistically significant,” said Dr. Robidoux. The phase III NSABP B-41 evalu� ated whether dual HER2 inhibition with trastuzumab plus lapatinib im� proves pathologic complete response rates over trastuzumab alone as neo� adjuvant chemotherapy. The study also compared the relative efficacy of the two anti-HER2 agents in this set� ting. The 529 patients received four cycles of standard neoadjuvant che� motherapy with doxorubicin plus cyclophosphamide (AC) followed by weekly paclitaxel (P). Concur� rent with the weekly paclitaxel, pa� tients were randomly assigned to re� ceive trastuzumab, lapatinib (1,250 mg/d), or trastuzumab plus lapa� tinib (750 mg/d) prior to surgery. After lumpectomy or mastectomy, all women received trastuzumab for 1 year.

Dual Inhibition The pathologic complete response rate was 52.5% with AC→P plus trastuzumab, 53.2% with AC→P plus lapatinib, and 62% with AC→P plus trastuzumab and lapatinib. “A higher percentage receiving the combination had a [pathologic complete response], but the difference was not statistically significant (P = .095),” he noted. The combination also produced a numeri� cally higher clinical complete response rate (76.8% vs 52% with trastuzumab and 69.9% with lapatinib), but there was no difference in rates of breastconserving surgery. By hormone receptor status as well, the addition of lapatinib to trastuzumab yielded a numeric, though not a statistically significant, benefit over the single agents. In hor� mone receptor–negative patients, the pathologic complete response rate was 73.0% with the combina� tion, 65.5% with AC→P plus trastu� zumab, and 60.6% with AC→P plus lapatinib. In the hormone receptor– positive cohort, pathologic complete responses were observed in 55.6% receiving the combination, in 46.7% receiving AC→P plus trastuzumab, and in 48.0% receiving AC→P plus lapatinib. “Despite the fact that 73% of the hormone receptor–negative popula� tion obtained a pathologic complete response, this was not significant,” said Dr. Robidoux. When pathologic complete re� sponse was defined as no residual disease in both the breast and nodal tissue, those rates were 49.4% with trastuzumab, 47.4% with lapatinib, and 60.2% with the combination, which was marginally significant (P = .056), he added.

Unplanned Analysis “Intriguing findings” were made in an unplanned analysis based on immunohistochemistry (IHC) stain�

Neoadjuvant Lapatinib in Breast Cancer ■■ NSABP B-41 showed that lapatinib was as effective as trastuzumab as a component of neoadjuvant chemotherapy.

■■ Patients receiving lapatinib had more toxicity and treatment discontinuations than those receiving trastuzumab.

EXPERT POINT OF VIEW

unter von Minckwitz, MD, PhD, of the German Breast Group and the University of Frankfurt, discussed the findings of the NSABP B-41 trial. He observed that lapatinib was not more effective than trastuzumab, which is in line with increasing evidence in various breast cancer settings showing greater activity for trastuzumab. “There is initial high efficacy of lapatinib that might be impaired by rapid development of sec� Gunter von Minckwitz, MD, PhD ondary resistance,” he said. Lapatinib is also associated with toxicity that results in diminished dose intensity and exposure, he noted, but he does not believe this compromises efficacy. “In GeparQuinto, we showed that only in patients receiving less than 700 mg/d was the [pathologic complete response] rate decreased,” he said. “The therapeutic window of lapatinib is quite wide, and therefore, discontinuation of treatment may not be so relevant for pa� tients.”

Anticipated Results The emphasis should be on dual HER2 blockade, he emphasized. “This is the most promising approach for the future,” he said, adding that highly anticipated results from the ALLTO and APHINITY studies will be infor� mative as to whether neoadjuvant results are predictive of outcomes in the adjuvant and metastatic settings. If this proves to be the case, he said, “this might open the regulatory pathway for conditional approval of agents in early development.”

■

Disclosure: Dr. von Minckwitz reported no potential conflicts of interest.

ing intensity, he said. In patients who were fluorescence in situ hybridiza� tion (FISH)-positive but IHC-low (0, 1, or 2), the pathologic complete response rate was 41.7% with trastu� zumab, 60.9% with lapatinib, and 25% with the dual inhibition; the differences were not statistically sig� nificant. However, in the IHC3+ group, pathologic complete responses were observed in 54.7%, 53.2%, and 71%, = .006 for the combi� respectively (P �� nation vs single agents). The test for interaction with IHC level was also statistically significant (P = .021), Dr. Robidoux reported. “This sug� gests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high de� gree of protein overexpression,” he maintained. “It might be of importance for on� going and future trials using dual in� hibition of HER2 to confirm what has been suggested in B-41—ie, that the dual inhibition seems to work better in patients with tumors overexpressing HER2,” he told The ASCO Post.

Toxicity Concerns While lapatinib was beneficial as a neoadjuvant agent, toxicity was a draw� back, he acknowledged. Fewer patients receiving lapatinib completed treat� ment, compared to those receiving trastuzumab alone (63% vs 68%; P = .01). And grade 3 See Page 86 and 4 adverse events were more common in the lapatinibcontaining arms (60% and 62%) com� pared to trastuzumab (50%). Diarrhea accounted for most of the toxicity with lapatinib but was rare with trastuzum� ab (P < .001). Other toxicities were similar.

■

Disclosure: Dr. Robidoux has served as consultant or advisor to GlaxoSmithKline and has received honoraria and research funding from GlaxoSmithKline and Roche.

Reference 1. Robidoux A, Tang G, Rastogi P, et al: Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ oper� able breast cancer: NSABP protocol B-41. 2012 ASCO Annual Meeting. Abstract LBA506. Presented June 3, 2012.

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

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

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

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

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

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

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

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

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

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

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

Visit www.jakafi.com/regulate

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

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

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

b Symptom

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

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

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

JAK targeted to make a difference

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

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

ASCOPost.com | AUGUST 15, 2012

PAGE 49

Trailblazer in Argentinean Oncology Remains Optimistic about War on Cancer By Ronald Piana

Eduardo Cazap, MD, PhD

duardo Cazap, MD, PhD, is founder and first President of the Latin American and Caribbean Society of Medical Oncology (SLACOM). In 2008, he was elected to a 2-year term as President of the International Union against Cancer (UICC). The ASCO Post recently spoke with Dr. Cazap about his roots in oncology and his mission to en� hance global cancer care.

Oncology Training What inspired your decision to pursue a career in oncology? When President Richard Nixon signed the National Cancer Act of 1971, I was just graduating from medical school in Argentina. Cancer was a new and exciting field, so after completing my residency in internal medicine, I applied and was accepted for a 2-year training program in oncology at the military hos� pital in Buenos Aires under the super� vision of Prof. Roberto Estevez, who is considered the father of Argentinean and Latin American chemotherapy. Back then, we were limited to a few anticancer drugs, and we were called chemotherapists, not oncologists. The concept at the time was far from the multidisciplinary one of today. In a nutshell, we were doctors trained to administer chemotherapy. That said, in Argentina, the disciplines of solid tumor oncology and hematology are separate. As a student, if you are in� terested in cancer, you must choose one or the other as your career path. I chose oncology. This model still exists.

Early Career Were there any pivotal experiences ear� ly on in your career that helped shape your

future role on the international stage? Yes, I had the opportunity to be in� volved in a very interesting project con� ducted by a couple of institutions in Argentina, the NCI in the United States, and several international organizations, which was called the Collaborative Cancer Treatment Research Program (CCTRP). I was fortunate to be one of the young investigators on the CCTRP team that went to the United States. Our U.S. counterpart for the project was Georgetown University in Washington, DC. The Lombardi Cancer Center af� filiated with Georgetown had just been launched, and the Director was ASCO Past President Philip Schein, MD. One of our clinical trials was in gas� tric cancer, looking at the then new agent epirubicin. The trial was suc� cessful, and we reported the results in the journal Tumori. Epirubicin subse� quently received approval in Japan and then later in the United States. We also participated in a study of the FAP regi�

tin and carboplatin in cervical cancer. Breast cancer has classically been considered a major problem of devel� oped nations, much more so than in developing nations. However, over the past 20 years, my interest in breast can� cer developed largely because of the prevalence of the disease in our region. For example, Uruguay, which sits on the northwest border of Argentina, is a small country with only 3�� million peo� ple, and it has one of the highest breast cancer incidence rates in the world. Since most of the world’s breast cancer treatments came from data gathered in developed nations, we were treating our patients in Uruguay and Argentina with therapies that were designed for patients who had biologic differences. To me, that was a contra� diction, so I began conducting breast cancer investigations in Latin America to develop treatments better tailored to those populations. In fact, in one of my lectures, “Breast

I firmly believe that over the next 20 to 30 years, we will see an astounding leap in our ability to prevent, cure, and manage most cancers. —Eduardo Cazap, MD, PhD

men (fluorouracil, doxorubicin, cispla� tin) and published our findings in the NCI’s Cancer Treatment Reports. This early experience was an impor� tant juncture in my career. Even though I came from a country with limited re� sources, those valuable contacts and international collaborations helped me to become proactive and forwardlooking, as I led the way to using exter� nal resources to help build better cancer research and care in Argentina.

Focus of Investigations You are internationally recognized for work in breast cancer. What were your early clinical trial interests? My early interests were less personal choices and more decisions driven by other forces. I essentially began my in� vestigations where the funding took me. For instance, about 30 years ago we received some fairly generous support from Bristol-Myers in looking at cispla�

Cancer as a Global Health Problem,” I presented the genetic map of the world demonstrating that the genetic-based distribution of breast cancer varies quite a bit geographically. It is not clin� ically sound to develop one-size-fitsall therapies by extrapolating trial data originating from disparate regions. Has this region-targeted approach led to clinical trials in Argentina? Yes, we’re currently doing several breast cancer trials. One is in collaboration with a group from Memorial Sloan-Kettering Cancer Center led by Dr. Larry Norton. Interestingly, this particular trial is funded completely independent of the pharma� ceutical industry. Since we are developing trials that answer questions about our pa� tient populations within specific regions, our mission doesn’t really connect with the pharmaceutical industry, which tries to develop drugs that can be marketed to as many patients as possible.

Access to Cancer Care Is access to care an issue in Argentina? In Argentina, a law was passed about 10 years ago that covers people with cat� astrophic illnesses such as AIDS, some neurologic diseases, and cancer. Under the law, if a person is diagnosed with can� cer, he or she must have complete insur� ance coverage for all medical treatments. Moreover, our unions and private busi� nesses are also obliged to provide cov� erage for their workers, so between the government and the private sector, we have, in effect, universal coverage for can� cer care. Naturally, there are some delays and limitations within the system, but on the whole, it works well, providing qual� ity care for all our patients with cancer, regardless of their economic status.

Global Agenda Please tell the readers about your leadership role at the UICC. Today, UICC is an international can� cer control organization, which realizes that control goes beyond the diagnosis and treatment of cancer. We must em� phasize the complete spectrum of can� cer, including education, prevention, and registration data. Over the past 15 years I have been totally engaged in promoting cancer on the global agenda. With a growing worldwide cancer pop� ulation that is outstripping the capabilities of the existing doctor force, it is vitally important to have outreach efforts from worldwide organizations like UICC and ASCO, along with governmental support. We need a massive collaborative effort. Are you optimistic that we are up to the challenges posed by the global cancer problem? I am eternally optimistic. If you look at the dramatic increase in early detec� tion and cure rates over the past several decades, how can you not be optimistic? I firmly believe that over the next 20 to 30 years, we will see an astounding leap in our ability to prevent, cure, and man� age most cancers. Ultimately, we are all responsible for successful results in our collective War on Cancer. If each party clearly understands their vital role, we will advance in winning that war.

■

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

The ASCO Post | AUGUST 15, 2012

PAGE 50

2012 ASCO Annual Meeting Improving Outcomes and Prediction in Ductal Carcinoma in Situ By Caroline Helwick

isk stratification and outcomes can be improved for women with ductal carcinoma in situ (DCIS), ac� cording to two studies presented at the 2012 ASCO Annual Meeting.

RTOG 9804 Findings from the Radiation Therapy Oncology Group (RTOG) 9804 trial suggested that even for DCIS patients whose prognosis is al� ready favorable, radia� tion therapy is highly beneficial.1 “For pa� tients with ‘good risk’ disease, the addition See Page 86 of radiation signifi� cantly reduced the risk of local failure,” said Beryl McCormick, MD, of Memo� rial Sloan-Kettering Cancer Center, New York. The study was conducted among 585 patients with small, low-grade asymp� tomatic tumors who underwent lumpec� tomy and achieved adequate resection

margins. The patients were randomly assigned to observation or radiation therapy; 62% also received tamoxifen. Radiation therapy was initiated within 12 weeks of surgery and consisted of 42.5 to 50.4 Gy with no boost. Dr. McCormick reported that the ac� tuarial 5-year rate of local failure (invasive or noninvasive) was 3.2% in the observa� tion arm and 0.4% in the radiation arm, for an 86% reduction in risk (P = .002). With radiation, there were no local failures within the quadrant of the primary tumor, but in the observation arm, two-thirds of the failures occurred there. Contralateral cancers, disease-free survival, and overall survival were similar between the arms. Adverse events were comparable, and only 0.7% of the radiated group experienced late grade�� 3 or higher ra� diation therapy toxicity.

DCIS Score Adds Prognostic Information In a separate presentation, inves�

Update on Managing DCIS ■■ Radiation therapy is beneficial even for “good risk” patients with ductal carcinoma in situ.

■■ In RTOG 9804, local recurrences were diagnosed in 3.2% of the observation arm and 0.4% of the radiation therapy arm, for an 85% reduction in risk.

■■ In a subanalysis of E5194, the 12-gene DCIS score risk-stratifies patients into high-, intermediate-, and low-risk groups, whose 10-year recurrence risks were 27%, 24%, and 12%, respectively.

■■ The DCIS score adds prognostic information above and beyond traditional pathologic variables.

tigators reported that the new DCIS score independently predicted the risk of ipsilateral recurrence or invasive disease.2 The score is modeled on the Oncotype DX recurrence score, using the same validated technique but a dif� ferent 12-gene signature. The score divided patients into a high-risk group, which had a 27% risk of recurrence at 10 years; an intermediaterisk group, which had a 24% risk; and a low-risk group, whose risk was 12%.

EXPERT POINT OF VIEW

un-Sil Shelley Hwang, MD, MPH, of Duke University Medical Center, Durham, North Carolina, who discussed both papers on ductal carcinoma in situ at the ASCO Annual Meeting, noted that better risk stratification and treatments are substantially changing the outlook for DCIS. “We are getting close to the point where patients treated for DCIS have a local recurrence risk that is just as low as, and perhaps lower than, their risk for con� tralateral breast cancer,” she said. The positive results of the RTOG tri� al, she suggested, may be due to several factors. “There was a lower recurrence rate in the excision-only group than had been predicted, but what drove the posi� tive findings was the much lower rate in the radiation therapy group,” she said. The low rate of recurrence—only 3% even without radiation therapy— might also have been influenced by the administration of tamoxifen in two-thirds of the women, and perhaps by the short follow-up, she suggested, emphasizing that further follow-up of these women is required. “Although the reduction in recur� rence is low, the baseline recurrence risk is also extremely low,” Dr. Hwang told The ASCO Post. “Would most

women want to undergo 6 weeks of radiation to reduce their risk from 3% to below 1%? And there is still con� tralateral risk as well,” she added. “I am also worried that the overall risk is very low—much lower than an� ticipated. We know that low-risk disease takes longer to recur. Longer follow-up may reveal that the benefit of radiation is really not significant in this low-risk group…. In the meantime, the goal is to be smarter about whom we give treat� ment to, not to give treatment to every� one with negligible risk,” she said.

Risk-stratification Tools Commenting on the DCIS score, Dr. Hwang agreed with the investiga� tors: “The DCIS score gives additional information above and beyond tradi� tional pathologic variables,” she said. She said the observed weak associa� tion between nuclear grade and recur� rence answers some of the “often-heard criticism” that the DCIS score and Oncotype DX score “may just be surro� gates—very expensive surrogates—for proliferative index or Ki-67.” But while the DCIS score is “an interesting molecular tool,” Dr. Hwang said that other risk-

In a subgroup analysis of the pro� spective validation study, E5194, each 50-point increase in DCIS score was as� sociated with more than a doubling in the risk of recurrence of DCIS or invasive disease (HR = 2.41; P = .02), according to Sunil S. Badve, MBBS, FRCPath, of Indiana University School of Medicine, Indianapolis. The study followed 327 DCIS pa� tients treated with wide local excision; 29% received tamoxifen and none re� ceived radiation therapy.

Further Findings

Eun-Sil Shelley Hwang, MD, MPH

stratification tools are in development, including one that combines Ki-67, Cox-2, and P16, and if validated, these should also be useful. Additionally, nextgeneration sequencing, further molecu� lar characterization with epigenomics and proteomics, and better character� ization of stromal factors should lead to even greater refinement of risk stratifica� tion in breast cancer. “But none of this is important un� less we can implement them in the treatment of patients,” she cautioned. “And in this increasingly resourceconstrained environment, cost-effec� tiveness issues will also be very impor� tant to analyze as we go forward.”

■

Disclosure: Dr. Hwang has served as a consultant or advisor for Genomic Health and receives research funding from Merck.

Tumor size and postmenopausal status were also independent predic� tors, but the score was only moder� ately correlated with histologic grade and with the percentage of cells show� ing comedo necrosis, and was poorly correlated with tumor size. There was no correlation between the score and patient’s age, menopausal status, DCIS histologic pattern or margin status. “The DCIS score provides indepen� dent information on ipsilateral breast risk beyond clinical and pathologic vari� ables,” Dr. Badve said, noting that it will help identify a subset of patients who may be at increased risk despite their profile based on traditional criteria.

■

Disclosure: Dr. McCormick reported no potential conflicts of interest. Dr. Badve has served as a consultant or advisor for Genomic Health.

