TAP Vol 3 Issue 13 by Harborside Press LLC

Metastases of Unknown Primary

| Carfilzomib in Multiple Myeloma

| Coping with Liver Cancer

VOLUME 3, ISSUE 13

SEPTEMBER 1, 2012

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

ASCOPost.com

The Problem of Monitoring Remission

JCO Spotlight

No Advantage to Longer Adjuvant Chemotherapy in Women with Early Breast Cancer: CALGB 40101 Trial By Matthew Stenger

he ideal duration of Adjuvant Chemotherapy in Early Breast Cancer adjuvant therapy for women with lower-risk ■■ There is no survival advantage to six cycles of AC (doxorubicin/ primary breast cancer recyclophosphamide) or paclitaxel compared with four cycles in early-stage mains unknown. The Nabreast cancer, and longer treatment is associated with greater toxicity. tional Surgical Adjuvant ■■ Results of the comparison of outcomes with AC vs single-agent paclitaxel Breast and Bowel Projare not yet available. ect (NSABP) B-15 trial, reported more than 20 years ago, found no difference in outcomes between mens, but until recently, none has compared four vs six cycles of cyclophosphamide, methotrexate, and six cycles of identical regimens using the same dose fluorouracil and four cycles of doxorubicin plus cyper cycle and schedule of treatment. clophosphamide (AC)—although some believed The Cancer and Leukemia Group B (CALGB) that the AC arm might have fared 40101 trial compared four and six cycles of AC or better had they received six cycles single-agent paclitaxel in early breast cancer and of AC. Since then, several trials of found no difference in 4-year relapse-free survival adjuvant therapy have compared or overall survival between four-cycle and six-cycle four cycles vs four cycles and six regimens. The study was a 2×2 factorial design trial See Page 9 continued on page 7 cycles vs six cycles of various regiExpert’s Corner

The Science of Resilience: Exploring the Process of Grieving from a New Perspective A Conversation with George A. Bonanno, PhD

ow wonderful it is that we now have to concern ourselves with survivorship issues! The ever-increasing success of cancer therapy means that more and more patients can look to a life beyond cancer diagnosis and treatment. But living with cancer creates its own problems. While treatment often may be successful, cure is rare; patients need to be made aware that residual disease after primary treatment is always a possibility, and that one day a recurrence may (or will) occur. Of course, the specifics vary greatly according to disease type, response to treatment, and so forth, but there are common themes.

Emotional Cost of Surveillance One of the key issues of contemporary oncology is to decide how best to monitor continued on page 35

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

MORE IN THIS ISSUE

By Jo Cavallo

By John F. Smyth, MD

about Life after Loss (Basic Books, 2009), Dr. Bonanno reported on his studies of grief and loss. Nearly 50 years ago, Elisabeth Kübler-Ross, MD, advanced the theory that people suffering a traumatic event such as the loss of a loved one (or their own impending death) go through five stages of grief: denial, anger, bargaining, depression, and acceptance. Despite this long-held perspective, Dr. Bonanno’s research on loss and bereavement There is evidence showing that the found no evidence that type of person we are makes us more or these stages are relevant in the grieving process less resilient, but there are many other (although he has not factors that also come into play. studied dying patients). — George A. Bonanno, PhD According to Dr. Bonanno, the bereaved

ow human beings cope with bereavement, loss, extreme adversity, and life-threatening illness has dominated the research interests of George A. Bonanno, PhD, Professor of Clinical Psychology, Teachers College at Columbia University, New York, for more than 20 years. In his book, The Other Side of Sadness: What the New Science of Bereavement Tells Us

FDA Update �� 2 Hematology �� 2, 10 Margaret A. Tempero, MD, on Pancreatic Cancer Research �� 3 Nagi S. El Saghir, MD, FACP, on Cancer Care in Lebanon �� 15 Direct from ASCO �� 21 Psychosocial Support for Adolescent and Young Adult Patients �� 31

continued on page 8

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 1, 2012

PAGE 2

FDA Update

Liposomal Vincristine Approved in Acute Lymphoblastic Leukemia

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 vincristine sulfate liposome injection (Marqibo) to treat adults with Philadelphia chromosome– negative acute lymphoblastic leukemia (ALL). Administered once a week, liposomal vincristine is approved for patients whose leukemia has relapsed two or more times, or whose leukemia has progressed following two or more regimens of antileukemia therapy. The new drug is approved under the FDA’s accelerated approval program, which provides earlier patient access to promising new drugs while the manufacturer conducts additional clinical studies to confirm the drug’s clinical benefit and safe use. It also received orphan-product designation because it is intended to treat a rare disease.

Clinical Trials The drug’s effectiveness was evaluated in a single clinical trial in adult patients whose leukemia had relapsed at least two times despite standard treatments, and who had at least one previous treatment response lasting at least 90 days. Of 65 patients enrolled, 10 patients (15.4%) responded with either a complete remission or complete remission with in-

complete blood count recovery. In the 10 patients achieving either of those responses, the median duration of documented remission was 28 days. The median time to the first event (relapse, death, or next therapy) was 56 days. The safety of liposomal vincristine was evaluated in two single-arm trials of 83 patients who received the clinical treatment regimen. Serious adverse events such as low white blood cell counts with fever, low blood pressure, respiratory distress, and cardiac arrest occurred in 76% of patients studied.

Boxed Warning Prescribing information for Marqibo will carry a Boxed Warning alerting patients and health-care professionals that the drug must be administered only intravenously because it is deadly if administered in other ways, such as into the spinal fluid. The Boxed Warning also states that liposomal vincristine has different dosage recommendations than vincristine sulfate injection alone. To avoid overdose, it is important for health-care professionals to verify the drug name and the dose before administration. Special requirements for preparation of the drug are detailed in the label.

■

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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PAGE 3

Expert’s Corner Gastrointestinal Oncology

Ongoing and Future Directions in Pancreatic Cancer Research A Conversation with Margaret A. Tempero, MD By Barbara Boughton mit on pancreatic cancer sponsored by the American Association for Cancer Research, (AACR). Called Pancreatic Cancer: Progress and Challenges, the conference was held in Lake Tahoe, Nevada. Following the meeting, The ASCO Post spoke with Dr. Tempero about the conference and today’s most promising avenues of pancreatic cancer research.

Margaret A. Tempero, MD

argaret A. Tempero, MD, is a pioneer in pancreatic cancer treatment and research. She has long been a leader in the research and development of therapeutics for pancreatic ductal adenocarcinoma, particularly in studying investigational antibody-based therapies, developing the fixed-dose-rate concept for gemcitabine, and using effective gemcitabine combinations. Dr. Tempero’s research group has also provided a scientific foundation for using CA199 as a surrogate for survival in clinical trials. Currently, groundbreaking research by her group concerns the assessment of molecular subtypes and molecular enrichment in order to select new drugs for clinical evaluation. Dr. Tempero holds the Rombauer Family Distinguished Professorship in Pancreas Cancer Clinical and Translational Science and is Director of the University of California, San Francisco (UCSF) Pancreas Center at the UCSF Helen Diller Family Comprehensive Cancer Center.

AACR Pancreatic Cancer Conference In June, Dr. Tempero was one of the featured speakers at a leadership sum-

What were your impressions of the AACR pancreatic cancer conference, and what do you think were the most interesting research questions discussed? The conference was on point scientifically—there was a lot of energy, goodwill, and great science. I was impressed with a session on the stroma and the immunoregulatory environment. We have made real advances in understanding this biology and the immunoregulatory role of B cells, macrophages, and other

Research What other promising areas of research do you see bearing fruit in the future, and what kinds of research projects are you working with at UCSF? One very interesting area of research is detection. We would never use imaging to screen the general population for pancreatic cancer. Because there is a much lower incidence of pancreatic cancer, it’s not cost-effective to do expensive testing on everyone. One of the challenges is to find a model that can identify patients at risk. We have plenty of screening tools for imaging, and we know that they work. We just need to enrich our population through easily testable biomarkers and then apply the imaging screening tools to a selected population. At UCSF, I lead the Pancreas Center, and our research projects range

Our Pancreas Center is poised to learn from every patient and to rapidly apply our laboratory discoveries in the clinic. If we understand this disease, we can beat it. — Margaret A. Tempero, MD

myeloid-derived cells. That gives us the potential to change the environment through drugs or vaccines that can aid in tumor control. Another interesting area is in understanding the genetic mutations associated with this disease and how to interfere with them using new molecules. For example, mutations in RAS have been thought to be the most important driver in pancreatic cancer. Previously it was believed that RAS could not be addressed by drugs, but the scientific community is coming up with new ways to interfere with activated RAS.

Visit 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

from those centered on pancreatic cancer biology to those centered on treatment. I’m interested in the fact that this disease causes diabetes. A subset of people with new diabetes harbors an underlying pancreatic cancer. This suggests there are a lot of opportunities to coordinate with the research community that studies diabetes to better leverage our common resources.

Evolving Community How has the research community that studies pancreatic cancer changed over the years?

When I first started my career as a researcher in pancreatic cancer, it was hard to find other researchers in the same discipline with whom to talk. When we led the first Progress Review Group and Think Tank in 1999 and 2000, I was astounded at what we uncovered. There were few researchers working in pancreatic cancer, and there were only a handful—perhaps six researchers—funded by the National Cancer Institute. That has really changed. I don’t know how many researchers currently work in pancreatic cancer, but judging from the size of the audience at the recent AACR conference, this research community is growing by leaps and bounds.

Treating Patients What drew you to work in the area of pancreatic cancer, and how does your work with patients inform your research? I’m always drawn to areas of great need. People with pancreatic cancer are very sick and they need our help. Right now, we use combinations of chemotherapy that can help patients feel better and live longer. And we know we can improve on this much more. At UCSF, we have a concierge nursing team of extremely skilled caregivers who counsel patients about the resources available to them, particularly with regard to treatment, and help them navigate the medical system. It is always rewarding to me to help, even if we can only treat their pain Our Pancreas Center is poised to learn from every patient and to rapidly apply our laboratory discoveries in the clinic. If we understand this disease, we can beat it.

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

website at ASCOPost.com 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.