References 1. McCormick B, Winter K, Hudis C, et al: RTOG 9804: A prospective random� ized trial for “good risk” ductal carcinoma in situe, comparing radiation to observa� tion. 2012 ASCO Annual Meeting. Ab� stract 1004. Presented June 5, 2012. 2. Badve SS, Gray RJ, Baehner FL, et al: Correlation between the DCIS score and traditional clinicopathologic features in the prospectively designed E5194 clinical vali� dation study. 2012 ASCO Annual Meeting. Abstract 1005. Presented June 5, 2012.

ASCOPost.com | AUGUST 15, 2012

PAGE 51

2012 ASCO Annual Meeting Genitourinary Oncology

Patient Preference Studied in Treatment Selection for Renal Cell Carcinoma By Alice Goodman

ore attention is being paid to the importance of patient preference as a factor in treatment selection. An in� novative randomized, double-blind study in patients with metastatic kidney cancer demonstrates that quality of life and side effects drive patient preference.1 Results also suggest that physicians perceive qual� ity-of-life differences between therapies as less important than patients do.

than for those taking sunitinib (13% vs 20%, respectively). Likewise, fewer treat� ment interruptions occurred in patients on pazopanib (6% vs 12%, respectively).

■

Disclosure: Dr. Escudier has served in a

consulting or advisory role for AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer.

Reference 1. Escudier BJ, Porta C, Bono P, et al: Patient preference between pazopanib and

sunitinib: Results of a randomized, doubleblind, placebo-controlled, cross-over study in patients with metastatic renal cell carci� noma—PISCES study, NCT 01064310. 2012 ASCO Annual Meeting. Abstract CRA4502. Presented June 2, 2012.

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life?

Bernard J. Escudier, MD

“We expected patients would prefer one drug over another, but we didn’t ex� pect this great a difference,” said lead au� thor Bernard J. Escudier, MD, Institut Gustave Roussy, Villejuif, France. “This is an excellent method to report the way pa� tients are feeling about the side effects of drugs. Remember that low-grade toxici� ties may not seem bad to physicians, but toxicity over a long time can affect quality of life. Traditional adverse event reporting does not consider how patients feel when they take a drug over many months.”

Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health

Major Results Patients were treated with either pa� zopanib (Votrient) or sunitinib (Sutent), and they preferred pazopanib, in this study supported by GlaxoSmithKline (manufacturer of pazopanib). At the press conference where this study was discussed, experts said that they were assured that results were not biased be� cause of the blinded study design. The study included 169 patients ran� domly assigned to pazopanib for 10 weeks followed by a 2-week washout period and then sunitinib for 10 weeks, or vice versa. Pazopanib was preferred by 70% of pa� tients, sunitinib was preferred by 22%, and 9% had no preference. When physicians were asked which drug they preferred, 60% preferred pazopanib, 21% preferred sunitinib, and 21% had no preference. Improved quality of life and less fatigue were the most common reasons patients cited for preferring pazopanib over suni� tinib. Additionally, fewer dose reductions were needed for patients taking pazopanib

• Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

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

The ASCO Post | AUGUST 15, 2012

PAGE 52

2012 ASCO Annual Meeting Thoracic Oncology

FDG-PET Falls Short for Diagnosis of Non–Small Cell Lung Cancer By Alice Goodman

he ability to make a diagnosis of non–small cell lung cancer (NSCLC) with FDG-PET varies widely among centers, and this imag� ing modality performed more poorly in community and academic centers than in published studies.1 A second� ary analysis of the prospective Amer� ican College of Surgeons Oncol� ogy Group (ACOSOG) Z4031 trial based on written radiology reports found that FDG-PET had lower sen� sitivity and specificity in patients with known or suspected NSCLC than has been shown in previously published trials. No additional re� view of FDG-PET images was under� taken for the trial. “Current [National Comprehen� sive Cancer Network (NCCN)] guidelines recom� mend FDG-PET for diagnosis of suspected NSCLC, based on studies See Page 86 showing a high de�

was 82% and the specificity was 31%.

Study Details

Eric L. Grogan, MD

gree of accuracy. We found that FDGPET performs poorly at single institu� tions…. The results of PET scans in this population should be interpreted cautiously,” said lead author Eric L. Grogan, MD, Vanderbilt University Medical Center, Nashville. Previous meta-analyses of FDGPET used to diagnose NSCLC showed 94% sensitivity and 83% specificity, but the imaging was done at select cen� ters with more experience. ACOSOG Z4031 was conducted at 51 different sites at 39 cities in the United States and found the sensitivity of the scan

The study evaluated the accuracy of FDG-PET in diagnosing NSCLC in 682 patients enrolled in the trial between 2004 and 2006. All pa� tients had clinical stage I known or suspected NSCLC and underwent surgical resection. The sensitiv� ity, specificity, overall accuracy, and positive and negative predictive val� ue of FDG-PET scans was calculat� ed for all patients as well as for sites with more than 25 participants. Among 682 study participants (all of whom had preoperative FDGPET scans), there were 566 cancers and 116 benign lesions. The malig� nancy rate in patients with FDGPET scans was 83%; accuracy for di� agnosing lung cancer was 73%. The positive predictive value was 85%, and the negative predictive value was 26%. At the eight cities with more than 25 participants, the sensitivity

varied significantly—for example, 67% in Los Angeles and 91% in Dur� ham (P =.03). The accuracy of FDG-PET in� creased with lesion size. The accuracy was < 50% in lesions < 20 mm, but > 80% in lesions > 30 mm. Accuracy did not improve among subgroups of lesions larger than above 30 mm— that is, accuracy was similar for le� sions 31 to 50 mm, 51 to 70 mm, and > 70 mm. The investigators concluded that more research is needed to determine why performance of the scans varied so widely and did not match up with published studies.

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

Reference 1. Grogan EL, Deppen SA, Ballman KV, et al: Accuracy of FDG-PET to diag� nose lung cancer in the ACOSOG Z4031 trial. 2012 ASCO Annual Meeting. Ab� stract 7008. Presented June 4, 2012. Supportive Care

Antidepressant Drug Has ‘Clinically Meaningful’ Effect on Chemotherapy-induced Painful Neuropathy By Alice Goodman

he oral antidepressant dulox� etine (Cymbalta) at 60 mg/d improved chemotherapy-induced painful neuropathy in a randomized, double-blind, placebo-controlled, 1 phase III trial. Overall, 59% of pa� tients treated with duloxetine experi� enced some pain relief, 33% reported at least a 30% decrease in pain, and 21% reported at least a 50% decrease in pain.

Nursing, Ann Arbor. Duloxetine is the first drug shown to be effective for this disorder in a large randomized con� trolled trial. Painful chemotherapy-induced neuropathy interferes with activities of daily living and can manifest as numb� ness, tingling, or shock-like feelings, mainly in the feet and hands. Some pa� tients have this chronic painful adverse event for months or years, and it can be disabling.

About one-third of patients in the duloxetine arm had pain scores that were unchanged, and 11% had an increase in pain. “Unfortunately, no medication is completely effective,” she said.

Study Findings

Ellen Lavoie Smith, PhD

“The pain relief in this trial was clin� ically meaningful,” said Ellen Lavoie Smith, PhD, Assistant Professor in University of Michigan’s School of

The study included 231 patients treated with oxaliplatin or paclitaxel randomly assigned to duloxetine fol� lowed by placebo vs placebo followed by duloxetine. Although mean pain scores decreased in both treatment arms, the decrease was greater in the duloxetine arm. Also, when compared to placebo-treated patients, patients taking duloxetine reported less painrelated interference with activity, mood, walking, work, enjoyment of life, and social relationships.

Nicholas Vogelzang, MD

Side effects reported in less than 10% of patients included fatigue, insomnia, nausea, somnolence, and dizziness. Dr. Smith said that all patients were started on duloxetine at 30 mg/d for 1 week and then escalated to 60 mg/d for 4 additional weeks of treatment. The gradual dosing was used to re� duce the side effects of duloxetine.

‘A Step Forward’ Nicholas Vogelzang, MD, US Oncology in Las Vegas, said, “This is a step forward. Duloxetine won’t work for every patient, but a sig� nificant proportion gain pain con� trol. This gives a glimmer of hope for patients who are so debilitated by chemotherapy.” Dr. Vogelzang was moderator of an ASCO press confer� ence where this pa� See Page 86 per was discussed. Duloxetine is currently approved for the treatment of depression and painful diabetic neuropathy.

■

Disclosure: Drs. Smith and Vogelzang reported no potential conflicts of interest.

Reference 1. Smith EML, Pang H, Cirrincione C, et al: CALGB 170601: A phase III doubleblind trial of duloxetine to treat painful che� motherapy-induced peripheral neuropathy (CIPN). 2012 ASCO Annual Meeting. Abstract CRA9013. Presented June 5, 2012.

FOR PATIENTS WITH ADVANCED BCC

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

Turn the page to see more...

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

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

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

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

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

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea,

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3

Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

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

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 months (5.7-9.7)

7.6 months (5.6-NE)

ORR (95% CI)

Median response duration (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page. References: 1. Erivedge™ (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012; 366:2171-2179.

HED0001171901

See what you can offer your patients with advanced BCC at www.Erivedge.com

The ASCO Post | AUGUST 15, 2012

PAGE 56

2012 ASCO Annual Meeting Quality of Care

Taking Family History and Referral to Genetic Counseling Could Be Improved, Survey Finds By Alice Goodman

btaining a thorough family history of cancer should be a key component in evaluating pa� tients and deciding whether to refer

those at increased risk of either pri� mary or second cancers for genetic counseling and testing. Many com� munity oncology practices comply

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

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

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

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

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

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

with this practice, but there is room for improvement, according to a large survey of 271 practices and more than 10,000 charts of patients

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

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

with breast cancer or colon cancer.1 The retrospective sample included patients who were diagnosed within the previous 2 years and had at least two visits to the practice within 6 months. “This survey was a pilot test of quality measures regarding family history-taking and genetic counsel� ing and testing practices, as part of

Marie Wood, MD

ASCO’s Quality Oncology Prac� tice Initiative (QOPI),” explained Marie Wood, MD, University of Vermont, Burlington. “Family his� tory is the best criterion for identi� fying patients at risk for hereditary cancer who should be referred for screening.”

Key Data Key findings of the survey were as follows: 79% of patients’ charts included first-degree family histories of cancer, and 61% documented sec� ond-degree histories as well. A great� er number of patients with breast cancer than patients with colon can� cer had first- or second-degree fam� ily histories documented. However, less than one-third of patients’ charts documented the age of cancer diag� nosis of relatives. Twenty-two percent of all patients were referred for genetic counseling or genetic testing (29% of patients with breast cancer and 19% of those with colorectal can� cer). But among patients with he� See Page 86 reditary cancer risk, only 52% of pa� tients with breast cancer and 26% of those with colorectal cancer were re� ferred for counseling or testing. The survey also revealed that consent for testing conducted within a practice continued on page 57

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PAGE 57

2012 ASCO Annual Meeting Older Chemotherapy Studies in Breast Cancer Coming of Age By Caroline Helwick

esults of several long-running chemotherapy trials were report� ed at the 2012 ASCO Annual Meeting breast cancer oral session, reported in brief here.

NSABP B-38 The final analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 trial showed that the addition of gemcitabine (G) to a dose-dense regimen of doxoru� bicin/cyclophosphamide (AC) fol� lowed by paclitaxel (P) did not im� prove outcomes over AC→P alone or compared to the standard docetaxel/ doxor ubicin/c yclophosphamide (TAC) regimen in patients with breast cancer.1 “Gemcitabine did not improve outcome and the other regimens had differing toxicities, which can be taken into consideration when con� sidering which treatment to offer a patient,” said Sandra M. Swain, MD, of the Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC. The study enrolled 4,894 women with operable, node-positive breast cancer, randomly assigning them to (1) AC × 4 followed by paclitaxel × 4 every 2 weeks, (2) the same regi� men plus gemcitabine given with the paclitaxel, or (3) TAC every 3 weeks × 6. Disease-free survival at 5 years was 82.2% with dose-dense AC→P, 80.6% with dose-dense AC→PG, and 80.1% with standard TAC. Overall survival was approxi� mately 90% in all arms. The toxicity profiles, however, differed, with more neuropathy and anemia observed on the dose-dense arms and more diarrhea and febrile neutropenia on TAC. An exploratory analysis showed no outcome differ� ences according to whether or not patients received erythropoietin.

Genetic Counseling continued from page 56

was documented 77.7% of the time, and result disclosure documented for 78.8% of patients. “The survey found low rates of referral for those individuals who could benefit from genetic counsel� ing and testing,” Dr. Wood empha�

GEICAM/2003-02 The role of weekly paclitaxel in node-negative patients with breast cancer is being evaluated in the phase�� III Spanish Breast Cancer Re� search Group (GEICAM)/2003-02 trial, and the first efficacy analysis was reported at ASCO.2 The study randomly assigned 1,925 postsurgi� cal patients with high-risk node-neg� ative disease to adjuvant chemother� apy with fluorouracil/doxorubicin/ cyclophosphamide (FAC) × 6 or FAC ×�� 4 followed by weekly pacli� taxel at 100 mg/m2 for eight cycles. “Adjuvant FAC plus paclitaxel was associated with a slight but significant

ently contributed to more late cardiac toxicity. Dr. Martin acknowledged that the study was initiated 10 years ago, and with genomic testing, many of these patients would not have received che� motherapy at all. “We are going to evaluate these findings using Onco� type DX in tissue samples,” he said.

KCSG-BR 0702/NCT00561119 In patients with metastatic breast cancer who achieve disease control (complete response plus partial re� sponse plus stable disease) with pacli� taxel/gemcitabine (PG), maintenance with the same regimen doubled the

“Maintenance PG chemotherapy after six cycles should be considered in metastatic breast cancer patients with hormone receptor–negative tumors, visceral disease, high tumor burden, young age (< 50 years), and premenopausal status. —Young-Hyuck Im, MD

improvement in [disease-free surviv� al] with respect to FAC,” said Miguel Martin, MD, of the Hospital General Universitario Gregorio Marañon in Madrid. Disease-free survival rates were 93% vs 90%, respectively, at 5 years, representing a 27% reduction in risk (P = .0441). Overall survival was similar; the 24% reduction in deaths on the weekly paclitaxel arm was not statistically significant (P = .26). Both regimens were well tolerated. The addition of paclitaxel slightly in� creased grade 3/4 sensory neuropathy, fatigue, infection, irregular menses, and thrombosis, but the greater num� ber of cycles in the FAC arm appar�

time to progression and improved overall survival, vs observation, in this phase III Korean study of 324 patients. Patients received six cycles of PG, and the responders (complete or partial response or stable disease) were ran� domized to observation or to contin� ued treatment with the regimen. “Maintenance PG chemotherapy after six cycles should be considered in metastatic breast cancer patients with hormone receptor–negative tumors, visceral disease, high tumor burden, young age (< 50 years), and premeno� pausal status,” said Young-Hyuck Im, MD, of Samsung Medical Center in Seoul, South Korea.

sized. “Most insurers will pay for ge� netic testing,” she added.

about their family history,” com� mented Nicholas Vogelzang, MD, US Oncology, Las Vegas, who mod� erated an ASCO press conference where these findings were discussed. “I’m delighted to see this presenta� tion,” he concluded.

Toward More Online Research? “Taking a family history is labo� rious. We are hoping that more of these can be done online. It can be surprising how little patients know

■

Disclosure: Drs. Wood and Vogelzang reported no potential conflicts of interest.

From the time of randomization, pro� gression-free surviv� al was 3.8 months in the observation arm See Page 86 and 7.5 months in the maintenance arm, for a 27% reduc� = .026); 6-month pro� tion in risk (P �� gression-free survival was 60% vs 36% (P = .00023), respectively. Toxicities were manageable, and no impairment in quality of life was observed with maintenance.

■

Disclosure: Dr. Swain has served in an uncompensated consulting or advisory role for Genentech, Nektar Therapeutics, Novartis, Roche, and Sanofi, has received research funding from Bristol-Myers Squibb, Novartis, Pfizer, Roche/Genentech, and Sanofi, and has received other remuneration from Sanofi. Dr. Martin has served in a consulting or advisory role for Amgen, Genomic Health, and Roche. Dr. Im reported no potential conflicts of interest.

References 1. Swain SM, Tang G, Geyer CE, et al: NSABP B-38: definitive analysis of a ran� domized adjuvant trial comparing dosedense AC→ paclitaxel plus gemcitabine with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, nodepositive breast cancer. ASCO 2012. Ab� stract LBA1000. Presented June 5, 2012. 2. Martin M, Lluch A, Ruiz A, et al: Randomized phase III study of adju� vant chemotherapy for high-risk nodenegative breast cancer comparing FAC with FAC followed by weekly pacli� taxel: First efficacy analysis of the GEI� CAM/2003-02 trial. 2012 ASCO Annual Meeting. Abstract 1001. Presented June 5, 2012. 3. Im YH, Park YH, Jung KH, et al: A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical responses in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy. 2012 ASCO An� nual Meeting. Abstract 1003. Presented June 5, 2012.

Reference 1. Wood M, Kadlubek P, Lu KH, et al: Quality of cancer family history and re� ferral for genetic counseling and testing among oncology practices: A pilot test of quality measures as part of the ASCO Qual� ity Oncology Practice Initiative (QOPI). 2012 ASCO Annual Meeting. Abstract CRA1505. Presented June 4, 2012.

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2012 MASCC/ISOO International Symposium Supportive Care Experts Explore 30 Years of Progress in the Field By Alice Goodman

hirty years ago, when the first sup� portive care meeting as a forerun� ner of the Multinational Association of Supportive Care in Cancer (MASCC) Symposium was held in New York,

supportive care was largely ignored, with little discussion at major cancer meetings, which focused primarily on tumor-directed therapy. More recent� ly, patient-centered research has been

recognized as a major component of cancer care. Thus, 30 years later, at the Annual MASCC Symposium, again in New York, and now the MASCC/ ISOO Annual International Sympo�

sium, was an opportune time to review 30 years of progress in managing com� mon treatment-induced and cancerrelated symptoms, including febrile neutropenia, pain, psychosocial issues, and diarrhea.