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12066B

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

ASCOPost.com | SEPTEMBER 1, 2012

PAGE 7

JCO Spotlight

Early Breast Cancer continued from page 1

that also examined the effects of AC vs single-agent paclitaxel. The results from the four- vs six-cycle comparison were reported by Shulman and colleagues in a recent Journal of Clinical Oncology article.1

Study Details CALGB 40101 enrolled 3,171 women with operable primary breast cancer and zero to three positive nodes between 2002 and 2008. Patients were randomly assigned to receive four cycles of AC (n = 1,142; 1,002 in 2-week and 140 in 3-week cycles), six cycles of AC (n = 789; 645 in 2-week and 144 in 3-week cycles), four cycles of paclitaxel (n = 1,151; 1,005 in 2-week and 146 in 3-week cycles), or six cycles of paclitaxel (n = 789; 648 in 2-week and 141 in 3-week cycles). A year after the start of enrollment, study regimens were changed from 3-week to 2-week cycles based on the finding of superiority of dose-dense regimens in another major trial (CALGB 9741). AC was given as doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 once every 2 or 3 weeks, and paclitaxel was given at 80 mg/m2 when given weekly (with three weekly doses constituting a 3-week cycle) and at 175 mg/m2 when given every 2 weeks. Initially, only women with nodenegative disease were enrolled; patients with one to three positive axillary nodes were permitted to enter the study as of 2005. After 2005, when trastuzumab was recommended for treatment of patients with HER2-positive disease, patients randomly assigned to AC could receive trastuzumab after completing AC treatment and women assigned to paclitaxel could receive trastuzumab concurrently with or after completing paclitaxel treatment. The 1,593 patients receiving four cycles of therapy (either AC or paclitax-

NOW ! LE AVAILAB

el) were evenly matched with the 1,578 patients receiving six cycles for proportions of patients who were aged 50 years or older (59% vs 59%), nonwhite (16% vs 15%), premenopausal (44% vs 44%), and node-negative (94% vs 93%) and who had tumor size ≤ 2 cm (66% vs 62%), estrogen receptor (ER)-positive tumors (65% vs 64%), HER2-negative tumors (77% vs 77%), and high-grade tumors (47% vs 48%).

No Difference in Survival The primary endpoint of the trial was relapse-free survival. The median follow-up for surviving patents was 5.3 years, with a maximum of 8.9 years. Four-year relapse-free survival rates were 90.9% in the six-cycle arms and 91.8% in the four-cycle arms, and 4-year overall survival rates were 95.3% and 96.3%, respectively. Multivariate proportional hazards modeling showed that six cycles of treatment was not superior to four cycles for either relapse-free or overall survival after adjustment for tu-

of AC vs paclitaxel. However, investigators were informed that there was no interaction between number of treatment cycles and chemotherapy regimen with regard to outcome.

Greater Toxicity with Six Cycles Hematologic toxicities were more common with AC and were somewhat more common in patients receiving six cycles of AC compared with four cycles. Grade 3 and 4 neutropenia occurred in 11% and 23%, respectively, of patients receiving six cycles of AC and in 9% and 17%, respectively, of those receiving four cycles. Other grade 3 and 4 hematologic toxicities in the group receiving six AC cycles included anemia (6% and < 1%, respectively), and thrombocytopenia (3% and 1%). Neuropathy was more common in the paclitaxel arms. Grade 3 sensory neuropathy occurred in 4% of patients receiving four cycles of paclitaxel and 10% of patients receiving six cycles. Grade 3 and 4 motor neuropathy oc-

Patients can be spared longer and more toxic treatment with these [adjuvant] regimens without fear of compromising breast cancer outcome. mor size, number of positive nodes, hormone receptor status, and menopausal status. The adjusted hazard ratios (worse:better) for six vs four cycles were 1.03 (95% CI = 0.84–1.28, P = .77) for relapse-free survival and 1.12 (95% CI = 0.84–1.49, P = .44) for overall survival. Unplanned subset analyses showed no interaction between the number of cycles of therapy and tumor ER or HER2 status, suggesting that no subgroup benefited from more prolonged therapy. At the time of reporting, the Data and Safety Monitoring Board had not released results for the comparison

curred in 2% and < 1%, respectively, of patients receiving four cycles and 3% and <�� 1%, �� respectively, of patients receiving six cycles. Cardiac toxicity was infrequent but more common with six cycles of AC treatment; grade 3, 4, and 5 left-ventricular systolic dysfunction occurred in 18%, 5%, and 1%, respectively, of patients receiving six cycles of AC and in 5%, 0%, and 0%, respectively, of patients receiving four cycles. Acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) occurred in six patients in total, consisting of five patients receiving six cycles of AC and one patient

receiving four cycles of AC. Death occurred in 100 patients receiving six cycles of therapy, in 60 as a result of breast cancer–related causes, and in 91 patients receiving four cycles of therapy, in 55 due to breast cancer– related causes. There were seven treatment-related deaths, all occurring in the AC study arms; five were due to AML/ MDS and two to cardiac causes.