Febrile Neutropenia

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The MASCC scoring index for febrile neutropenia and the use of granulocyte-colony stimulating factor (G-CSF, filgrastim [Neupogen] and pegfilgrastim [Neulasta]) for preven� tion have been the major advances over the past 30 years. Febrile neutro� penia–related morbidity and mortality have declined dramatically over the past 3 decades, and newer chemo� therapies are less toxic, but challenges remain, especially in the management of high-risk individuals. “There is still room for improve� ment in managing febrile neutropenia.

There is still room for improvement in managing febrile neutropenia. The optimal use of G-CSF remains to be defined. —Jean Klastersky, MD

The optimal use of G-CSF remains to be defined,” said Jean Klastersky, MD, Institut Jules Bordet, Brussels, Belgium.1 In 1962, febrile neutropenia was of� ten fatal, but today, related mortality is about 5% and the rate of complications ranges from 10% to 20%. Complica� tions include hypotension, respiratory failure, admission to the intensive-care unit, and confusion. “Five percent mortality is still too high. Many of these patients are young and treated with neoadjuvant and ad� juvant therapy,” he added. Cost is a major issue in managing febrile neutropenia. Dr. Klastersky pointed out that if a patient can be treated on an outpatient basis, the cost can be reduced by 50% compared with in-hospital treatment.

MASCC Risk Index The MASCC risk index for febrile neutropenia, developed in 2000, is

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PAGE 59

2012 MASCC/ISOO International Symposium now an accepted tool. The index is based on burden of illness and weight� ed values for individual symptoms. A MASCC score > 20 predicts a 5% risk of complications (ie, low risk), and these patients can be treated with oral antibiotics as outpatients. He empha� sized that low-risk patients with febrile neutropenia should be hospitalized and observed for 24 hours prior to dis� charge for outpatient therapy. The rates of death and complica� tions are higher in individuals with a MASCC score < 15 compared with ≥ 21, he said. Patients at high risk should be hospitalized and treated with broad-spectrum intravenous an� tibiotics and vigorous resuscitation if needed. “Several studies have confirmed that a low MASCC score predicts for severe sepsis. We need clearly defined protocols. Patients with febrile neu� tropenia and poor MASCC score are sometimes kept too long in the emer� gency department (ie, several hours) without antibiotics. We should prob� ably be much more aggressive and se� lect patients at high risk,” Dr. Klaster� sky commented.

Use of G-CSF Prophylactic use of G-CSF reduces the incidence of febrile neutropenia by about 50% and reduces mortality as well. Both long-acting and shortacting G-CSF can be used for patients with a 20% or greater risk of develop� ing febrile neutropenia. The risk var� ies with different chemotherapy regi� mens. “By strict definitions, patients with a calculated risk <�� 20% are not eligi� ble for G-CSF. I take issue with that. When low-risk patients develop febrile neutropenia, they have rates of mortal� ity and complications similar to those of higher-risk patients, and lower-risk patients benefit when they get G-CSF,” he stated. Perhaps criteria should be expand� ed for use of G-CSF as effective pri� mary prophylaxis to include those at lower risk, Dr. Klastersky suggested. Also, more affordable formulations of G-CSF are needed, and perhaps short� er schedules can be used to reduce as� sociated costs.

Depression, Anxiety, and Beyond in Patients with Cancer “For a long time, we treated the tu� mor rather than the person. A patient’s psychological status was not taken into account, and mental problems were

State of the Art in Supportive Care for Patients with Cancer ■■ Prevention of febrile neutropenia is now possible, but relies on use of

expensive G-CSF therapies. Optimal use of G-CSF needs to be further refined and perhaps expanded to lower risk patients.

■■ Psychosocial distress is now appreciated as an important component

of quality of life for patients with cancer. Identification of distress and appropriate referral for support services needs to be better integrated into clinical practice.

Jimmie Holland, MD

not discussed. In about 1975, the stig� ma of silence was broken and the field of psycho-oncology was evolving with a multidisciplinary approach to mea� sure the psychological impact of can� cer on patients and the impact of per� sonality and behavior on cancer risk and survival,” said Jimmie Holland, MD, Memorial Sloan-Kettering Can� cer Center, New York, a pioneer in the field.2 Quantitative instruments are now available to measure patients’ subjec� tive symptoms, including health-re� lated quality of life, pain, fatigue, anxi� ety, depression, and delirium. “About one-third of patients with cancer ex� hibit significant psychosocial prob� lems at some point in their illness,” Dr. Holland said, and the percentage is even higher with specific tumor sites such as lung, brain, and pancreas. Use of the term “distress” has normalized the physician-patient conversation about psychological issues since words such as “psychiat� ric” and “psychological” are seen by many as stigmatizing. Doctors are of� ten equally uncomfortable with such words, but all agree it is normal for the patient to be distressed—the is� sue is how much. The National Comprehensive Cancer Network (NCCN) now has standards of care and practice guide� lines for recognizing, monitoring, and documenting psychosocial dis� tress. The NCCN brief screening tool known as the Distress Ther� mometer is based on a single ques� tion: What is your distress level this past week on a 0–10 scale? A score of 4 or above triggers a second level of questions to determine the cause and to triage patients to the proper psychosocial resources if needed.

New Standard A strong evidence base in the lit� erature supports the benefit of psy� chosocial interventions for patients with cancer, as well as psychotropic medications. Based on the data, the Institute of Medicine established a

■■ The science is there, the guidelines are there, the international advocacy is

there, yet for many patients, optimal control of cancer-related pain remains elusive.

■■ Complete control of vomiting is possible with modern therapies, but

complete control of nausea lags behind. Better trial designs and new drug targets will move the field forward.

new quality standard of care noting that quality care today must integrate the psychosocial into routine cancer care. Patients should continue to be screened for psychosocial distress at regular intervals, she said. “This is a new standard, and we are working on incorporating this into clinical care,” Dr. Holland stated. The American College of Surgeons Commission on Cancer has endorsed the new standard as part of their ac� creditation for centers. Over 30 in� ternational cancer organizations in� cluding the UICC, SIOP (pediatric), LiveStrong, and the International Psycho-Oncology Society have en� dorsed the standard on a global level. The quality of psychosocial care delivered in oncology practices also needs to be assured. “Most cancer care is delivered in community oncol� ogy offices, but these practices have the fewest psychosocial resources,” Dr. Holland noted. ASCO is address� ing this with its Quality Oncology Practice Initiative (QOPI). Thus far, 100 community practices have gotten QOPI certification, and the number is expected to grow. “Now we have evidence-based in� terventions and treatment guidelines. We need to screen every patient and make this part of routine care. We needed science to bring to the table to be taken seriously. Science is impor� tant, but don’t forget the humanism,” she emphasized.

Cancer Pain “We now have great science, great policy, and great advocacy for cancer pain. We still need better drugs and better treatments, and we need to en� sure that patients are treated for their pain. We know the epidemiology, the syndromes, and the barriers. We have

validated measures to assess pain and related symptoms. I would like to say we have reduced those barri� ers, but they continue to exist,” stated Kathleen M. Foley, MD, Palliative Care & Pain Management, Memorial Sloan-Kettering Cancer Center, New

Kathleen M. Foley, MD

York, who was one of the earliest ad� vocates for the importance of relieving cancer-related pain.3 “The need for alleviation of can� cer-related pain is not over yet,” Dr. Foley stated. “The good news is that there is an enormous international consensus that we should treat can� cer pain. We have science to support this, and now it is a matter of policy. Organizations such as the Inter� national Narcotic Control Board, World Medical Association, Inter� national Association for the Study of Pain, World Health Organization, Human Rights Council, and UICC agree that pain control is a human rights issue,” Dr. Foley told listeners. “In some countries, like the Ukraine, inadequate pain treatment is consid� ered a form of torture.”

Advances in Pain Control The various mechanisms of break� through pain, incidence pain, move� ment pain, and spontaneous pain have been described, and treatments exist for each of these types of pain. continued on page 60

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PAGE 60

2012 MASCC/ISOO International Symposium 30 Years of Progress in Supportive Care continued from page 59

Opioids are the mainstay of therapy and come in different formulations, including slow-release, transdermal, transmucosal, intranasal, sublingual, and patient-controlled analgesia. New topical agents have been identified, including a eutectic mixture of local anesthetics (EMLA) cream for blood draws, and lidocaine patches (Lido� derm) for allodynia associated with neuropathic pain. Understanding of the molecular biology of pain has im� proved, and pharmacogenetic studies are identifying which patients can re� spond to specific pain medications. Other fairly recent developments include new opioid analgesics with� out the side effects of traditional opi� oids, identification of NMDA recep� tors as mediators of pain tolerance and neuropathic pain, and bisphos� phonates for the treatment of bone pain.

Complete control of emesis then oc� curred in about 50% to 60% of pa� tients by 1995. In 2010, the combination of a 5-HT3 receptor antagonist plus corticosteroids plus a neurokinin 1 (NK1) receptor antagonist resulted in achieving complete control in 85% of cisplatin-treated patients and 75%

of those receiving anthracyclines plus cyclosphosphamide. Palonosetron (Aloxi), the most recently introduced 5-HT3 antago� nist, plus dexamethasone improved control of delayed emesis when com� pared in a large randomized trial with granisetron plus dexamethasone in patients treated with cisplatin or an�

thracycline plus cyclophosphamide chemotherapy, and is now recom� mended by all major guideline groups in various emetic settings. Addition� ally, oral 5-HT3 antagonists are as ef� fective as IV 5-HT3 antagonists, Dr. Gralla noted. Aprepitant (Emend), the only NK1 receptor antagonist on the market, rep�

Throughout the course of castration-resistant prostate cancer (CRPC)

T HE R OOT O F T U M OR G R O W TH A N D R O G E N R E C E P TO R S I G N A L I N G

Chemotherapy-induced Nausea and Vomiting In 2012, control of chemotherapyinduced vomiting has been largely achieved, but complete control of nau� sea continues to be elusive, according to Richard Gralla, MD, Medical Di�

Richard Gralla, MD

rector, Quality of Life Research Asso� ciates, New York.4 “Patients with complete control of emesis during chemotherapy rank their quality of life the same as they did 3 days before the initiation of che� motherapy. If we don’t control emesis, patients experience more than a 30% decline in quality of life. No other side effect in the immediate period around chemotherapy has this magnitude of an effect on quality of life,” he said. In the 1990s, the 5-HT3 antago� nists graniseteron, ondansetron, and dolasetron (Anzemet) were intro� duced. Along with corticosteroids (such as dexamethasone), complete control rates of both acute and de� layed emesis were greatly improved.

Androgen receptor signaling promotes tumor growth and drives prostate cancer progression.1-3 Despite low or undetectable levels of testosterone, androgen receptor signaling persists.1,4 Visit www.TargetAR.com to learn more.

GUTTER

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PAGE 61

2012 MASCC/ISOO International Symposium resents the newest class of antiemetics to be FDA-approved. Other NK1 an� tagonists, such as netupitant and ro� lapitant, are under study, he said. A three-drug combination of a serotonin antagonist, dexametha� sone, and aprepitant improved con� trol of emesis even further when given with each cycle when patients

were receiving anthracyclines plus cyclophosphamide. “Patients [on emetogenic chemotherapy] need protection during every cycle of che� motherapy. This three-drug regimen was better initially and increasingly superior when compared with a twodrug regimen over multiple cycles of treatment,” he stated.

Vomiting is now controlled in the large majority of patients receiving guideline-recommended antiemetics, and in nearly 100% of patients in some newer trials. “Nausea is still a miserable problem for our patients. We need qual� ity trial designs and new agents,” Dr. Gralla said.

ADDITIONAL MECHANISMS OF ANDROGEN RECEPTOR ACTIVATION1,2,4-9 In castration-resistant prostate cancer (CRPC), androgen receptor signaling can persist through additional mechanisms of activation including receptor overexpression, testosterone-independent receptor activation, and receptor activation by non-androgens.

Androgen Production Androgen

Androgen binding

Androgen Receptor

Androgen receptor overexpression

Prostate Cancer Cell

Testosteroneindependent receptor activation

Receptor activation by nonandrogens

“MASCC has led the way in de� veloping evidence-based antiemetic guidelines…. Our goals are to com� pletely eliminate vomiting and nausea in every patient during every cycle of chemotherapy,” Dr. Gralla stated.

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Disclosure: Drs. Klastersky, Holland, and Foley, reported no potential conflicts of interest. Dr. Gralla is a consultant to and receives honoraria from Merck and Helsinn.

References 1. Klastersky J: A 30-year perspective: Progress in febrile neutropenia in patients with cancer. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012. 2. Holland J: A 30-year perspective: Progress in approaching depression and anxiety in patients with cancer. MASCC/ ISOO International Symposium on Sup� portive Care in Cancer. Presented June 28, 2012. 3. Foley K: A 30-year perspective: Alle� viation of pain: From research to practice. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012. 4. Gralla R: A 30-year perspective: Progress in antiemetic therapy in patients with cancer. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012. MEDPC9151 DSE - ISLAND SPREAD 4CP BLEED — ASCO Post Color: 4C + trim/live: DO NOT PRINT Bleed: 15.5"w x 10.75" Trim: 15.25"w x 10.5"h Live: 15"w x 10"h, .25” from center Output @ 100% Giant Creative Strategy

KEY STEPS IN THE ANDROGEN RECEPTOR SIGNALING PATHWAY 1,4 Key steps include androgen production, androgen binding, nuclear translocation, and DNA binding and transcription of tumor growth genes.

Looking Ahead

The ASCO Post

Nuclear translocation

Nucleus

DISRUPTION BY HORMONE THERAPY2,3,8,10-20 Hormonal therapies can disrupt these and other mechanisms of androgen receptor signaling in prostate cancer, leading to apoptosis in vitro.

REFERENCES: 1. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Nat Clin Pract Urol. 2009;6:76-85. 2. Knudsen KE, Scher HI. Clin Cancer Res. 2009;15:4792-4798. 3. Sawyers CJ, Tran C, Wongvipat J. Poster presented at: ASCO 2007 Prostate Cancer Symposium; February 22-24, 2007; Miami, FL. 4. Chen Y, Clegg NJ, Scher HI. Lancet Oncol. 2009;10:981-991. 5. Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A. Nucl Recept Signal. 2008;6:e008. 6. Grossmann ME, Huang H, Tindall DJ. J Natl Cancer Inst. 2001;93: 1687-1697. 7. Hu R, Denmeade SR, Luo J. Expert Rev Endocrinol Metab. 2010;5:753-764. 8. Molina A, Belldegrun A. J Urol. 2011;185:787-794. 9. Waltering KK, Urbanucci A, Visakorpi T. Mol Cell Endocrinol. [published online ahead of print January 8, 2012]. PubMed ID: 22245783. 10. Antonarakis ES, Armstrong AJ. Prostate Cancer Prostatic Dis. 2011;14:206-218. 11. Clegg NJ, Wongvipat J, Joseph JD, et al. Cancer Res. 2012;72:1494-1503. 12. Courtney KD, Taplin ME. Curr Opin Oncol. 2012;24:272-277. 13. Knudsen KE, Kelly WK. Expert Rev Endocrinol Metab. 2011;6:483-493. 14. Maluf FC, Smaletz O, Herchenhorn D. Clinics (Sao Paulo). 2012;67:389-394. 15. Miyamoto H, Messing EM, Chang C. Prostate. 2004;61:332-353. 16. Rathkopf DE, Danila DC, Morris MJ. http://www.aragonpharm.com/assets/pdfs/ASCO_GU_2012_Phase_1_ﬁnal_poster.pdf. Accessed April 25, 2012. 17. Sethi R, Sanﬁlippo N. Clin Interv Aging. 2009;4:259-267. 18. Tran C, Ouk S, Clegg NJ, et al. Science. 2009;324:787-790. 19. Yang Q, Fung KM, Day WV, Kropp BP, Lin HK. Cancer Cell Int. 2005;5:8. 20. Lee EC, Zhan P, Schallhom R, Packman K, Tenniswood M. Cell Death Differ. 2003;10:761-771. © 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012D-075-5383-2 7/12

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DNA binding and transcription

@ASCOPost

The ASCO Post | AUGUST 15, 2012

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2012 ASCO Annual Meeting Perspective

A Physician, Who Is Also a Cancer Patient, Talks about Medical Errors By Ronald Piana

Itzhak Brook, MD, MSc

n a whispered but resolute voice, Itzhak Brook, MD, MSc, led off his presentation at the 2012 ASCO Annual Meeting1 by telling the audience his voice is weak because he doesn’t have vocal cords. He spoke with the aid of a tracheoesophageal voice prosthesis. “I have practiced medicine for more than 40 years. After I was diagnosed with neck cancer, I was left shaken, seeing firsthand how common medical errors are,” Dr. Brook said, adding that as a cancer patient, he encountered at least one or two errors a day, running the gamut from minor to lifethreatening.

When Doctor Becomes Patient Dr. Brook, Professor of Pediatrics and Medicine, Georgetown University School of Medicine, said that after the hospitalization following his laryngectomy, he was emotionally unprepared to change roles from doctor to patient. “I had to deal with pain and weakness and being completely dependent on others. On top of that, I couldn’t speak, which compounds anxiety because I couldn’t convey the extent of the problems I was having,” Dr. Brook said. Dr. Brook pointed out that timely and thoughtful patient-doctor com-

munication is a vital component in preventing medical errors that, as he witnessed, occur with similar frequency at all levels, from nurses to physicians. Moreover, patients are often reluctant to complain to the people they are dependent on. “Laryngectomees are even more vulnerable because they are less able to abort medical errors, given their inability to speak,” Dr. Brook said. In Dr. Brook’s case, the first, and arguably most serious medical error he encountered was a failure to detect his cancer. “This serious error was probably the result of a failure to do the correct ENT examination that would have revealed the cancer. It was a resident who finally found the cancer,” Dr. Brook said.

It is important to perform regular records review to detect and correct errors, and it is equally important to counsel, reprimand and educate staff who make errors. You need to be straightforward about this problem, to the point of dismissing those who habitually make medical errors. “The surgeon also made a serious error when he attempted to remove the cancer,” he added. “During the surgery, he inadvertently removed scar tissue, mistaking it for the tumor. And by not checking the tissue in the OR with a frozen section, it was a week later before the pathology lab identified it to be scar tissue and not cancer,” Dr. Brook noted.

Nursing Errors According to Dr. Brook’s experience, nursing errors can include not responding to calls, not washing hands or using gloves, not placing the oral thermometer in a plastic cover, or administering an incorrect medication dose.

Preventing Medical Errors ■■ Increase supervision and communication among health-care providers. ■■ Respond to complaints and admit responsibility when appropriate. ■■ Investigate all errors and take preventive action. ■■ Employ only well-trained staff. ■■ Dismiss those who continue to make errors. ■■ Develop and meticulously follow algorithms, set procedures, and bedside checklists.

“As a patient—especially one who is a doctor—it is very frustrating to realize that errors occur so frequently. I actually needed to become my own watchdog, waiting to catch mistakes, which meant I could never relax. I also realized that in most cases, there was no self-recognition of these errors.… Once, when I was in the ICU, the nurse forgot to connect me to the call button and I was choking, helpless because of her oversight. I was in plain sight of a nursing station—yet no one came to my help until my wife walked in,” Dr. Brook said. “Instead of administering my medication through the NG tube,” Dr. Brook continued, “sometimes the nurse would try to give me the meds orally, causing me to choke, or admin-

ister medication that was dissolved in hot water, burning my esophagus.”

Preventing Medical Errors As common as medical errors are, Dr. Brook’s observations as a patient left him confident that better and more uniform training and adherence to established standards of hospital care could avert the majority of harms from errors. “It is important to perform regular records review to detect and correct errors, and it is equally important to counsel, reprimand and educate staff who make errors. You need to be straightforward about this problem, to the point of dismissing those who habitually make medical errors,” Dr. Brook said. He pointed to recent data indicating that developing and following algorithms, use of set procedures, and meticulously following a bedside checklist for all procedures markedly decreases the chance of errors. Dr. Brook commented, “Increased supervision and communication between health-care providers serves as a firewall to errors. Moreover, we need to spend more time educating patients and caregivers about medical conditions and treat-

ment plans. This way they can participate in preventing medical errors.”

Be Your Own Advocate Dr. Brook’s travails within the hospital system reinforced the need for self-reliance on the part of the patient. In other words, it’s your health—be an assertive advocate for yourself. “You decrease the chances of being the victim of a medical error by being informed and not hesitating to challenge health-care providers and ask for explanations. Become an expert on your condition and how the care should be delivered,” he said. According to Dr. Brook, an area that needs special attenSee Page 86 tion is postsurgical care. “Educating the patient and family about the short- and long-term implications of surgical procedures is vital. To that end, make sure that the surgical team provides personal attention and spends time giving patients and caregivers information,” he said. Dr. Brook continued, “I would say to very busy surgeons, as challenged for time as you are, you need greater vigilance and communication among the staff to avoid medical errors. Plus, it’s important to understand the need for better medical and psychological postsurgical care, especially for patients who have had major surgery.” Dr. Brook concluded his presentation with a brief note about a book he wrote, My Voice—A Physician’s Personal Experience With Throat Cancer, detailing the physical and emotional difficulties of vulnerable cancer patients, especially when their care is compromised by a slew of preventable medical errors. “I would stress to all clinicians that the solution to dangerous medical errors is in their hands. By increasing their awareness and vigilance, they will radically decrease the likelihood of medical errors.”

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Disclosure: Dr. Brook is the author of My Voice—A Physician’s Personal Experience With Throat Cancer. For more information about the book, visit http://dribrook.blogspot.com/.

Reference 1. Brook I: Medical errors in cancer care. 2012 ASCO Annual Meeting. Presented June 3, 2012.

NOW

APPRO ED For Patients With Advanced HR+ BC AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

Important Safety Information

There have been reports of non-infectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR® (everolimus), some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared to patients <65 years of age. Oral ulceration is the most frequently occurring adverse event and occurred at an incidence ranging from 44% to 86% of AFINITOR-treated patients across the clinical trials experience. Most of these events were Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 4%-8% of patients. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported; monitoring of laboratory tests is recommended. The use of live vaccines and close contact with those who have received live vaccines should be avoided. AFINITOR can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Please see Brief Summary of Prescribing Information on adjacent pages. For more information, please visit www.AFINITOR.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

7/12

AFB-1039129

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

T:14”

B:14.25”

S:13”

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years. A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITORtreated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-132 July 2012

The ASCO Post | AUGUST 15, 2012

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2012 MASCC/ISOO International Symposium New Assessment Tools in Development to Guide Care for Older Patients By Jo Cavallo

ore than 1,400 people from 62 countries attended the 2012 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held in New York last June. One of the featured sessions, which was jointly sponsored by the International Society of Geriatric Oncology (siog. org), centered on improving oncology care for older patients with cancer, an increasing concern for oncologists as the rate of older adults with cancer rises. According to the National Institute on Aging, the number of people aged 65 and over is expected to double between 2000 and 2030, growing to 72 million and representing nearly 20% of the U.S. population. Because the chances of developing cancer increase with age—60% of all cancers and 70% of cancer-related deaths occur in people 65 and older— the incidence of cancer among this population is expected to skyrocket by 67%.

More Treatment Challenges “Cancer is very common among older patients, and oncologists are increasingly caring for patients who are older than 70. We have to start integrating geriatric oncology more into our practices in order to make better decisions for our patients,” said Supriya Gupta Mohile, MD, MS, Associate Professor of Medicine and Director of the Geriatric Oncology Program at the University of Rochester, New York, and a presenter at the MASCC/ISOO conference. For myriad reasons, older patients with cancer can be more challenging to treat than their younger counterparts, said Dr. Mohile. For example, the presence of two or more comorbidities, disabilities that require help with performing routine daily activities such as bathing and feeding, and cognitive impairment resulting from dementia, delirium, or depression can all complicate treatment decisions. Determining the most effective—and safe—chemotherapy agents for geriatric patients with cancer and how to assess whether older patients will even reap a benefit from such therapy were the focal concerns at the meeting’s geriatrics session.

More Effective Assessment Tools Clinical tools such as the Comprehensive Geriatric Assessment

Supriya Gupta Mohile, MD, MS

(CGA), Karnofsky performance status, and Eastern Cooperative Oncology Group (ECOG) performance status are currently available to help oncologists measure patients’ functional status, comorbid conditions, cognition, and medication use as well as aid in predicting appropriate treatment, disease prognosis, and chemotherapy toxicities. That said, newer, more efficient assessment tools are being developed. The Chemotherapy Risk Assessment Scale for High-age Patients (CRASH) is specifically designed to score laboratory test values and geriatric assessment parameters besides age, such as functional and nutritional status, comorbidity, cognition, psychological state, and social support, to

Assessment. They will help identify patients who are more at risk from treatment, especially when you have a patient with a very poor prognosis from a difficult cancer and you know that the chemotherapy doesn’t work very well even in younger patients,” said Dr. Mohile, a CARG researcher and coauthor of a study on predicting chemotherapy toxicity in older adults with cancer.2 “These tools can help oncologists decide whether or not to initiate the treatment, which is sometimes worse than the cancer. Some patients may make different decisions if we approach the discussion with more information on toxicity.”

Increasing Clinical Trial Participation Even with more effective assessment tools to measure how well older patients with cancer will fare during chemotherapy, one of the central roadblocks to better care for aging individuals is their lack of participation in clinical trials. As a result, less is known about the risks and benefits of cancer treatment in this age group, and there are fewer medical guidelines that specifically address the evaluation and

These [new] tools are shorter and easier to give (and results easier to evaluate) than the Comprehensive Geriatric Assessment. —Supriya Gupta Mohile, MD, MS

predict the risk of severe toxicity from chemotherapy in older patients. The CRASH score has been validated in clinical studies as a new tool to predict significant differences in the risk of severe chemotoxicity and as a way to individualize treatment on an objective basis. It is moving into greater clinical use. The Cancer and Aging Research Group (CARG) incorporates measures within geriatric assessment, which is also meant to identify risk factors for chemotherapy toxicity in older patients with cancer and develop a risk stratification schema for chemotherapy toxicity. The Cancer and Aging Research Group is in the process of validating the CARG chemotoxicity assessment tool. “Both of these tools are shorter and easier to give (and results easier to evaluate) than the Comprehensive Geriatric

renal function, such as nonsteroidal antiinflammatory agents, all need to be considered before choosing a chemotherapy regimen and dosage. “Chemotherapy dose reduction for renal dysfunction depends mainly on the type of therapy you are giving. If you are giving nephrotoxic chemotherapy, such as cisplatin, you have to provide all the supportive care measures around that therapy, including

treatment of this population. “There are very few people over the age of 75 enrolled in clinical trials,” said Stuart M. Lichtman, MD, FACP, Attending Physician, 65+ Clinical Geriatrics Program at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York. “We talk about evidence-based medicine, but there is no evidence-based medicine for treating older people, so everything is an extrapolation to some degree.” Co-chair of the geriatrics panel session, Dr. Lichtman also presented information at the MASCC/ISOO conference on the effect of renal function in the aging patient with cancer.3 He stressed that serum creatinine blood level alone is insufficient as a means of evaluating renal function. Moreover, obesity, cardiovascular disease, and drugs that affect

Stuart M. Lichtman, MD, FACP

hydration, to make it safe for elderly patients,” said Dr. Lichtman. However, Dr. Lichtman cautioned, there is insufficient data to allow oncologists to modify their clinical decisions about many standard chemotherapy drugs prescribed for older patients with renal impairment or to be able to determine how comorbidities affect cancer outcomes. That information will only be learned through clinical studies designed with realistic parameters, so that older patients are not unnecessarily excluded from trials because of renal dysfunction—or other health issues—alone, he said.

Upcoming Conference To develop strategies to increase enrollment of older patients with cancer into clinical trials, a conference supported under the National Institutes of Health’s Cooperative Agreement (U13) Program will be held November 17–18, 2012, in Chicago. The conference, “Design and Implementation of Therapeutic Clinical Trials for Older and/or Frail Adults With Cancer,” is being developed by the Cancer and Aging Research Group in collaboration with the Geriatrics and Clinical Gerontology branch of the National Institute on Aging and the National Cancer Institute. The principal investigators of this U13 grant include two leaders in the field of geriatric oncology, Arti Hurria, MD, Associate Professor of Medical continued on page 67

ASCOPost.com | AUGUST 15, 2012

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Technology

Information Service Provides Innovative Resource for Patients and Providers A Conversation with Jennifer Levin Carter, MD, MPH By Randi Londer Gould

cians and patients struggled when they tried to access, interpret, and manage this complex web of evolving information at the point of care. N-of-One was founded to bridge this gap.

The Process

Jennifer Levin Carter, MD, MPH

ennifer Levin Carter, MD, MPH is Founder and President of N-of-One. A board-certified internist and entrepreneur, she has more than 20 years of experience evaluating existing and emerging markets, new medical technologies, and early-stage companies in the health-care field. Formerly, Dr. Carter was a consultant and analyzed biotechnology, pharmaceutical, and medical device firms on behalf of investors. She received an MD degree from Harvard Medical School and a Master’s degree in Public Health from The Harvard School of Public Health. Like other diagnostic labs that provide additional content with the results of their testing, N-of-One uses data from a patient’s tumor molecular profile to generate reports that help physicians and patients identify optimal diagnostic and treatment strategies. Recently, The ASCO Post spoke with Dr. Carter about her company.

Project Origins What led you to start this company? After training as a physician, I worked in biotech and medical technology and I saw first-hand how the incredible advances of the basic science in cancer biology were ready to be applied clinically. But I also saw how many clini-

New Assessment Tools continued from page 66

Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, and William Dale, MD, PhD, Chief, Section of Geriatrics and Palliative Medicine, The University of Chicago Medicine, and Supriya Gupta Mohile, MD, Asociate Professor of Medicine in Hematology/Oncology, University of

What is your approach to identifying a personalized treatment strategy for the patient with cancer? Our scientific team gathers clinically relevant information for an individual patient and generates a list of molecular tests that are specific to that patient’s cancer. We use a proprietary database, called MarkerMine, as in mining data. The database is comprised of several years of annotated data and is constantly updated. The clinical team then oversees all the logistics required for molecular testing. Once all the data from testing are back, we analyze the results with expert opinion provided by our network of clinicians. Based on the aggregated molecular data, our scientific team compiles an individualized Treatment Strategy Roadmap, outlining potential treatment options, including information on FDA-approved therapeutics and drugs in clinical trials.

Costs and Finances Does insurance pay for your services? Some parts are covered by insurance and some parts are an out-ofpocket expense. N-of-One identifies and manages the cost structure for patients and physicians, and customizes programs to fit their needs. We’re in the process of establishing collaborations with medical practices and community cancer centers to accommodate them. How is the company supported other than through user fees? Rochester Medical Center. “This is our second U13 conference and our goals are to discuss research priorities in geriatric oncology and how we can design better therapeutic clinical trials for older patients with cancer,” said Dr. Mohile. “We need evidencebased data to reduce medical costs and to provide better care for our patients. There also needs to be more funding for

We’ve been expanding our business beyond the direct-to-patient business over the past 18 months. We now have a significant segment of our business that is based on the interpretation of molecular test results for several large diagnostics companies, and this represents hundreds of reports per month. Presently, we are bringing our capabilities to large heathcare networks and are helping them to implement a comprehensive molecular diagnostics and treatment programs. We believe this segment will become the largest portion of our business.

Interaction with the entire health-care community is crucial to moving the field of individualized medicine forward. —Jennifer Levin Carter, MD, MPH

Is there any conflict of interest in terms of tests you recommend? We’re agnostic in terms of particular testing providers and technologies. Our goal is to outline the tests with the highest impact for the treating physician. As the field changes, we keep pace with the most relevant testing resources.

Collaborative Efforts How do you interact with institutions? Because we take a data-based approach to molecular medicine, we collaborate with academic partners throughout the country. Our goal is to become a natural partner for any group that is trying to provide cost-effective, efficient genomic profiling for individual patients. research and more advocacy for older patients with cancer.” For more information on the U13 meeting, visit mycarg.org.

■

Disclosure: Drs. Mohile, Hurria, and Dale reported no potential conflicts of interest.

References 1. Smith BD, Smith GL, Hurria A: Future of cancer incidence in the United

There is incredible fragmentation in the system—different institutions offer different tests and clinical trials. N-of-One is creating an infrastructure to make molecular medicine available across institutions, by ensuring that physicians and patients, regardless of where they are, know what the best test is, where to get it done, and how this relates to therapy. How are your data being used? We are looking for opportunities to collaborate and share the outcomes of our work. Interaction with the entire health-care community is crucial to moving the field of individualized medicine forward. Precision medicine requires careful assessment of efficacy in order to ensure that appropriate patient groups are being offered access to key drugs. As more data about markers in different disease types are collected, it’s important to ensure that all outcome data generated in the field are available to the broader academic community.

Clinical Trials You also suggest clinical trials as part of your personalized strategies? Yes, matching the patient to the appropriate targeted medicine is an important aspect of the N-of-One approach. Many of the drugs currently in development are targeted treatments. This past year has been phenomenal in terms of the numbers of new targeted treatments approved by the FDA. Appropriate genetic selection of patient populations will become the standard in future clinical trials and will help expedite targeted drug development.

■

Disclosure: Dr. Carter is founder and president of N-of-One.

States: Burdens upon an aging, changing nation. J Clin Oncol 27:2758-2765, 2009. 2. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 25:34573465, 2011. 3. Lichtman SS: Renal function: A key element in the aged patient. 2012 MASCC/ISOO Symposium. Abstract 2001028. Presented June 29, 2012.

The ASCO Post | AUGUST 15, 2012

PAGE 68

Journal Spotlight Thoracic Oncology

Response Rate Is Significantly Improved with Nab- vs Solvent-based Paclitaxel plus Carboplatin in Advanced NSCLC By Charlotte Bath

inal results of a phase III trial found nanoparticle albuminbound (nab)-paclitaxel (Abraxane) plus carboplatin as first-line therapy in patients with advanced non–small cell lung cancer (NSCLC) resulted in a significantly improved overall response rate vs conventional solventbased paclitaxel plus carboplatin. The study was published recently in the Journal of Clinical Oncology.1

Study Results Overall response rate was 33% for nab-paclitaxel recipients compared to 25% for those on the conventional paclitaxel arm (P = .005). Patients receiving nab-paclitaxel also had nonsignificant improvements in progression-free survival (6.3 vs 5.8 months) and overall survival (12.1 vs 11.2 months). “Patients with squamous cell histology responded remarkably well to treatment with [nab-paclitaxel/

carboplatin], with a 68% improvement compared with that in the [solvent-based paclitaxel/carboplatin] arm, which is the highest reported in a phase III study in this

static disease. Patients were randomly assigned, 521 to receive 100 mg/m2 nab-paclitaxel weekly and carboplatin at area under the concentrationtime curve (AUC) 6 once every 3

Taken together, the [nab-paclitaxel] regimen has a favorable risk-benefit profile compared with that of [solvent-based paclitaxel] as first-line therapy for all patients with NSCLC. patient population,” the trial investigators reported. “This is particularly intriguing because improved therapeutic options for the subset of patients with squamous histology are needed.”

Study Overview The study involved 1,052 patients with stage IIIB to IV NSCLC who were previously untreated for meta-

weeks, and 531 to receive 200 mg/m2 solvent-based paclitaxel plus carboplatin AUC 6 once every 3 weeks. The authors noted that preclinical models suggest that nab-paclitaxel may reach the tumor environment more efficiently than solvent-based paclitaxel and may be preferentially taken up by cancer cells. “The [nab-paclitaxel/carboplatin] regimen produced less severe

neuropathy, neutropenia, myalgia, and arthralgia compared with [solvent-based See Page 86 paclita xel/carboplatin]. The increased risk of thrombocytopenia and anemia in the [nabpaclitaxel–containing] regimen was readily manageable,” the researchers reported. “Taken together, the [nabpaclitaxel] regimen has a favorable risk-benefit profile compared with that of [solvent-based paclitaxel] as first-line therapy for all patients with NSCLC,” the authors concluded.

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Reference 1. Socinski MA, Bandarenko I, Karaseva N, et al: Weekly nab-paclitaxel in combination with carboplatin vs solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non–small cell lung cancer: Final results of a phase III trial. J Clin Oncol 30:2055-2062, 2012.