Conclusions As summarized by the investigators, “Our study demonstrates … that for women with relatively low-risk primary breast cancer, there is no evidence that extending chemotherapy of AC or single-agent paclitaxel regimens from four to six cycles improves clinical outcome. It should be noted that the 2×2 factorial design of this study combines the AC and paclitaxel groups in the four vs six analysis and, though there was no interaction with type of therapy, single-agent paclitaxel should not be considered a standard regimen for these patients, pending the results of the AC vs paclitaxel comparison…. It should also be noted that more than 90% of these patients had nodenegative disease and 77% had HER2negative disease. Taking these issues in context, patients can be spared longer and more toxic treatment with these regimens without fear of compromising breast cancer outcome.”

■

Disclosure: Among the JCO study authors, Dr. Donald A. Berry reported employment or a leadership position with Berry Consultants, and Dr. Eric P. Winer reported research funding from Genentech. All other coauthors reported no potential conflicts of interest.

Reference 1. Shulman LN, Cirrincione CT, Berry DA, et al: Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. July 23, 2012 (early release online).

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PAGE 8

Expert’s Corner

George A. Bonanno, PhD continued from page 1

exhibit different patterns of grief reactions across time, ranging from overwhelming feelings of loss for long periods of time (more than 2 years) to less pronounced feelings of sadness over a year or less. However, most people rebound from loss fairly quickly, experiencing intense periods of sadness for several weeks, which then taper off. It is this natural resilience to trauma and loss that allows people to regain their equilibrium and return to their dayto-day lives even though they may still experience moments of anguish and sadness. The ASCO Post spoke with Dr. Bonanno about how human resilience factors into how well people deal with a life-altering event like a cancer diagnosis.

Understanding Resilience What is resilience in the context of your research? I take a scientific approach to resilience, so I define resilience exclusively as the stable trajectory of healthy adjustment after a highly aversive event, like getting a cancer diagnosis or being in a disaster. Are people born with a certain amount of resilience, or can we learn to become more resilient? There isn’t much scientific research on this issue, but my personal view is that we are born with the tools to be resilient. Resilience is predicted by a lot of different factors. It isn’t a simple matter of either you are or you aren’t resilient. There is evidence showing that the type of person we are makes us more or less resilient, but there are many other factors that also come into play, including economic, social, and health resources available to us and the amount of stress we have in our lives. Personality traits such as optimism or hardiness predict resilience, but that’s only a little piece of it, like a slice

g Cominn Soo

of the pie. You can have the healthiest personality in the world, but if everything else in your life is negative—you live in poverty or lack access to adequate education—you are less likely to be resilient. Other personality factors that have been shown to affect resilience include self-enhancement, which is actually a kind of narcissistic selfserving trait that has to do with the positive reframing of a bad situation. Another factor is self-confidence in one’s ability to cope, which is called

when a person struggles for a long time, and everything is in flux. When people are going through chemotherapy and a prolonged physical assault, they are going to be emotionally up and down a lot. In our study of women diagnosed with breast cancer, one of the variables that predicted a better outcome was less difficulty with treatment decisionmaking.1 Another predictor was the patient’s confidence in the treatment choice. That finding seemed to suggest the patient was saying, “I have to deal

The most common pattern of resilience is that in which people are disturbed for a little while—a few days to a few weeks—but then they are okay and resume their life. hardiness, but you can also call it optimism—these traits are all related. Resilient people have the sense that they’ll be able to deal with any adversity. Most of us will respond to a cancer diagnosis with fear, but ultimately you have to decide to somehow deal with the disease, as opposed to saying, “I can’t deal with it.”

Long-term Stress How does experiencing long periods of ongoing treatment and the potential for relapse affect a person’s ability to remain resilient? With cancer and diseases that require long-term treatment, patients face repeated challenges and stressors, and how well they are able to cope is not well understood. We know that people are able to bounce back fairly quickly from acute events and get on with their lives. But when they experience repeating events, or when there is a long, long period of rehabilitation, that can be really tough to overcome. There are different types of resilience. Minimal-impact resilience is when a person takes a blow and keeps going. Emergent resilience is

with my cancer. I am going to consider my options, make the best choice, and do my best to survive.” And you can imagine that with recurrent cancer, there comes a point when people decide to give up.

Patterns of Outcome What has your research found on peoples’ ability to cope after a traumatic event or the death of a loved one? How long does it take to recover from these situations? What I found across all kinds of events, including people dealing with a cancer diagnosis and bereavement, is that there isn’t one pattern of outcome. By the same token, it is not random either. We have repeatedly identified a set of prototypical outcome patterns. Some people are completely overwhelmed by an event in their life and take years to regain their footing. Between 5% and 25% of people show this pattern and will be debilitated psychologically for a long time. In another pattern, which we call the recovery pattern, people struggle for a number of months, and then it takes a year or two for them to gradually come back to where they

were before the event took place. The most common pattern of resilience is that in which people are disturbed for a little while—a few days to a few weeks—but then they are okay and resume their life. When people lose a loved one, they have intense emotional reactions, but the reactions are not encompassing, they are episodic. The grieving person may be intensely sad for a short period of time and then have flashes of sadness over a longer period of time, coming in and out of that state, but he keeps functioning and has positive phases in which the sadness is replaced with laughter and being connected to other people. I think that’s why we are able to cope so well after a loss; we are hardwired to deal with loss efficiently.