Study Reports ‘Strong and Consistent Relation’ between Exposure to Diesel Exhaust and Risk of Dying of Lung Cancer By Charlotte Bath

nested case-control study of 198 lung cancer deaths among a cohort of 12,315 mine workers “showed a strong and consistent relation between quantitative exposure to diesel exhaust and increased risk of dying of lung cancer,” researchers reported in the Journal of the National Cancer Institute.1 “To our knowledge, this is the first report of a statistically significant exposure–response relationship for diesel exposure and lung cancer based on quantitative estimates of historical diesel exposure with adjustment for smoking and other potential confounders,” the researchers stated. The mineworkers had been employed in a blue-collar job for at least 1�� year after the introduction See Page 86 of diesel equipment into the mining facility. The eight mining facilities where they worked were all in the United States, and “consid-

ered to have had high air levels or diesel exhaust underground but low levels of potential occupational confounders (ie, radon, silica, asbestos),” according to the study report The researchers estimated diesel exhaust exposure, represented as re-

a three times greater lung cancer risk than workers in the lowest quartile.

Study Implications “Our findings are important not only for miners but also for the 1.4 million American workers and

We observed statistically significant increasing trends in lung cancer risk with increasing cumulative [respirable elemental carbon] and average [respirable elemental carbon] intensity. spirable elemental carbon, using extensive retrospective assessment at each mining facility. “We observed statistically significant increasing trends in lung cancer risk with increasing cumulative [respirable elemental carbon] and average [respirable elemental carbon] intensity,” the researchers reported. Workers in the top quartile of exposure had

the 3 million European workers exposed to diesel exhaust and for urban populations worldwide,” the authors noted. “Some of the higher average elemental carbon levels reported in cities,” the authors pointed out, include Los Angeles, the Bronx, nine urban sites in China, Mexico City, and Estarreja, Portugal. “Environmental exposure to aver-

age elemental carbon levels in the 2–6 μg/m3 range over a lifetime as would be experienced in highly polluted cities approximates cumulative exposures experienced by underground miners with low exposures in our study. Because such workers had at least a 50% increased lung cancer risk, our results suggest that the high air concentrations of elemental carbon reported in some urban areas may confer increased risk of lung cancer. Thus, if the diesel exhaust/lung cancer relation is causal, the public health burden of the carcinogenicity of inhaled diesel exhaust in workers and in populations of urban areas with high levels of diesel exposure may be substantial.”

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Reference 1. Silverman DT, Samanic CM, Lubin JH, et al: The diesel exhaust in miners study: A nested case-control study of lung cancer and diesel exhaust. J Natl Cancer Inst 104:855-868, 2012.

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The ASCO Post | AUGUST 15, 2012

PAGE 70

News

Data Liquidity Coalition Takes Shape By Caroline McNeil

coalition to promote and implement data sharing in cancer by facilitating data ‘liquidity,’ first proposed in February at an Institute of Medicine (IOM) workshop, is taking shape with the formation of a steering committee and action plans that include a demonstration project. For several years, data sharing has been on the agenda of oncology meetings and organizations, spurred by the growing volume of genomic and clinical data that reside in separate institutional databases. Proponents cite many benefits to sharing: reducing duplication and costs, informing clinical care, fueling research, and the overarching goal, getting new and effective treatments to patients more quickly.

John Mendelsohn, MD

Biggest Bottleneck Three IOM meetings over the past few years have addressed the issue. At a recent meeting on personalized cancer care in Washington, DC, keynote speaker John Mendelsohn, MD, of The University of Texas MD Anderson Cancer Center, Houston, said that for personalized cancer care, “the biggest bottleneck is information management.” Massive amounts of data need to be analyzed and stored, and that is made more difficult by “data balkanization.” Now, the champions of data sharing say the time may be ripe for significant movement forward. And the new coalition, they say, could be a catalyst for achieving not just data sharing, but data liquidity—the rapid, seamless, secure exchange of useful, standardsbased information among authorized individual and institutional senders and recipients. “We were happily surprised by the amount of engagement at the IOM Workshop [on Informatics Needs and Challenges in Cancer Research],” said Amy Abernethy, MD, of Duke Uni-

versity, Durham, North Carolina, one of the authors of the proposal and a member of the new steering committee. “There seemed to be a real groundswell of interest.”

Steering Committee Encouraged by that response, the authors, led by Marcia Kean, MBA of Feinstein Kean Healthcare, quickly formed a steering committee for the group, which they named the Data Liquidity Coalition. Steering committee members include a range of experts and stakeholders. The cancer centers, for instance, are represented by William Dalton, MD, PhD, from H. Lee Moffitt Cancer Center, Tampa, Florida, and Lawrence Shulman, MD, of Dana-Farber Cancer Institute, Boston, as well as Dr. Abernethy from Duke; the pharmaceutical industry by Charles Hugh-Jones, MD, and Joel Beetsch, MD, both from Sanofi; patient groups by Andrea Ferris, the President of LUNGevity; and the IT industry by Kris Joshi, PhD, of Oracle and William Tulskie of Healthcare IT, Inc. Ms. Kean is the Chairman of Strategic Initiatives at Feinstein Kean Healthcare, a strategy and communications firm that assists life sciences innovators. Other members include Kathleen Foley, PhD, of Thomson Reuters Healthcare; George Poste, DVM, PhD, of Arizona State University; Tom Kean, CEO of C-Change; and Brad Pollock, PhD, from the Epidemiology and Biostatistics Department of The University of Texas Health Science Center at San Antonio. One of the committee’s first acts was to lay out five activity tracks (see sidebar), including demonstration projects. Some members are now working on a proposal for the first demo and beginning to look for funding. Coalition participants will provide some resources, such as in-kind donations of services, but they are also talking to potential funders about grants, Ms. Kean said. The demonstration project will need to show that a data-sharing project can make data accessible and usable by the whole research community, serving as proof of that broad principle. More specifically, it will also test and demonstrate how the coalition will operate.

Coalition Activities

he new Data Liquidity Coalition has identified five activity tracks. Marcia Kean, MBA, a leader of the coalition steering committee, described the tracks: 1. Intellectual Capital is a set of activities that would seek to identify and illuminate some of the key issues in the space, such as the economic impact of biomedical data liquidity (or the converse, illiquidity) and through white papers, etc, inform key opinion leaders of the importance of this issue. Marcia Kean, MBA 2. Advocacy is the process of identifying policy barriers to the achievement of data liquidity, or new policies that could facilitate such achievement, and informing policymakers about the potential benefits of change. 3. Community Building and Communications are the activities by which we would disseminate the white papers and other materials, and get more and more organizations and individuals involved in the coalition. The Landscape Analysis is a start-up activity in that track, designed to scan the environment for the wide variety of initiatives and entities that have gotten underway in the biomedical data space and to keep track of what they are doing so that we can potentially partner or find synergies, but avoid replicating or reinventing a wheel within the community. 4. Patient Education is the process of informing the patient community about these issues, which have not been well discussed in that community. 5. Demonstration Projects are just what they sound like: specific projects that would show proof of principle on how we can address particular obstacles to achieving data liquidity, and showing how that can have a positive impact on research and/or care, with the ultimate aim of making all the requisite IT capabilities available to the community.

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An Honest Broker Envisioned as an “honest broker,” the coalition will not undertake datasharing projects directly. Instead, it will work with cancer organizations needing data exchange to develop specifications, standards, and software. The actual IT work will be done by vendors or the open-source community, but the coalition will help craft the request for proposal, which would require that the system developed be kept open at the interfaces so that others could connect to it. The coalition will share the framework with all members. It could also maintain the common infrastructure so that over time, Ms. Kean said, the data-exchange capabilities could constitute a national biomedical resource. For the demonstration projects— and the coalition itself—to succeed, it will need to deal with more than technical issues. “Data liquidity is about more than IT,” Ms. Kean said. “Potentially it involves policy, advocacy, culture.… It’s what people are calling a

systems problem.” The other four activity tracks are designed to address such problems. Industry competition and intellectual property issues are the most obvious obstacles, but other entrenched practices also work against data sharing. The academic hierarchy, for example, rewards individual researcher achievement and publication rather than collaboration. And health-care providers and patient groups have economic incentives to guard the data gained from their own patient population.

Life Sciences Consortium The question remains whether such systems will change. Steering committee member Charles Hugh-Jones, MD, of Sanofi, thinks the time is ripe. “There’s a confluence of several factors,” he said, including the technology to make data sharing possible and the growing realization that it could lead to faster, cheaper, and better drugs. Dr. Hugh-Jones is involved in another collaborative effort, the CEO

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News

mercial, are working to identify oncology datasets to contribute. Work on the technical infrastructure by the SAS Corporation, a Life Sciences Consortium member, is underway, and the first data should be available by the end of this year. Progress on DataSphere may be one more sign that the benefits of data

sharing are increasingly seen to outweigh the risks. “Somewhere along the line, all will benefit by sharing data,” said Ms. Kean. This has been very hard to convey in the biomedical community, she added, but interest is clearly growing. “I think we’re approaching a tipping point.”

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Charles Hugh-Jones, MD

Roundtable on Cancer’s Life Sciences Consortium, a task force of Roundtable companies and academic organizations involved in the life sciences. The Consortium is working on a project called DataSphere (formerly MetaPharm), in which research groups will put their clinical trial data online in a format accessible to any bone fide research organization, Dr. Hugh-Jones said. To that end, Sanofi-Aventis is releasing two recent large phase III datasets together with case report forms and data descriptors. Other Consortium members, academic and com-

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

Disclosure: Dr. Abernethy has received research funding from the National Institutes of Health, Agency for Healthcare Research and Quality, Robert Wood Johnson Foundation, Pfizer, Helsinn, Amgen, Kanglaite, Alexion, Biovex, DARA, and MiCo, has served as a consultant for Novartis and Pfizer, and is on the corporate board of directors for Advoset and Orange Leaf Associates, LLC. Ms. Kean, Dr. Hugh-Jones, and Dr. Mendelsohn reported no potential conflicts of interest.

References: 1. Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol. 2008;3(suppl 2):S146-S149. 2. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380. 3. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967. 4. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 5. Data on ﬁle. Synovate US Oncology Monitor (USTOM), Jan-Dec 2011. 6. National Cancer Institute. Lung cancer. Non-Small Cell Lung Cancer Treatment (PDQ). Cellular classiﬁcation of NSCLC. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional /page2. Accessed January 18, 2012. Copyright ©2012. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (5/12) OC209900PROF-A

™

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2012 Oncology Meetings August Australian and New Zealand Children’s Haematology/Oncology Group Annual Scientific Meeting August 24-26 • Surfers Paradise, Queensland, Australia For more information: www.anzchog2012.org ICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec For more information: www.worldcancercongress.org

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

2nd World Congress on Cancer Science & Therapy September 10-12 * San Antonio, Texas For more information: www.omicsonline.org/ cancerscience2012 11th International Conference of the International Mesothelioma Interest Group September 11-14 • Boston, Massachusetts For more information: www.imig2012.org 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com British Association for Cancer Research: Chasing Cancer Stem-like Cells September 12 • Harrogate, North Yorkshire, United Kingdom For more information: www.bacr.org.uk 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org

8th International Jordan Oncology Society Conference September 6-8 • Amman, Jordan For more information: http://jo-events.com/jos-conference

Modern Principles of Treatment of Neurooncology Diseases: Prospects for Functional Neurosurgery September 15-16 • Yalta, Ukraine For more information: http://nbscience.com

9th Asia Pacific Musculoskeletal Tumor Society Meeting September 6-9 • Kuala Lumpur, Malaysia For more information: apmsts2012.com

Issues of Neurosurgery, Vascular Neurosurgery, Neurooncology, Spinal Surgery, and Spinal Cord September 16-17 • Kiev, Ukraine For more information: http://nbscience.com

International Conference on Antimicrobial Agents & Chemotherapy September 9-12 • San Francisco, California For more information: www.icaac.org

1st Multidisciplinary Symposium: Molecular Oncology: From Laboratory Bench to Medicine September 17-22 • Kyiv, Ukraine For more information: http://rmd.org.ua/en

17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc. org/conference/17th_ICCN

Cancer Vaccines: Advances in Design, Therapy and Efficacy September 19-20 • London, United Kingdom For more information: www.smi-online.co.uk/events

32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu Congress of Oncologists September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com Molecular Diagnostics World Congress September 25-26 • San Diego, California For more information: selectbiosciences.com/conferences 1st Malaysian Proteomics Conference September 26-27 • Penang, Malaysia For more information: www.informm.usm.my/mpc2012 Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu. au/cancer-research/SCC2012 European Conference of Oncology Pharmacy September 27-29 • Budapest, Hungary For more information: www.ecco-org. eu/home/conferences 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org American College of Surgeons Annual Clinical Congress September 30-October 4 • Chicago, Illinois For more information: www.facs.org

6th Next-Generation Histone Deacetylase Inhibitors October 1-2 • Boston, Massachusetts For more information: www. discoveryontarget.com/HDACInhibitors Targeting the Ubiquitin Pathway: Discovery and Development of Novel Inhibitors October 1-2 • Boston, Massachusetts For more information: www. discoveryontarget.com/UbiquitinPathway 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu Functional Genomics Screening Strategies October 2-3 • Boston, Massachusetts For more information: www. discoveryontarget.com/RNAiScreens-Functional-Genomics ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org 14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer 44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org

October 2nd Annual Next Generation Sequencing Asia Congress October 1-2 • Singapore For more information: www. discoveryontarget.com/HDACInhibitors

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

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2012 Oncology Meetings Oncology Clinical Development Congress October 10-11 • Manchester, Cheshire, United Kingdom For more information: www.oncologyclinicaldevelopmentcongress.com 3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Markers in Cancer: A Joint Meeting by ASCO, EORTC, and NCI October 11-13 • Hollywood, Florida For more information: www.molecularmeeting.org 14th Biennial Meeting of the International Gynecologic Cancer Society October 13-16 • Vancouver, Canada For more information: www2.kenes.com/igcs2012/Pages/ home.aspx Current Approaches to Diagnosis and Treatment of Non-Hodgkin’s Lymphoma October 18-19 • Kiev, Ukraine For more information: nbscience.com/current-approachesto-diagnosis-and-treatment-of-nonhodgkins-lymphoma Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com Society for Immunotherapy of Cancer Workshop—Focus on the Target: The Tumor Microenvironment October 24-25 • North Bethesda, Maryland For more information: www.sitcancer.org/meetings/am12/ workshop12

Society for Immunotherapy of Cancer: Primer on Tumor Immunology and Cancer Immunotherapy October 25 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/primer 12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org 9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com Society for Immunotherapy of Cancer 27th Annual Meeting October 26-28 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/annualmeeting Optimization Methods for Radiation Diagnosis in Oncology October 27-28 • Odessa, Ukraine For more information: nbscience. com/optimization-methods-forradiation-diagnosis-in-oncology 3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

November 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 2012 Science of Global Prostate Cancer Disparities Conference November 1-4 • Nassau, The Bahamas For more information: cancer.ufl.edu/research/symposiaand-conferences 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 PEGS Europe – The Essential Protein & Antibody Engineering Summit November 6-9 • Vienna, Austria For more information: www.pegsummiteurope.com Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org 7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com 2nd Symposium Targeted Cancer Therapy November 19-20 • Heidelberg, Germany For more information: www.dfkz.de/ en/symposiumTCT/ RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp 2nd Annual Best of Oncology Conference November 30 • Toronto, Ontario For more information: www.oncologyeducation.com/ conferences/best-of-oncology-2012. html ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org

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

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Joint Meeting of IPOS 14th World Congress and COSA’s 39th Annual Scientific Meeting November 13-15 • Brisbane, Australia For more information: www.iposcosa.org

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

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News

Symposium Focuses on Policy Issues in Personalized Cancer Care By Caroline McNeil

“W

hat is the biggest barrier to progress in personalized medicine?” asked moderator Anna Barker, PhD, leading a panel discussion at a recent meeting convened by the Washington-based advocacy

group, the Personalized Medicine Coalition, with the American Association for Cancer Research and Feinstein Kean Healthcare. Five well-known experts responded without hesitation:

“A greater understanding of the disease,” said Richard Pazdur, MD, from the FDA. “This will lead to more effective drugs.” “On my side, it’s payment issues,” said Aetna’s Ira Klein, MD.

ANOTHER INNOVATION AT JCO:

O ncOlOgy g rand r Ounds • Case-based descriptions of treatment or diagnostic approaches • Places report’s findings into practical, clinical, real-world context Journal of Clinical Oncology— essential reading for oncologists

“There is a fundamental mismatch with that incremental nature [of progress] and the time frame and focus of the public policy progress,” added John J. Castellani, President and CEO of the Pharmaceutical Research and Manufacturers of America. “There’s no business model for developing the diagnostic tests that guide the use of targeted drugs,” said David Parkinson, MD, a Venture Partner at New Enterprise Associates. “Who’s going to pay for the development of companion diagnostic tests?” “Complexity,” responded academic researcher, Kenneth C. Anderson, MD, from Dana-Farber Cancer Institute. “We need to identify not just targets but accessory pathways.”

Anna Barker, PhD

Dr. Barker herself, who leads two initiatives to develop innovative research models at Arizona State University, noted that “increased costs are a major barrier to achieving personalized cancer medicine.” Indeed, she continued, “rising costs are a problem on many fronts—but for the introduction of innovative molecularly based interventions for cancer, they could be a catastrophic barrier.”

Long List of Issues

TO SUBSCRIBE OR ACTIVATE YOUR ONLINE ACCESS , CONTACT : JCO Customer Service PHONE: 888-273-3508 or 703-519-1430 E-MAIL: jcoservice@asco.org ONLINE: jco.org/subscriptions FAX: 703-518-8155

These and other viewpoints emerged repeatedly in talks and panel discussions throughout the symposium, Turning the Tide Against Cancer Through Sustained Medical Innovation, held June 12 in Washington, DC. The meeting’s purpose was to focus attention on regulatory, reimbursement, and education issues. But panels and speakers often took a broader look at the challenges confronting developers of targeted cancer drugs. The morning keynote speaker, John Mendelsohn, MD, Director of the Khalifa Institute for Personalized Cancer Therapy at The University of

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News

Texas MD Anderson Cancer Center, ran down a long list of issues, from the heterogeneity of cancer cells and genes to clinical trial design to ethical concerns. “The biggest bottleneck,” he said, “is information management.” Massive amounts of data need to be analyzed and stored in personalized medicine research, and that is made more diffi-

Laura Esserman, MD

cult, by “data balkanization”—the tendency toward territoriality and competition.

Data-sharing Models How to counter that tendency and encourage data sharing became the theme of the panel assigned to discuss innovative models in cancer research and care, moderated by Ramsey Baghdadi, Editor of The RPM Report. Panelist Laura Esserman, MD, noted that data sharing is vital to the success of the I-SPY 2 breast cancer trial, which is designed to speed drug development by testing multiple phase II drugs. The trial incorporates precompetitive collaboration for biomarker identification and makes study data publicly available. “It’s an illusion that having data kept to yourself is an advantage, because now time to market will become much more important (now that there is a neoadjuvant path for accelerated approval),” said Dr. Esserman, who is Director of the Breast Care Center at the University of California, San Francisco, and principal investigator on ISPY2. But data sharing can be a hard sell, said panel member Kathy Giusti, MBA, Founder and CEO of the Multiple Myeloma Research Foundation. Her organization has launched a landmark study to collect data on

The Future of Personalized Medicine ■■ The field of personalized medicine is at an inflection point, as advances

in the science converge with the need to apply them in the clinic and the need for health-care cost containment.

■■ New models incorporating precompetitive collaboration and data sharing can help speed the development of new agents.

■■ In defining the value of cancer care, individualized approaches must be Kathy Giusti, MBA

the molecular and genetic changes underpinning the evolution of myeloma by closely following newly diagnosed patients for at least 5 years. All inventions from the study are dedicated to the public domain. At first, academic centers were reluctant to relinquish rights to intellectual property, Ms. Giusti said, so her advocacy group turned to the community cancer centers, such as those run by US Oncology, as the first sites to participate in the study. Now academic centers and industry are also participating in a precompetitive consortium where all data generated

J. Leonard Lichtenfeld, MD, MACP

from the study will be placed onto a free public portal prior to publication. J. Leonard Lichtenfeld, MD, MACP, Deputy Chief Medical Officer of the American Cancer Society, also highlighted the importance of community cancer centers and stressed the need for access to the best medicine for all patients, including the disadvantaged. We have to make data “accessible and actionable” at the clinical level, he said.

Determining Value The other panel of the day considered how to demonstrate and measure the value of targeted therapies. Moderator Kathleen Foley, PhD, of

balanced with the need for evidence-based care.

■■ Patient-centered and patient-provided data will be important in defining value.

■■ Coordination, or “alignment” among agencies and organizations is one key to more rapid development.

■■ A public dialogue is needed on what health-care costs should or should not be paid for by society.

Thomson Reuters Healthcare, began by asking panelists how they would define value. Gwen Darien of the Pathways Project and William S. Dalton, PhD, MD, Director of the H. Lee Moffitt Cancer Center and Research Institute, suggested that discussions of value should be framed around individual need. “You can’t individualize coverage as a payer,” pointed out Lee Newcomer, MD, Senior Vice President at UnitedHealthcare. “We need to prospectively define the standards of evidence for coverage to provide fairness to all our members.” The need for both evidence-based medicine and personalized care—a system that combines evidence and expectation, as Dr. Dalton put it— continued to occupy this panel. The move to care based on individual

Amy Abernethy, MD

Comprehensive Cancer Center of Northwestern University. He advocated “constant discussion” on how to get good evidence and on what is truly appropriate care. The day ended with a wrap-up by Duke University’s Amy Abernethy, MD, of recurrent themes, such as the need for collaboration and sharing among companies and agencies; for a public dialogue on costs and reimbursement; and for more research on the basic science of targets and pathways. And, she noted, there was the overriding theme that emerged from the discussion on determining the value of targeted drugs: We need data.

■

Kathleen Foley, PhD

circumstances and preferences will influence how we look at data, comparative effectiveness, and clinical trial design noted Al B. Benson III, MD, FACP, of the Robert H. Lurie

Disclosure: Dr. Abernethy has received research funding from the the National Institutes of Health, Agency for Healthcare Research and Quality, Robert Wood Johnson Foundation, Pfizer, Helsinn, Amgen, Kanglaite, Alexion, Biovex, DARA, and MiCo, has served as a consultant for Novartis and Pfizer, and is on the corporate board of directors for Advoset and Orange Leaf Associates, LLC. Drs. Barker, Pazdur, Anderson, Mendelsohn, Esserman, Lichtenfeld, Newcomer, and Benson, and Ms. Giusti reported no potential conflicts of interest.

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

736 355

657 306

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. 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 clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 Muscle discomfort3 26.2 3.0 General disorders 4 26.7 1.9 Edema Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

5.1 4.1

0.3 0

2.3

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

Issued: May 2012

08Z12155B

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In the Clinic

Pertuzumab: New Drug for HER2-positive Metastatic Breast 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

n June 2012, pertuzumab (Perjeta) was approved for use in combination with trastuzumab (Herceptin) and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.1,2

Pivotal Trial Approval was based on a multicenter, double-blind trial in which 808 patients with HER2-positive metastatic breast cancer were randomly assigned to receive docetaxel and trastuzumab plus either pertuzumab (n = 402) or placebo (n = 406) as firstline treatment for metastatic disease.2,3 Pertuzumab was given via IV infusion at an initial dose of 840 mg followed by 420 mg every 3 weeks. Docetaxel was given at 75 mg/m2 every 3 weeks for six cycles, and the dose could be increased to 100 mg/m2 if the initial dose level was tolerated. Trastuzumab was given at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. No dose adjustments were permitted for pertuzumab or trastuzumab.

OF NOTE The most common grade 3/4 adverse events with pertuzumab therapy are neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. Patients who had received prior neoadjuvant or adjuvant therapy had to have a disease-free interval of more than 1 year prior to starting the study. HER2 overexpression was defined as 3+ on immunohistochemistry or a fluorescence in situ hybridization amplification ratio ≥ 2.0 on FDA-approved tests performed at a central laboratory. Treatment was continued until disease progression or unacceptable toxicity.

Patients had a median age of 54 years; 59% were white, and 78% had visceral disease. Most patients were from Europe (38%) or Asia (31%). Forty-eight percent of patients were hormone receptor–positive, 47% had received adjuvant or neoadjuvant chemotherapy, 11% had received hormonal therapy for metastatic disease, and 11% had received adjuvant or neoadjuvant trastuzumab. Among hormone receptor–positive patients, 45% had received adjuvant hormonal therapy. Median durations of treatment were 18.1 months in the pertuzumab group and 11.8 months in the placebo group. Independently assessed progressionfree survival, the primary endpoint, was significantly increased with pertuzumab, which reduced risk of progression by 38% (HR = 0.62, 95% CI = 0.51– < .0001). Results for investiga0.75, P �� tor-assessed progression-free survival were similar. Pertuzumab treatment increased median progression-free survival by 6.1 months (18.5 vs 12.4 months). A planned overall survival interim analysis performed at the time of the progression-free survival analysis showed a strong trend for improvement with pertuzumab treatment (HR = 0.64, 95% CI = 0.47– 0.88, P = .0053), but the HR and P value for this analysis did not meet the predefined stopping boundary (HR ≤ 0.603, P ≤ .0012).

How It Works Pertuzumab blocks the extracellular dimerization domain (subdomain II) of HER2, inhibiting ligand-dependent heterodimerization of HER2 with other HER family members (eg, EGFR, HER3, and HER4) and thus inhibiting ligand-initiated intracellular signaling through the MAPK and PI3K pathways. Inhibition of these pathways can result in cell growth arrest and apoptosis, respectively. Pertuzumab also mediates antibody-dependent cellmediated cytotoxicity. Pertuzumab alone inhibits proliferation of human tumor cells, but the combination of pertuzumab and trastuzumab has been shown to significantly increase antitumor activity in HER2-overexpressing xenografts.

How It Is Given The initial dose of pertuzumab is 840 mg given as a 60-minute IV

Pertuzumab in Metastatic Breast Cancer ■■ Pertuzumab (Perjeta) was approved for use in combination with

trastuzumab (Herceptin) and docetaxel to treat patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

■■ Pertuzumab is initially given at 840 mg as a 60-minute IV infusion, followed every 3 weeks by a dose of 420 mg given as a 30- to 60-minute infusion.

infusion, followed every 3 weeks by a dose of 420 mg given as a 30- to 60-minute infusion. When administered with pertuzumab, trastuzumab should be given at an initial dose of 8�� mg/kg via 90-minute infusion followed by 6 mg/kg via 30- to 90-minute infusion every 3 weeks, and docetaxel should be given at 75 mg/ m2 every 3 weeks. The docetaxel dose can be increased to 100 mg/m2 if the initial dose is tolerated. Pertuzumab infusion should be reduced in rate or interrupted for infusion-related reactions and discontinued immediately for severe hypersensitivity reactions. Pertuzumab and trastuzumab should be withheld for 3 weeks in patients with a reduction in left-ventricular ejection fraction to < 40% or a ≥ 10% absolute reduction in leftventricular ejection fraction to 40% to 45%. Pertuzumab can be resumed if left-ventricular ejection fraction recovers to > 45% or to 40% to 45% in patients with an absolute reduction of <�� 10%. Discontinuation of pertuzumab and trastuzumab should be strongly considered if such recovery does not occur within 3 weeks. Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued. Dose reductions of pertuzumab are not recommended.

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

Safety Profile In the pivotal clinical trial,2,3 adverse events led to discontinuation of all study treatment in 6.1% of pertuzumab patients and 5.3% of placebo patients, with docetaxel alone being discontinued in 23.6% and 23.2%, respectively. The most common adverse events (> 30%) in pertuzumab patients were neutropenia (53% vs 50% in placebo group), nausea (42% in both groups), fatigue (38% vs 37%), rash (34% vs 24%), and peripheral neuropathy (32% vs 34%).

OF NOTE Pertuzumab carries a boxed warning for embryo-fetal toxicity and birth defects, and additional warnings/precautions about left-ventricular toxicity, infusion-related reactions, and HER2 testing. The most common grade 3 or 4 adverse events (>�� 2%) �� were neutropenia (49% vs 46%), febrile neutropenia (13% vs 7%), leukopenia (12% vs 15%), diarrhea (8% vs 5%), peripheral neuropathy (3.2% vs 2.0%), anemia (2.5% vs 3.5%), asthenia (2.5% vs 1.5%), and fatigue (2.2% vs 3.3%). Asian patients in both treatment groups had a higher incidence of febrile neutropenia compared with patients of other races, with the incidence among Asian patients being higher in pertuzumab recipients (26% vs 12%). Pertuzumab was not associated with an increase in the incidence of symptomatic left-ventricular systolic dysfunction or reductions in left-ventricular ejection fraction compared with placebo. The incidence of leftventricular dysfunction was 4.4% in the pertuzumab group vs 8.3% in the placebo group. Other significant adverse events observed in pertuzumab patients incontinued on page 80

The ASCO Post | AUGUST 15, 2012

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Patient’s Corner

Living with the Aftermath of Breast Cancer

Even though I’ve beaten my survival odds, my quality of life is changed forever. By Sherry Cohen, as told to Jo Cavallo

y battle with breast cancer began 10 years ago, but the aftereffects of the disease and the treatment will be with me for the rest of my life. As a professional woman who has had several diverse careers, including one as a corporate controller and another as an art teacher, I’m driven to want to succeed in life. But since my breast cancer diagnosis in 2002, I’ve not only been unable to continue working, even doing the simplest tasks like cooking or cleaning leave me exhausted.

Cumulative Effect of Treatment Now I wonder, if I had been immediately diagnosed when I first felt a huge lump in my right breast, whether some of these issues could have been avoided. An earlier mammogram in that same breast had shown a cluster of microcalcifications, which was diagnosed as stage I ductal carcinoma in situ and required two lumpectomies to remove. Though they performed sonograms when I felt the new mass, the doctors in California said it was noth-

Pertuzumab continued from page 79

cluded infusion-associated reactions, hypersensitivity reactions (10.1% vs 8.6%), and anaphylaxis (4 vs 2 patients). Pertuzumab infusion-related reactions were assessed by administering the initial pertuzumab dose the day before See Page 86 trastuzumab/paclitaxel. Reactions occurred in 13.0%

Visit

ing to worry about. It wasn’t until I moved from California to Missouri in the spring of 2003 and found a new medical team that a biopsy of the tumor in my right breast was taken. It was found to be a stage IIIC HER2-positive invasive ductal carcinoma. Even with therapy,

with anastrozole has helped me beat those odds, but the cumulative effect of my treatment has left the quality of my life permanently altered. The combination of 15 surgeries—to repair a crater on my right side (the result of the radiation therapy) and for breast reconstruction—plus the chemother-

People tell me that I must be so strong to be able to cope with the ongoing ramifications of having cancer. But I don’t think I’m that strong. I’ve just made a decision to get up every morning and have the best possible day I can have. —Sherry Cohen

which included a bilateral mastectomy, 8 rounds of doxorubicin and docetaxel, and 38 rounds of radiation therapy, my oncology team said that my life expectancy was between 2 and 3 years. Fortunately, maintenance therapy

apy has left me so fatigued and cognitively impaired that I’ve had to go on disability.

of pertuzumab patients vs 9.8% of placebo patients, with the most common reactions being pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. Grade 3 or 4 infusion reactions occurred in < 1% of patients. Pertuzumab carries a boxed warning for embryo-fetal toxicity and birth defects, based on observations of oligohydramnios, delayed renal development, and embryo-fetal death in animal studies. Patients should be

advised of these risks and the need for effective contraception prior to starting pertuzumab. Pertuzumab carries additional warnings/precautions for left-ventricular toxicity, infusionrelated reactions, and HER2 testing. HER2 testing should be performed using FDA-approved tests by laboratories with demonstrated proficiency in testing.

Overcoming Isolation Not being able to perform two activities, like cooking and cleaning, in

■

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

the same day sounds like a minor inconvenience, but the effect is crushing to someone who is used to an active and productive lifestyle. Plus, I constantly live with the fear that my cancer will come back. What has helped me work through that fear and overcome a sense of isolation I’ve felt since my diagnosis is my involvement with the American Cancer Society’s Cancer Survivors Network (csn.cancer.org). Just knowing that I can go online any time of the day or night and speak to other cancer survivors and vent about my problems or joke with them has saved my life. I’ve also gone back to my artistic roots and have taken up modular origami, which has been therapeutic and helped lift my depression. People tell me that I must be so strong to be able to cope with the ongoing ramifications of having cancer. But I don’t think I’m that strong. I’ve just made a decision to get up every morning and have the best possible day I can have.

■

Sherry Cohen lives in Cedar Hill, Missouri.

Pertuzumab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm307592.htm. Accessed June 25, 2012. 2. PERJETATM (pertuzumab) injection prescribing information, Genentech, Inc, June, 2012. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2012/125409lbl.pdf. Accessed June 25, 2012. 3. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

website at ASCOPost.com

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Integrative Oncology Barrie R. Cassileth, PhD, Guest Editor

he use of dietary supplements by cancer patients has risen significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on alternative and complementary therapies commonly used by patients with cancer. For this installment, we chose Astragalus, an herb widely used in traditional Chinese medicine, because of its growing popularity among cancer patients.

also commonly included in recipes for soups. The root is dried and sliced to prepare a decoction by boiling in water for an extended period. The herb is also available as a dietary supplement in various forms, including tablets, capsules, tinctures, and ointments for topical use, and in injectable form for use in clinical studies.

The Science

Of the more than 2,000 species of Astragalus distributed worldwide, Astragalus membranaceus, which is prevalent in China, has been extensively studied. Its biologically active compounds include saponins, polysaccharides, and flavonoids. When used with Angelica sinen-

sis, an herb used widely in traditional Chinese medicine, Astragalus exhibits renoprotective effects,1 decreases proteinuria associated with idiopathic membranous nephropathy,2 and displays natriuretic action.3 It also suppresses airway hyperreactivity associated with allergic asthma in vivo.4 continued on page 82

Astragalus Scientific Name: Astragalus membranaceus Common Names: Huang chi, ogi, hwanggi, milk vetch.

Overview

Astragalus is a perennial flowering plant prevalent in northern China, Mongolia, and Korea. Its root has a long history of medicinal use to increase metabolism, stamina, strength, and vitality. Astragalus continues to be widely used in traditional Chinese medicine, often combined with other herbs, to boost immune function, improve endurance, prevent upper respiratory infections and colds, lower blood pressure, control night sweats, and to treat heart disease and diabetes. The medicinal value of Astragalus was first mentioned in Shen Nong Ben Cao Jing, the classical Chinese herbal treatise, written in 200 AD. Depending on the disease and the desired therapeutic effect, Astragalus is combined with specific herbs. It is

Our world centers around theirs ACTION PURPOSE IMPACT

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

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Integrative Oncology Astragalus continued from page 81

Astragalus was shown to increase M-cholinergic receptor density in senile rats,5 suggesting that it may help combat senility. Astragalus extract acts as a nerve growth–promoting factor in vitro and in vivo.6 In combination with Angelica sinensis and standard care, it alleviates obstructive uropathy in rats.7 A formulation containing Astragalus has been shown to alleviate fatigue in athletes.8

OF NOTE

mine if it affects hormone-sensitive cancers.

Astragalus/Drug Interactions

Cyclophosphamide: Astragalus reduces cyclophosphamide-induced immunosuppression.16 Aldesleukin: Concomitant administration of aldesleukin (Proleukin) with Astragalus caused a 10-fold potentiation of tumoricidal activity with decreased side effects.19 Cytochrome P450 Substrates: Astragalus inhibits CYP3A4 and can affect the metabolism of certain drugs metabolized by this enzyme.20

■

Disclosure: Dr. Cassileth and Ms. Gubili reported no potential conflicts of interest.