Healthy Response What is the healthy response to a serious illness or the realization of impending death from the illness? The healthy response to an illness you can recover from is different from a healthy response to an illness that you can’t recover from. A healthy response to an illness you can survive is to accept the situation as a challenge and do your best to cope with it. I have not studied how people respond to terminal illness. But my understanding from anecdotal evidence of hospice caregivers is that when people realize their death is imminent, the healthiest response is to come to terms with this fact and to do what they can to live as comfortably as possible— and to do that with the people with whom they are closest.

■

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

Reference 1. Lam WW, Bonanno GA, Mancini AD, et al: Trajectories of psychological distress among Chinese women diagnosed with breast cancer. Psycho-Oncology 19:1044-1051, 2010.

The ASCO Post’s webcast “Case Studies in Rare Lymphomas” moderated by James O. Armitage, MD, and featuring the following experts:

• Joseph M. Connors, MD, on Hodgkin lymphoma following failure of autologous stem cell transplant • Andreas Engert, MD, on relapsed and refractory Hodgkin lymphoma • Steven M. Horwitz, MD, on systemic anaplastic large cell lymphoma following failure of one or more combination regimens View this special webcast at ASCOPost.com and watch for your supplement on this presentation mailing with the September 15 issue of The ASCO Post.

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PAGE 9

Journal Spotlight Unknown Primary

Ipsilateral Radiotherapy for Cervical Lymph Node Metastases By Charlotte Bath

psilateral neck–only radiation therapy “demonstrated excellent locoregional control with no adverse effect on diseasefree survival or overall survival” among patients with cervical metastases from an unknown primary site, according to a retrospective review of medical records from 46 patients treated at an academic tertiary care hospital for cervical metastases from an unknown primary site. “All patients were treated with radiation therapy. Radiotherapy target volumes were categorized as either ipsilateral neck only or comprehensive, including both the potential mucosal surfaces and ipsilateral or bilateral neck,” reported the reviewers in the Archives of OtolaryngolSee Page 9 ogy—Head and Neck Surgery.1 They found no differences in overall survival with either category of radiation therapy. Overall survival was 87% at 2 years and 77% at 5 years. Cause-specific survival was 89% at 2 years and 81% at 5 years. “There were no ipsilateral neck failures,” the authors reported. “There was no difference in overall survival between patients treated with [ipsilateral neck only] or [comprehensive] ra-

diation therapy. The contralateral neck was controlled in all patients receiving bilateral neck irradiation and in 95% receiving ipsilateral neck irradiation.” Human papillomavirus status, as determined by p16 immunohisto-

chemical analysis was evaluated for 34 patients, and results for 16 (47%) were positive. “There was a nonsignificant trend toward improved overall survival in p16-positive patients (P = .06).” the authors noted.

■

Reference 1. Perkins SM, Spencer CR, Chernock RD, et al: Radiotherapeutic management of cervical lymph node metastases from an unknown primary site. Arch Otolaryngol Head Neck Surg 138:656-661, 2001.

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PAGE 10

In the Clinic Hematology

Carfilzomib: New Drug with Accelerated Approval for Multiple Myeloma 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 July 2012, carfilzomib (Kyprolis) was granted accelerated approval for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib (Velcade) and an immunomodulatory agent and exhibited disease progression during or within 60 days of completing their last therapy.1 Approval was based on results of a single-arm, multicenter trial of carfilzomib in 266 patients with relapsed multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide (Thalomid) or lenalidomide (Revlimid).2,3 Carfilzomib was given by IV infusion over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks followed by a 12-day rest period in each 28-day treatment cycle. Patients received 20 mg/m2 at each dose in the first cycle and 27 mg/m2 at each dose in subsequent cycles for a maximum total of 12 cycles. To reduce carfilzomib-associated infusion reactions, patients were premedicated with dexamethasone (4 mg orally or IV) before carfilzomib doses during the first cycle, during the first dose-escalation cycle, and thereafter when symptoms of infusion reaction occurred. The primary outcome measure was overall response rate determined by an independent review committee.

OF NOTE Carfilzomib is a second-generation proteasome inhibitor that exhibits greater selectivity for chymotrypsin-like proteasomal activity than first-generation inhibitors (eg, bortezomib). Exclusion criteria included bilirubin levels at least two times the upper limit of normal, creatinine clearance < 30 mL/min, New York Heart Association class III/IV congestive heart failure, symptomatic cardiac ischemia, myocar-

dial infarction within the past 6 months, peripheral neuropathy of grade 2 with pain or grade 3 or 4, and pleural effusion. Patients had a median age of 63 years, with 45% being 65 years of age or older; 58% were male, and 71% were Caucasian. Patients had undergone a median of five prior treatments; 74% had undergone transplantation, and 74% had shown disease progression during their last therapy. The overall response rate was 22.9%, including 1 complete response, 13 very good partial responses, and 47 partial responses. The median duration of response was 7.8 months. As a condition of the accelerated approval, Onyx must submit the complete analysis of an ongoing randomized phase�� III trial comparing carfilzomib, lenalidomide, and low-dose dexamethasone vs lenalidomide/lowdose dexamethasone in patients with relapsed/refractory multiple myeloma after one to three prior therapies. The primary endpoint of this trial is progression-free survival.

OF NOTE The most common adverse effects of carfilzomib are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

How It Works Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, which is the proteolytic core particle within the 26S proteasome.3 It is a second-generation proteasome inhibitor that exhibits greater selectivity for chymotrypsin-like proteasomal activity than first-generation inhibitors (eg, bortezomib).4 The proteasome is a multicatalytic protein complex that acts to degrade cytosolic and nuclear proteins that are turned over as result of such processes as oxidation, proteolysis, and deamination. The new drug also plays a regulatory role in cell proliferation by destroying proteins that trigger endoplasmic reticulum stress, cell-cycle progression, cellsignaling, apoptosis, and cell survival pathways. Carfilzomib produces antiproliferative and proapoptotic effects in solid and hematologic tumor cells and

Carfilzomib in Multiple Myeloma ■■ Carfilzomib (Kyprolis) was approved to treat multiple myeloma after

two or more prior therapies including bortezomib (Velcade) and an immunomodulatory agent, in patients who exhibit disease progression within 60 days of their last therapy.

■■ The drug is given IV over 2 to 10 minutes on 2 consecutive days each week for 3 weeks (first cycle, 20 mg/m2; if tolerated, 27 mg/m2 beginning with the second cycle), followed by a 12-day rest period in 28-day cycles.

delays tumor growth in models of multiple myeloma and other hematologic tumors and solid tumors.

How It Is Given Carfilzomib is given intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period in 28-day treatment cycles. The dose is 20 mg/m2 in the first cycle; if tolerated, the dose is increased to 27 mg/ m2 in the second and subsequent cycles. Patients must be hydrated to reduce the risk of renal toxicity and tumor lysis syndrome; adequate fluid volume status must be maintained throughout treatment, and blood chemistries must be closely monitored. Prior to each dose in cycle 1, patients should receive 250 to 500 mL of IV normal saline or other appropriate IV fluid. An additional 250 to 500 mL of IV fluids should be given as needed following administration, and IV hydration should be continued as needed in subsequent cycles. Patients need to be monitored for fluid overload. Patients must be premedicated with dexamethasone 4 mg orally or IV prior to all doses during cycle 1, prior to all doses during the first cycle of dose escalation to 27 mg/m2, and thereafter if infusion reaction symptoms occur during subsequent cycles. The full prescribing information for carfilzomib includes dose-modification guidelines for grade 3 or 4 neutropenia; grade 4 thrombocytopenia; grade 3 or 4 or new onset or worsening of congestive heart failure, left-ventricular dysfunction, and myocardial ischemia; pulmonary hypertension; grade 3 or 4 pulmonary complications; grade 3 or 4 elevation of transaminases or bilirubin or other liver abnormalities; serum creatinine at least two times the baseline value; grade 3 or 4 peripheral neuropathy; and other grade 3 or 4 nonhematologic toxicities.

Safety Profile The safety of carfilzomib has been evaluated in 526 patients with relapsed multiple myeloma receiving carfilzomib monotherapy in clinical trials.3 The most common adverse events (≥ 30% of patients) were fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). Serious adverse events occurred in 45% of patients, with the most common being pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse events leading to discontinuation of carfilzomib occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Death occurred in 37 patients (7%) on-study. The most common See Page 9 causes of death other than underlying disease were cardiac effects (5 patients), end-organ failure (4 patients), and infection (4 patients). Carfilzomib carries warnings/precautions for cardiac adverse effects including heart failure and ischemia, pulmonary hypertension and pulmonary complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, hepatic toxicity and hepatic failure, and embryo-fetal toxicity.

Cost The estimated cost of carfilzomib is approximately $10,000 for a 28-day cycle.

■

References 1. U.S. Food and Drug Administration: Approved drugs: Carfilzomib. http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm. continued on page 14

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis. Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (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. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60

Not reached

7.9

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash 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) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, 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.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment 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. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common (≥30%) adverse reactions of any grade 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 accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

The ASCO Post | SEPTEMBER 1, 2012

PAGE 14

News

Preclinical Research Finds Gene that Permanently Stops Cancer Cell Proliferation

esearchers at Case Western Reserve University School of Medicine, Cleveland, have discovered a mutant form of the gene Chk1 that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any

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

chemotherapeutic drugs.1 This study illustrates an unprecedented finding: that artificially activating Chk1 alone is sufficient to kill cancer cells. “We have identified a new direction for cancer therapy, and the new direction is leading us to a reduction in tox-

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.

icity in cancer therapy, compared with chemotherapy or radiation therapy,” said Youwei Zhang, PhD, Assistant Professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. “With this discovery,

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 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes 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. Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

disorders Cough Injury, poisoning and procedural complications Sunburn

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

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

scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.” While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a nonnatural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team See Page 9 discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.

Biggest Advantage The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs. Cells respond to DNA damage by activating networks of signaling pathways, termed cell-cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell-cycle progression and coordinating repair programs to fix the DNA errors.

■

Reference 1. Wang J, Han X, Zhang Y: Autoregulatory mechanisms of phosphorylation of checkpoint kinase 1. Cancer Res 72:37863794, 2012.