Astragalus is a popular immunostimulant sought by many cancer patients. Oncologists should be aware of its interactions with immunosuppressive agents. Data on the anticancer potential of Astragalus are limited but promising. Extracts of astragalus inhibit tumor growth,9 delay chemical-induced hepatocarcinogenesis in rats,10 and display antiangiogenic properties.11 In vitro, animal, and human data indicate that it reduces immune suppression, a side effect of chemotherapy.12,13 Astragalus extract also enhanced the effect of platinum-based chemotherapy.14 A meta-analysis suggests that Astragalus-based treatments for hepatocellular cancers may be viable, but larger trials are required.15 Use of an injectable form of Astragalus See Page 86 with vinorelbine and cisplatin in patients with advanced non–small cell lung cancer improved quality of life.16 Whether orally administered Astragalus exerts the same effects is not known. A recent study suggests that Astragalus extract may help manage cancer-related fatigue.17 Astragalus demonstrated estrogenic effects in vitro.18 Studies are needed to deter-

References 1. Yu L, Lu Y, Li J, et al: Identification of a gene associated with astragalus and angelica’s renal protective effects by silver staining mRNA differential display. Chin Med J (Engl) 115:923-927, 2002. 2. Ahmed MS, Hou SH, Battaglia MC, et al: Treatment of idiopathic membranous nephropathy with the herb Astragalus membranaceus. Am J Kidney Dis 50:1028-1032, 2007. 3. Ai P, Yong G, Dingkun G, et al: Aqueous extract of Astragali radix induces human natriuresis through enhancement of renal response to atrial natriuretic peptide. J Ethnopharmacol 116:413-421, 2008. 4. Shen HH, Wang K, Li W, et al: Astragalus membranaceus prevents airway hyperreactivity in mice related to Th2 response inhibition. J Ethnopharmacol 116:363-369, 2008. 5. Shi R, He L, Hu Y, et al: The regulatory action of radix astragali on M-cholinergic receptor of the brain of senile rats. J Tradit Chin Med 21:232-235, 2001. 6. Lu MC, Yao CH, Wang SH, et al: Effect of Astragalus membranaceus in rats on peripheral nerve regeneration: in vitro and in vivo studies. J Trauma 68:434-440, 2010. 7. Wojcikowski K, Wohlmuth H, Johnson DW, et al: Effect of Astragalus membranaceus and Angelica sinensis combined with Enalapril in rats with obstructive uropathy. Phytother Res 24:875-884, 2010.

ntegrative Oncology is guest edited by Barrie R. Cassileth, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 260 and growing number of entries offers health-care professional and patient versions, and entries are regularly updated with the latest research findings. 8. Chen KT, Su CH, Hsin LH, et al: Reducing fatigue of athletes following oral administration of huangqi jianzhong tang. Acta Pharmacol Sin 23:757-761, 2002. 9. Cho WC, Leung KN: In vitro and in vivo anti-tumor effects of Astragalus membranaceus. Cancer Lett 252(1):4354, 2007. 10. Cui R, He J, Wang B, et al: Suppressive effect of Astragalus membranaceus Bunge on chemical hepatocarcinogenesis in rats. Cancer Chemother Pharmacol 51:75-80, 2003. 11. Auyeung KK, Woo PK, Law PC, et al: Astragalus saponins modulate cell invasiveness and angiogenesis in human gastric adenocarcinoma cells. J Ethnopharmacol. August 12, 2011 (early release online). 12. Chu DT, Wong WL, Mavligit GM: Immunotherapy with Chinese medicinal herbs. II. Reversal of cyclophosphamideinduced immune suppression by administration of fractionated Astragalus membranaceus in vivo. J Clin Lab Immunol 25:125-129, 1988. 13. Taixiang W, Munro AJ, Guanjian L: Chinese medical herbs for chemotherapy side effects in colorectal cancer patients. Cochrane Database Syst Rev (1):CD004540, 2005. 14. McCulloch M, See C, Shu XJ, et al: Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: Meta-analysis of randomized trials. J Clin Oncol 24:419430, 2006. 15. Wu P, Dugoua JJ, Eyawo O, et al: Traditional Chinese medicines in the treat-

Visit the About Herbs website at

www.mskcc.org/aboutherbs

ment of hepatocellular cancers: A systematic review and meta-analysis. J Exp Clin Cancer Res 28:112, 2009. 16. Guo L, Bai SP, Zhao L, et al: Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: Effects on quality of life and survival. Med Oncol. September 18, 2011. (early release online). 17. Chen HW, Lin IH, Chen YJ, et al: A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: A phase II double-blind, randomized placebo-controlled study. Clin Invest Med 35:E1-11, 2012. 18. Zhang CZ, Wang SX, Zhang Y, et al: In vitro estrogenic activities of Chinese medicinal plants traditionally used for the management of menopausal symptoms. J Ethnopharmacol 98:295-300, 2005. 19. Chu DT, Lepe-Zuniga J, Wong WL, et al: Fractionated extract of Astragalus, a Chinese medicinal herb, potentiates LAK cell cytotoxicity generated by a low dose of recombinant interleukin-2. J Clin Lab Immunol 26:183-187, 1988. 20. Pao LH, Hu OY, Fan HY, et al: Herb-drug interaction of 50 Chinese herbal medicines on CYP3A4 activity in vitro and in vivo. Am J Chin Med 40:5773, 2012. Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan-Kettering Cancer Center. The About Herbs website is managed by K. Simon Yeung, PharmD, MBA, Lac, Memorial Sloan-Kettering Cancer Center.

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In the News

Genomics vs Site of Cancer Origin as Basis for Treatment of Cancer Is ‘False Dichotomy’ By Charlotte Bath

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

espite recent news reports suggesting that the basis of cancer treatment is shifting from the site of cancer origin to the genetic mutations driving cancer growth, genomics is not altering treatment for most current patients with cancer, nor is the site of cancer likely to become inconsequential.

George W. Sledge, Jr, MD

“I think it is a false dichotomy,” George W. Sledge, Jr, MD, stated in an interview with The ASCO Post. A Past President of ASCO, Dr. Sledge is Codirector of the Breast Cancer Program at Indiana University and Distinguished Professor at Indiana University School of Medicine in Indianapolis. “In the breast cancer clinic here, we have breast surgeons, radiation oncologists, and breast pathologists—we call it a multidisciplinary team, and we think that is a good thing.” In addition, “our group, like many others, is in the process of developing a genomics-based clinic,” he noted. “But the idea that organ site–specific therapies are going to magically vanish in the genomic era is just wrong,” he said.

Context-dependent Biology “It is wrong for another reason, which is that we see a great deal of context-dependent biology, biology that is fairly organ-specific,” he continued. “For instance, if one looks at epidermal growth factor receptors, the resistance mechanisms in one organ are not infrequently different from resistance mechanisms in another organ. In colorectal cancer, KRAS mutations are very im-

portant. But in non–small cell lung cancer, mutations in the epidermal growth factor receptor itself appear to be important. So I think it is wrong to suggest that the organ no longer matters.” The site of cancer also matters in a patient’s choice of physician and initial treatment. A patient with breast cancer is “still going to have a lumpectomy and radiation therapy,” Dr. Sledge said. “If you have non–small cell lung cancer, you still want to have a lung surgeon operating on you, not a genitourinary surgeon. A lot of what we have done in the past is going to continue.”

Layer Cake Model One reason for basing cancer treatment on genetic aberrations rather than the site or type of cancer is that some newer drugs that target genetic mutations are effective in more than one type of cancer, Dr. Sledge said. As an example he cited the ALK inhibitor crizotinib (Xalkori), which was approved by the FDA for treating patients who have lung cancer with an ALK mutation. “ALK is anaplastic lymphoma kinase,” Dr. Sledge explained. “It appears to be very active in this particular type of lymphoma but is probably not going to be very important in many other lymphomas. We are going to see a lot of drugs that will be used in more than one disease, just because the biology will direct us to multiple different diseases or disease subtypes,” he said. “But that it not to say that the old methods are automatically going away,” Dr. Sledge continued. He said that he viewed the use of targeted therapies based on a patient’s genomic testing “more as a new layer on top of the old,

Expect Questions from Your Patients

or now, genomic sequencing seems to have a greater presence in the news than in the clinic. What can physicians tell their patients who ask about genetic testing to identify mutations driving cancer growth? “The real answer is that when you get down to it, genomics is like any other test,” George W. Sledge, Jr, MD, told The ASCO Post. “We order tests because they are likely to change our understanding of the disease and therefore the treatment of the disease. Genomics so far—not for all patients, but for most patients—hasn’t been proven to alter available therapies for patients.” Dr. Sledge is Co-director of the Breast Cancer Program at Indiana University and Distinguished Professor at Indiana University School of Medicine, Indianapolis, as well as a Past President of ASCO.

Actionable Mutation? As an example, Dr. Sledge proposed the theoretical case of a woman with breast cancer who is shown to have an ALK (anaplastic lymphoma kinase) mutation by genetic testing. “Crizotinib [Xalkori] is approved for patients with non–small cell lung cancer who have the ALK mutation,” Dr. Sledge noted. “It is probably going to be approved for that particular type of lymphoma in the not-too-distant future. But if I were to order the test today, and I found an ALK mutation in a patient with breast cancer, I don’t necessarily know that it’s an actionable mutation, because we haven’t treated a population of patients who have it in breast cancer yet. I don’t know whether it would be beneficial to the patient, and even if it were, it certainly isn’t FDA-approved in that indication.” In the example cited, the result of genetic testing “is not actionable at a scientific level and is not actionable at a practical level yet,” Dr. Sledge said. In addition, he said, the price of many new targeted therapies keeps them “out of reach for the average patient.”

■

‘Splitters vs Lumpers’ In a Reuters report1 from this year’s ASCO Annual Meeting, Dr. Sledge was quoted as saying, “We’ve had this biological revolution that has sliced the pie for these cancers finer and finer as we’ve learned more about the genomics of cancer.” He used the example of acute lymphoblastic leukemia, for which at least 17 different subtypes have been recognized.

Our group, like many others, is in the process of developing a genomics-based clinic…But the idea that organ site–specific therapies are going to magically vanish in the genomic era is just wrong. —George W. Sledge, Jr, MD

rather than something that is just going to immediately replace the old.” He called this “the layer cake model, where you’ve got the base layer that represents locoregional treatments, on which you’ve got more standard systemic treatments, on top of which you may add more specific molecularly targeted treatments.”

Asked if there are other types of cancer with so many slices of the pie, Dr. Sledge replied, “It depends on whom you talk to. For instance, breast cancer has what are widely recognized as four or five intrinsic subtypes. But Dr. Jennifer Pietenpol and her colleagues at Vanderbilt University have said that one of those subtypes—

triple-negative breast cancer—can be further divided into another six subtypes.2 That’s 15% of breast cancer cases with six different subtypes at a molecular level,” according to that study, Dr. Sledge said. “At some level, the question becomes, how do you define a subtype? In theory, every patient could represent his or her own subtype, because everyone has different mutations. So you can slice it as finely or as nonfinely as you want, depending on whether you are a ‘lumper’ or a ‘splitter,’” Dr. Sledge explained. “But is it important from a treatment standpoint? A lot of the supersubtypes may not be particularly important from a treatment standpoint, in part, because we haven’t yet identified the driver mutations.” Among those involved in genomics research, “the sense is that there are a huge number of passenger mutations and a relatively fewer number of driver mutations,” Dr. Sledge said. In addition, a mutation that might not initially be considered a driver mutation may become more important once it is treated with a drug. “There is a fascinating recent article by Dr. Charles Perou’s group at the Univer-

ASCOPost.com | AUGUST 15, 2012

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In the News

sity of North Carolina,3 which said that if you shut down a particular kinase in triple-negative See Page 86 breast cancer, another kinase immediately pops up as being important. So some things that may not be drivers in the absence of therapy may become drivers in the presence of targeted therapy.”

Less-expensive Sequencing Targeted treatment and personalized medicine require gene sequencing of the individual’s genome, the tumor, or both. Ultimately, the decision to sequence or not will be driven at least partly by price. “The price of genomics is falling like a rock,” Dr. Sledge said, adding that the

prevailing prediction is “this is the year when we get the $1,000 genome. What we don’t get with the $1,000 genome is the $1,000 explain-the-genome kit,” he noted. “Even though we now can identify all these mutations, we don’t yet have the clinical data to tell us which ones are important.” Those data, he said, should be coming within the next 5 years from

studies that are now ongoing.

■

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

References B:8.625” 1. SteenhuysenT:7.625” J: Doctors try to make sense of cancer’s genetic jumble. Thomson S:6.75” Reuters, June 5, 2012. Available at www. reuters.com. Accessed June 6, 2012.

2. Lehman BD, Bauer JA, Chen X, et al: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapy. J Clin Invest 121:2750-2767, 2011. 3. Duncan JS, Whittle MC, Nakamura K, et al: Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple negative breast cancer. Cell 149:307-321, 2012.

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases

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The ASCO Post

CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

•Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

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Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib (60 mg qd) Randomization Prednisone

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

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In the Literature

Emerging Clinical Data on Cancer Management radiotherapy according to protocol, 1 withdrew consent for participation and received radiotherapy elsewhere, and 1 had early disease progression prior to radiotherapy and received retrieval therapy,” the investigators reported.

HODGKIN LYMPHOMA Children with Favorablerisk Disease and Complete Response to Chemotherapy Have High Survival Rates without Radiotherapy

Key Results

Among children with favorable-risk Hodgkin lymphoma, those who achieved a complete response after two cycles of chemotherapy and received no radiotherapy had high rates of survival similar to those who had a less complete response to chemotherapy and received radiotherapy, according to a study in the Journal of the American Medical Association. “To our knowledge, this is the first trial in which a select group of children with favorablerisk Hodgkin lymphoma experienced a high rate of 2- and 5-year event-free survival without exposure to radiotherapy, alkylating agent, epipodophyllotoxin, or bleomycin chemotherapy and a relatively low cumulative dose of anthracyclines,” the researchers commented. The multi-institutional, unblinded, nonrandomized phase II clinical trial included 88 patients with stage I/II Hodgkin lymphoma and a median age of 13.9 years (range, 4.4–20.6 years). The study was designed to evaluate the efficacy of four cycles of VAMP (vinblastine, doxorubicin, methotrexate, prednisone) in patients with favorable–risk Hodgkin lymphoma who had a complete response after two cycles and did not receive radiotherapy. The 47 patients who achieved a complete response after two cycles of VAMP completed therapy without involved-field radiotherapy. “Among the 41 (47%) who did not achieve a complete response (39 partial responses, 2 stable diseases), 39 received

The 2-year event-free survival rate was 90.8% overall, 89.4% for those who achieved early complete response and did not receive involved-field radiotherapy, and 92.5% for those who did not achieve complete response and did require radiotherapy (P = .61). The estimated 5-year survival was 89.4% for patients who did not undergo irradiation and 87.5% for patients who did. “Therapy was well tolerated without major complications. Delay or dose modifications due to adverse toxic effects were rare,” the investigators noted. “The most common adverse effects were neuropathic pain (2% of patients) and nausea and vomiting (3% of patients), all of which are readily managed with supportive care.” Long-term adverse effects after radiotherapy included subclinical pulmonary dysfunction in 12 patients (14%), asymptomatic compensated hypothyroidism in 9 patients (10%), asymptomatic left-ventricular dysfunction in 4 patients (5%), and osteonecrosis and moderate osteopenia in 2 patients (2%). “No second malignant neoplasms were observed,” the authors added. Evaluation of quality of life during and after treatment will be reported in a future manuscript.

Hodgkin lymphoma,” the authors concluded. “It would be important to confirm the results in a larger cohort,” they noted. “These findings highlight the continued commitment to reduce complications in the treatment of childhood malignancies and add to the growing body of evidence detailing the utility of early response-adapted therapy,” according to an accompanying editorial. “The emphasis on minimizing therapy when possible is especially important in the treatment of childhood malignancies, for which the consequences of late complications [are] well documented. However, any attempt to decrease therapy to minimize late effects must be balanced with the risk of relapse because the primary cause of death the first 10 years after diagnosis remains recurrent disease,” the editorialists continued. “Even though the outcomes reported by Metzger et al are encouraging, these results must be corroborated in larger, randomized studies because earlier attempts to decrease both the intensity of chemotherapy and to omit radiation in select low-risk patients have not been as promising,” they added.

Metzger ML, et al: JAMA 307:26092616, 2012. Whelan KF, Goldman FD: JAMA 307:2639-2640, 2012.

NEUROENDOCRINE TUMORS

Study Implications

Bevacizumab/Temozolomide Combination Safe and Active against Advanced Neuroendocrine Tumors

“Our results suggest that a risk-adapted response-based approach may be very effective and well-tolerated for a selected group of patients with favorable-risk

The combination of bevacizumab (Avastin) and temozolomide can be safely administered together in patients with advanced neuroendocrine tumors,

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

and “the combination regimen appears promising for patients with pancreatic [neuroendocrine See Page 86 tumors],” according to results of a phase II study reported in the Journal of Clinical Oncology. “Temozolomide was developed as a less toxic alternative to dacarbazine and has demonstrated activity in [neuroendocrine tumors] in both retrospective and prospective studies,” the investigators noted. Bevacizumab has shown activity when evaluated in advanced carcinoid tumors in two phase II studies. “Given the reported activity of both agents in carcinoid tumors and pancreatic [neuroendocrine tumors], we conducted a multi-institutional phase II study to assess the safety and efficacy of temozolomide given with bevacizumab in patients with advanced [neuroendocrine tumors],” the authors explained. The study involved 34 patients, 19 with carcinoid tumors and 15 with pancreatic neuroendocrine tumors. The median age of patients was 60 years, and the male/female ratio was 19:15. All patients received temozolomide at 150 mg/m2 orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg/d intravenously on days 1 and 15 of each 28-day cycle, along with prophylaxis against Pneumocystis carinii and varicella zoster.

Study Data “Although the overall radiographic response rate was 15% (5 of 34), response rates differed between patients with pancreatic [neuroendocrine tumors] (33%; 5 of 15) and those with carcinoid tumors (0 of 19),” the re-

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Position your device in front of the code so that it fills about half your screen.