Carfilzomib continued from page 10

2. Siegel DS, Martin T, Wang M, et al: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. July 25, 2012 (early release online). 3. KYPROLISTM (carfilzomib) for injection prescribing information. Onyx Pharmaceuticals, Inc, July 2012. http:// www.accessdata.fda.gov/drugsatfda_docs/ label/2012/202714lbl.pdf. 4. Parlati F, Lee SJ, Aujay M, et al: Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsinlike activity of the proteasome. Blood 114:3439-3447, 2009.

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PAGE 15

Despite Challenges, Initiatives Bring Gradual Improvements to Cancer Care in Lebanon A Conversation with Nagi S. El Saghir, MD, FACP By Ronald Piana

After graduating medical school, I came to the United States and did my residency in internal medicine at The Brooklyn Hospital, affiliated with the State University of New York–Downstate Medical Center. In 1983, I completed my fellowship in Hematology-Oncology at St. Luke’s–Roosevelt Hospital Center, Columbia University, New York.

Nagi S. El Saghir, MD, FACP

agi S. El Saghir, MD, FACP, Professor of Clinical Medicine and Hematology-Oncology at the American University of Beirut, is the founding President of the Lebanese Society of Medical Oncology (LSMO). Dr. El Saghir has focused much of his research on the early detection, prevention, and treatment of young Lebanese and Arab women with increasing breast cancer incidence rates. The ASCO Post recently spoke with Dr. El Saghir about his experiences as a global oncologist.

Medical Training Please describe your introduction to medicine. I went to high school in Beirut, Lebanon, and then traveled to Belgium for a 7-year program that incorporates college and medical school. I originally wanted to become an engineer; however, on the day I was leaving for college, my father walked me across the tarmac to the airplane, and before I boarded, he said, “Please go into medicine, it’s more worthwhile for us.” In those days, particularly in Lebanon, we sought to honor our fathers, so his advice greatly influenced my first step toward a medical career. I traveled throughout France learning the language, and then I went to Brussels, Belgium. I really liked Belgium, so I decided to enroll at the Free University of Brussels, where I received my medical degree in 1978. Where did you do your residency?

Was there a specific turning point—a mentor, perhaps—that helped steer your decision to pursue oncology? Not really; the decision was more of a natural progression. I actually started my career in hematology. I found the laboratory work in blood cancers very exciting. I later moved to oncology and solid tumors. I also had two friends who had cancer, one in Brussels with melanoma, and one in Brooklyn who had leukemia. Maybe seeing the effects of cancer on a human level, combined with the intellectual scientific challenges in oncology, in some way, helped inform my career decisions.

Day-to-day Activity What does your current work entail? My normal day begins with hospital rounds with fellows and house staff at about 8:30 in the morning. Then I have clinical hours about four times a week. Naturally, there are numerous conferences, tumor boards, and meetings with research fellows and administrative personnel. I also do quite of bit of traveling in the Arab region to give lectures. So my schedule is full, and my current activities are varied. I often end up writing my articles, reviewing manuscripts, and completing my PowerPoint slides in the evenings and on weekends.

Lebanese Society of Medical Oncology You are the founding President of the Lebanese Society of Medical Oncology. What inspired the development of the organization? When I returned home in 1993, I became aware that many of the region-

When ASCO began licensing overseas Best of ASCO meetings, Lebanon became one of the first countries to host one, and it is now an annual tradition. —Nagi S. El Saghir, MD, FACP

Continued Travel When did you return to Lebanon? THere was a civil war in Lebanon that began in 1975 and lasted until 1990. It was a very difficult period in the country’s history. After a couple of years of practice at Long Island College Hospital and Brooklyn Hospital–SUNY Downstate, I went to Saudi Arabia and worked at the King Khalid University Hospital for a couple of years, then moved to Michigan, where I worked at Oakwood Hospital in Dearborn and was also on the clinical faculty of Wayne State University. In 1993, a few years after the civil war ended, I decided to return to Lebanon and take a position at the American University of Beirut.

specific needs in developing countries like Lebanon were unmet. In particular, there wasn’t enough of a collaboration network for Lebanese oncologists. Lebanon is a small country, with roughly 4 million people. Even so, at the time the Lebanese Society of Medical Oncology was founded in 1997, we had only 30 oncologists. We now have more than 100, which is an improvement. We needed to collaborate, have CME programs, look after the rights of oncologists and help improve patients’ access to care. Interestingly, we held our first ASCO Highlights meeting at our first LSMO meeting in 1997. I presented a summary of that year’s ASCO Annual Meeting in Denver, and it was an

exciting way to kick off the LSMO’s activities. When ASCO began licensing overseas Best of ASCO meetings, Lebanon became one of the first countries to host one, and it is now an annual tradition. At this year’s Best of ASCO in Lebanon, we had more than 400 attendees from within the country as well as neighboring Arab and Middle Eastern countries.