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In the Literature

searchers reported. “The median progression-free survival was 11.0 months (14.3 months for pancreatic [neuroendocrine tumors] vs 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic [neuroendocrine tumors] vs 18.8 months for carcinoid tumors).” Grade 3 to 4 toxicities included lymphopenia (53%) and thrombocytopenia (18%). “The most common nonhematologic adverse events were fatigue (76%), nausea (68%), vomiting (65%), anorexia (44%), constipation (32%), and diarrhea (29%). Most toxicities were relatively mild,” the authors stated. “Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted,” they concluded. Chan JA, et al: J Clin Oncol. July 9, 2012 (early release online).

GASTRIC CANCER ‘Strong Persistent Benefit’ from Radiochemotherapy after Curative Gastric Cancer Resection An update, with more than a 10year median follow-up, from Intergroup 0116 (INT-0116), a randomized phase III trial of postoperative chemotherapy in patients at moderate risk of locoregional failure following curative gastric cancer resection, “demonstrates strong persistent benefit from adjuvant radiochemotherapy.” Median overall survival was 35 months among patients receiving chemoradiotherapy vs 27 months for observation after resection, and the median relapse-free survival was 27 vs 19 months. The hazard ratio for overall survival was 1.32 (95% CI = 1.10–1.60; P = .0046), and the hazard ratio for relapse-free survival was 1.51 (95% CI =1.25–1.83; P < .001), the investigators reported in the Journal of Clinical Oncology. Among the 559 eligible patients with primaries ≥ T3 and/or node-positive gastric cancer, 277 were randomly assigned to observation and 282 to radiochemotherapy. Fluorouracil and leucovorin were given before, during, and after radiotherapy, which was given to all locoregional failure sites to a dose of 45 Gy, the authors explained. “[Locoregional failure] reduction may account for the majority of overall relapse reduction,” they added.

Treatment-related Toxicities Previously reported acute toxicity effects were predominantly hematologic and gastrointestinal. There were no reports of excess treatment-related toxicities during long-term follow-up. Among patients receiving radiotherapy, 21 patients had second malignancies (25 separate cancers) vs 8 patients in the observation group. “Toxicities, including second malignancies, appear acceptable, given the magnitude of [relapse-free failure] and [overall survival] improvement,” the investigators noted. “Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes,” they concluded.

■

Smalley SR, et al: J Clin Oncol 30:23272333, 2012.

PERIAMPULLARY CANCER Adjuvant Chemotherapy May Improve Survival for Patients with Periampullary Disease The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary cancer trial found that adjuvant chemotherapy following surgical resection of periampullary adenocarcinoma “was not associated with a significant survival benefit in the primary analysis; however, multivariate analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy.” The phase III randomized controlled trial was conducted in 100 centers in Europe, Australia, Japan, and Canada, and reported in the Journal of the American Medical Association. “Periampullary carcinomas arise from the head of the pancreas in the region of the ampulla of Vater and apart from pancreatic ductal adenocarcinoma comprise carcinomas of the bile duct, the ampulla itself, and the periampullary duodenum,” according to background information in the article. “The clinical presentation is similar to that of pancreatic ductal adenocarcinoma, and together they represent a major cause of death.” Although adjuvant chemotherapy had been shown to have a survival benefit for pancreatic cancer, there were previously no controlled trials for periampullary adenocarcinomas. Of the 428 patients included in the primary analysis of the ESPAC-3 trial, 297 had ampullary cancer, 96 had bile duct cancer, and 35 had other cancers.

Patients were divided into three groups: (1) 144 to the observation group, (2) 143 to receive leucovorin via intravenous bolus injection followed by fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and (3) 141 to receive intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.

Hypothesis-generating Results At the time of analysis, 244 patients (57%) had died—88 (61 %) in the observation group, 83 (58%) in the fluorouracil-plus-leucovorin group, and 73 (52%) in the gemcitabine group. For the primary analysis, median survival was 35.2 months in the observation group, 38.9 months for patients treated with fluorouracil plus leucovorin, and 45.7 months for patients treated with gemcitabine. “After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI = 0.57–0.98; Wald X2 = 4.53, P = .03),” the investigators reported. The statistically significant survival benefit to chemotherapy was found “specifically for gemcitabine compared with observation, notwithstanding the better safety profile compared with fluorouracil plus leucovorin, but these results should be considered hypothesis generating,” the authors noted. A total of 162 treatmentrelated serious adverse events were reported by 70 patients (49%) receiving

fluorouracil plus leucovorin compared to a total of 81 events reported by 43 patients (30%) receiving gemcitabine. “Although this study found support for the use of adjuvant chemotherapy to improve survival in patients with periampullary cancers, this effect was modest, indicating a need for further improvements and warranting the testing of combination chemotherapies,” the researchers concluded. Neoptolemos JP, et al: JAMA. 308:147156, 2012.

GASTROINTESTINAL STROMAL TUMOR Regorafenib Has ‘Notable Anticancer Activity’ after Patients Develop Resistance to Imatinib and Sunitinib The orally administered investigational multikinase inhibitor regorafenib demonstrated “notable anticancer activity” in a phase II trial among patients with advanced gastrointestinal stromal tumor (GIST) who developed resistance to imatinib (Gleevec) and sunitinib (Sutent). Researchers reported in the Journal of Clinical Oncology that clinical benefit, defined as complete or partial response or stable disease ≥ 16 weeks, was documented in 26 (75%) of the 33 eligible patients. Four patients had stable disease ≤ 16 weeks, two had disease progression at first tumor evaluation, and one withdrew from the study continued on page 88

The ASCO Post | AUGUST 15, 2012

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In the Literature

Emerging Data on Clinical Management continued from page 87

before the first tumor assessment. The median progression-free survival was 10 months and overall survival had not been reached at the time the study was published. Six patients had died, five secondary to disease progression and

one from an unrelated illness. An international phase III trial evaluating regorafenib in this setting is underway “Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28day cycle,” the researchers noted. Handfoot skin reaction occurred in 85% of patients, fatigue in 79%, hypertension in 67%, and diarrhea in 61%. Most of

these events were grade 1, but grade 3 or 4 hypertension occurred in 34% of patients, hand-foot skin reaction in 24%, and hypophosphatemia in 15%. “Despite the majority of patients requiring at least one dose reduction for toxicity, many patients were able to have the regorafenib dose re-escalated without recurrence of unaccept-

able adverse effects,” the investigators stated. “Only one patient discontinued participation in the study because of toxicity,” the authors added, “suggesting that in this cohort, toxicity was manageable with dose modification and other supportive measures.” George S, et al: J Clin Oncol 30:24012407, 2012.

ESOPHAGEAL CANCER

All of your

Oncology News...

Most Hospitals Do Not Meet Benchmark for Examining Lymph Nodes following Esophagectomy “Fewer than one-third of patients and fewer than 1 in 10 hospitals met the benchmark of examining at least 15 lymph nodes” following esophagectomy for patients with esophageal cancer, according to a retrospective observational study reported in the Archives of Surgery. That benchmark was set by the National Comprehensive Cancer Network,” the authors noted. Using the National Cancer Data Base, researchers identified 13,995 patients with stage I through III esophageal cancer undergoing esophagectomy at a total of 639 hospitals and not treated with neoadjuvant chemoradiotherapy. “Overall, 4,014 patients (28.7%) had at least 15 lymph nodes examined, which increased from 23.5% to 34.4% during the study period, [1998–2007],” the researchers reported.

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“At the hospital level, only 45 centers (7.0%) examined a median of at least 15 lymph nodes. In the most recent period (2005–2007), at least 15 nodes were examined in 38.9% of patients at academic centers vs 28.0% at community hospitals and in 44.1% at high-volume centers vs 29.3% at low-volume centers. On multivariable analysis, hospital type, surgical volume status, and geographic location remained significant predictors of having at least 15 lymph nodes examined.” Patients in the Northeast were more likely to have at least 15 lymph nodes examined. “After controlling for confounding factors, compared with the Northeast, the South and Midwest were both 32% less likely to examine 15 nodes,” the investigators noted. The authors concluded that hospitals “should perform internal process improvement activities to improve guideline adherence.”

■

Merkow RP, et al: Arch Surg 147:505511, 2012.

ASCOPost.com | JUNE 15, 2012

PAGE 89

Awards

Conquer Cancer Foundation Honors Oncology Professionals for High-quality Research in Breast Cancer

MPHS, Washington University School of Medicine: Barriers to mammography among underserved women in a breast health center outreach program. ■■ Bruna Jardim, MSc, Henry Ford Health System: Response of angiogenic factors to the treatment with melatonin in breast cancer cell lines. ■■ Jiali Li, MD, PhD, University of California, San Francisco Helen

he Conquer Cancer Foundation of ASCO recently announced the recipients of its 2012 Breast Cancer Symposium Merit Awards, which recognize leading oncology professionals for their work in the area of breast cancer research. This year, the Foundation honors 16 individuals for their research in the areas of breast cancer disease management, survivorship care, health-care disparities, and more. The recipients will be recognized at the 2012 Breast Cancer Symposium taking place September 13–15 in San Francisco. “This year’s Merit Award recipients are helping to contribute to the growing body of clinical evidence in breast cancer that that helps patients live longer and have better outcomes,” said Gary Levine, MD, Chair of the Breast Cancer Symposium Steering Committee. “We are honored to recognize the scientific advances of this year’s recipients as well as their dedication to improving care for patients living with breast cancer.” The Conquer Cancer Foundation of ASCO Merit Awards are designed to promote clinical cancer research by young oncology investigators and provide them with the opportunity to present their research at the 2012 Breast Cancer Symposium, a multidisciplinary meeting for breast cancer clinicians and other oncology team members who treat and care for patients with breast cancer. This year’s Symposium will focus on taking the latest scientific results in the field and bringing them into the clinic for practi-

cal application. The Breast Cancer Symposium Merit Award winners and the research they will be presenting at the Symposium include: ■■ Lisa Allen, MD, University of Texas MD Anderson Cancer Center: Nomogram to predict sentinel lymph node involvement in patients with clinically node-negative breast cancer receiving neoadjuvant chemotherapy.

■■ Amanda Arrington, MD, City of Hope: Rural and urban disparities in the evolution of sentinel lymph node utilization in breast cancer. ■■ Conceicao Campos, MD, PhD, Escola Cearense de Oncologia: Hypofractionated breast irradiation in elderly cancer parients: A Brazilian pilot study. ■■ Farrah Datko, MD, Memorial Sloan-Kettering Cancer Center: Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC). ■■ Rachel Farkas, MD, University of Rochester Medical Center: Axillary recurrence (AR) after negative sentinel node biopsy (SNB): Who is at risk? ■■ Oluwadamilola Fayanju, MD,

Diller Family Comprehensive Cancer Center: Correlation of receptor activator of nuclear factor kappa b (RANK) expression in breast cancer (BC) at the time of diagnosis with recurrence-free survival (RFS) and risk of bone-dominant metastases (BDM) in the I-SPY 1 trial (CALGB 150007/150012; ACRIN 6657). ■■ Shai Libson, MD, Sylvester Cancer Center: Postmastectomy radiation for stage ll breast cancer patients with T1/T2 lesions. ■■ Herdee Gloriane Luna, MD, National Kidney and Transplant Institute: Association of dyslipidemia with the aggressive molecular subtypes and pathologic profile of newly diagnosed nonmetastatic breast cancer patients.

Maintenance of Certfication continued from page 1

Less and Less about More and More

and research for 2 decades, I was annoyed to have to tear myself away from the study hour I had hoped to sneak in. I felt compelled to bone up on “everything but breast cancer” in anticipation of taking this recertification examination. But there it was; I had to get back to my day job. Knowing that I could sneak in an hour at Starbucks before a planned lecture the next day, I tucked the board review materials away and began screening the potential clinical trial candidate.

I am far from unique in this professional dilemma. In an era of rapidly changing diagnostic and therapeutic interventions for the wide spectrum of malignancies, many oncologists are increasingly challenged to maintain sufficient expertise in managing many diseases. The “jack of all trades” who does not keep up with the dynamic landscape of lung, breast, colon, prostate, and many other cancers runs the proverbial risk of knowing less and less about

more and more until he/she knows nothing about everything. Many medical oncologists in academic centers—but also increasingly in community cancer centers and practices—have a much narrower focus. Like myself, these super-specialists spend all or the vast majority of their time treating one or two types of cancer. In effect, one could argue that this phenotype runs the risk of knowing more and more about less and less until they may know everything about nothing. Of course, this is an exaggeration, but it underscores

This year’s Merit Award recipients are helping to contribute to the growing body of clinical evidence in breast cancer that that helps patients live longer and have better outcomes. — Gary Levine, MD

■■ Aimee Mackey, MD, Columbia University Medical Center: Experience with nipple-sparing mastectomy after prior whole-breast radiation. ■■ Jennifer Plichta, MD, Loyola University Health Systems: Does atypical ductal hyperplasia require 6 months of postoperative surveillance? ■■ Gregory Thompson, MD, University of Cincinnati: Axillary lymph node coverage of tangent radiotherapy: Comparison of supine versus prone positioning. ■■ Lori Uyeno, MD, City of Hope: Contralateral breast cancer: Effect of stage on survival after unilateral breast cancer. ■■ Barbara Wexelman, MD, MBA, St. Luke’s Roosevelt Hospital: Socioeconomic and geographic disparities in immediate reconstruction after mastectomy in the United States. ■■ John Wilkinson, MD, Oakland University William Beaumont School of Medicine: Evaluation of current consensus panel guidelines for APBI: A pooled analysis of William Beaumont Hospital and American Society of Breast Surgeons MammoSite registry trial data. The 2012 Breast Cancer Symposium Merit Awards are supported by Amgen, Astellas, AVEO Pharmaceuticals, Inc, Bristol-Myers Squibb, Celgene Corporation, Lilly USA, LLC, Millennium: The Takeda Oncology Company, Novartis Oncology, and Onyx Pharmaceuticals.

■

an important dichotomous reality of contemporary medical oncology practice. By extension, there is a disconnect in how the American Board of Internal Medicine (ABIM) approaches recertification. Despite the heterogeneity that exists in clinical medical oncology practice, the ABIM’s recertification process has not evolved substantially—it remains a “one size fits all” proposition.

Ensuring Quality Care? Presumably,

maintenance

continued on page 90

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Opinion

AVASTIN® (bevacizumab)

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

compared to 0.8% 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).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Maintenance of Certfication

sessed by an examination that focused on the care of the disease that I indeed board certification is desirable to treat—an examination that would ensure quality care of patients with actually dig even deeper into the nucancer. Whether recertification truly ances of breast cancer prevention, diresults in ensuring quality care is a agnosis, and treatment, and demand critical issue beyond the scope of this that the super-subspecialist demoncommentary; certainly this should strate proficiency and knowledge in be assessed with validated tools and the unique area of purported expermetrics. The ABIM Medical Oncoltise and clinical practice? Should the ogy Maintenance of Certification male patients of my colleague Dr. Examination Blueprint states, “The Michael Morris, a renowned prosexam is designed to evaluate the extate cancer specialist, take comfort in tent of the candidate’s knowledge knowing that he got all the gynecoand clinical judgment in the areas in logic oncology questions right on his which a Medical Oncologist should recertification exam? demonstrate a high level of compeIt is time for the ABIM to detence. Expertise in the broad domain velop and implement a more nimof Medical Oncology and the diagble, relevant, and flexible recertinosis and treatment of both common fication process, one that at least and rare conditions that have imporwould tailor the written examinatant consequences for patients will tion to the narrower patient probe assessed.”1 files of the many practitioners who Really? This statement reflects are “masters of one.” The rationale the faulty notion that my specific seems clear, and the tools are availprofessional activable. 2,3 I am certain ity requires broad that there would expertise in diagIt is time for the be many supernosing and treatABIM to develop and specialists in all ing both common disease types who and rare condiimplement a more would support this tions. My patients nimble, relevant, and effort by volunteerscratch their heads ing to draft tailored when I mention flexible recertification examination questhat I spent innuprocess. tions relevant to merable hours in —Andrew D. Seidman, MD their area of experthe early months tise. In the current of 2011 learning era of informatics, about the molecthe machinery is readily available to ular basis of resistance to imatinib provide a regularly updated, dynamic (Gleevec) for chronic myelogenous library of examination questions taileukemia, or the role of temozololored to address the unique realities of mide, bevacizumab (Avastin), and contemporary oncology practices— radiotherapy in treating glioblastoto meaningfully assess the jacks of all ma multiforme. trades as well as the masters of one. I try to convince myself, porI’m just not sure I have it in me to ing over the latest management of go through this exercise again in 2021, cutaneous T-cell lymphoma while as it is currently designed. I am hoping sipping my second doppio espresthat by then there will be increasing so macchiato, that somehow this sensitivity and responsiveness to my knowledge will cross-fertilize and widely shared concerns. make me a better breast cancer doc. Disclosure: Dr. Seidman reported no Unfortunately, despite my hypercafpotential conflicts of interest. feinated state, I struggle to make that leap. I am distracted by all of the othReferences er clinical and academic work that 1. Available at http://www.abim.org/ I’ve pushed aside to carve out time to pdf/blueprint/medon_moc.pdf. Accessed prepare for this examination (which May 3, 2012. happily I did pass). continued from page 89

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A More Relevant Recertification Process Shouldn’t the ABIM and the medical community feel more secure in knowing that my competence was as-

2. Madewell JE: Lifelong learning and the maintenance of certification. J Am Coll Radiol 1:199-203, 2004. 3. Epstein RM, Hundert EM: Defining and assessing professional competence. JAMA 287:226-235, 2002.

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 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 (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 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. 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 2.6%

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 4198 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) 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 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who 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. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. 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 receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment,

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AVASTIN® (bevacizumab)

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 5, 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).]

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))

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 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

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).]

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

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.

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

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%

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%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 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 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%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. 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).

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 3: 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.

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 (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

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Congestive Heart Failure (CHF) 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 metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 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. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

7% 5% 5%

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Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, 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 7). [See Warnings and Precautions (5.8).]

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%

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

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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 5, 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%.

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

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

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).]

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 7, 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 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).] 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

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

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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. 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. 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.

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 In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events 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 were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, 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%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

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, 2.6%) — Proteinuria (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

Avastin is not approved for use in combination with irinotecan.

†

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.