Challenges to Cancer Care in Lebanon What are the main challenges you face in ensuring that your patients have access to high-quality cancer care? We do our best to deliver care to our patients, but access to care in Lebanon is complicated by a rather difficult situation. Lebanon is a beautiful, small, but overall low-income country. Around 10% of the population has a relatively high income. The health insurance structure is fractured between private payers and the government. Although doctors and hospitals struggle to provide care to all patients, regardless of their economic status, there are holes in the system. Some people have started to obtain private insurance coverage but still pay many expenses outof-pocket. The Ministry of Health allocates part of its budget to pay for cancer care for those who don’t have the money or insurance, but the needs sometimes exceed the budget. Reimbursement for medical services is difficult, and most doctors in Lebanon work very hard to make a living. Another big challenge here is that many people in Lebanon have a college education, are well-read, and demand the most advanced diagnostic and surgical technologies as well as the latest systemic therapies regardless of the costs. Therefore, we struggle with ensuring cost-effectiveness. The challenges of caring for breast cancer patients in a developing country push me to be more involved with international societies such as ASCO, continued on page 16

The ASCO Post | SEPTEMBER 1, 2012

PAGE 16

Oncology Worldwide

Nagi S. El Saghir, MD, FACP continued from page 15

the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European School of Oncology (ESO), and the Breast Health Global Initiative (BHGI). On the ASCO International

Affairs Committee, we have major international projects to improve access to education for oncologists and to cancer care for patients worldwide.

Closing Thoughts Any last thoughts about your work in oncology? I practice medicine as an art and

a science. Oncologists have a special relationship with their patients and families, one that is built on trust and caring. Moreover, the advances we’ve seen over the past decades have increased survival, and so our relationships with patients have become much longer and richer. I have patients who have invited me to their

children’s weddings and birthdays. The personal relationships that I’ve developed over the years sustain me through the difficult clinical times. Caring for patients through the continuum of care, right to the end of life, or most often nowadays with the goal of cure and survivorship, is what I consider the best personalized care. Also, since we have begun various campaigns to raise awareness about the importance of screening and early detection, we’ve seen a decrease in the number of patients presenting with advanced disease. These step-by-step improvements in care demonstrate that despite the challenges, we are making considerable progress in the battle against cancer.

■

Disclosure: Dr. El Saghir reported no potential conflicts of interest.

Contact

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

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PAGE 17

Patient’s Corner

Coping with Liver Cancer

A cancer diagnosis can remind you to treasure life. By Margaret Brandt, as told to Jo Cavallo

rom the moment I had a partial hysterectomy in 2010, I started having unexplained bouts of nausea. My surgeon and even my primary care physician chalked it up to everything from the difficult 6-hour surgery I had just had to anxiety over a move I’d recently made from Connecticut to North Carolina. But after 8 months went by and I still had no relief, I knew something was wrong and insisted that my doctor do an ultrasound, which picked up a mass in my liver. After a biopsy of the tumor was taken, I nervously awaited the results. As days went by with no call from the doctor I thought, “No news is good news.” But after several calls to the doctor went unanswered, I decided to take control of the situation and went to the medical records department of the hospital and asked for a copy of my biopsy report.

Shocking News That’s how I found out that I had stage I liver cancer. The news couldn’t have been more shocking. I don’t have the typical risk factors for the disease. I never drink or smoke, I don’t do drugs,

I’ve never had hepatitis, and there’s no history of liver disease in my family. There was nothing to explain why I would have this cancer. Fortunately, the cancer was confined to one part of my liver. After removal of half my liver, my oncologist said that the tissue margins were clear of any errant malignant cells and that I didn’t need

my position as a radiology coordinator at a local hospital after I became ill. The reason given was that I had exceeded my allotted medical-related disability leave. But I’m convinced that the real reason is that no one expected me to live longer than 6 months after my diagnosis. The experience of having cancer has made me reevaluate my career choice, and

Being told you have a life-threatening disease allows you to face your fears head-on and take chances you might not otherwise take . — Margaret Brandt

adjuvant chemotherapy or radiation therapy. I have follow-up visits with my oncologist every 3 months, and now, nearly 1½ years later, I’m thrilled to say that I’m still in remission. That said, having liver cancer has certainly upended my life—in ways both bad and good. I was laid off from

I’m now in graduate school working on a master’s degree in education. It also gave me the courage to make the decision to remarry after promising myself that I would never take that step again. Being told you have a life-threatening disease allows you to face your fears head-on and take chances you might not otherwise take.

Celebrating Life I lost a 3-year-old son in 1992 to Hunter syndrome, and that tragedy taught me the importance of not taking anything for granted and to treasure life. But I think I lost that feeling over the years. I forgot to appreciate that every day is a gift. My cancer diagnosis has reminded me of that fact. I was just 49 when I was diagnosed with liver cancer. I used to think that if I ever got cancer it would be breast or ovarian. The possibility of getting liver cancer never crossed my mind. I know how lucky I am. My oncologist said he was amazed that the cancer was confined to a small area of my liver and had not spread to other organs. His positive and upbeat attitude throughout my ordeal has helped me cope with the enormity of being a cancer survivor. I know that the positive outcome I’ve had is not the usual one for a deadly cancer such as mine. Now I look at life every day as a precious gift. And I never take anything for granted.

■

Margaret Brandt lives in Winston-Salem, North Carolina.

Chemotherapy plus Radiation Improved Progression-free Survival in Adults with Low-grade Glioma By Charlotte Bath

dult patients with supratentorial low-grade glioma who received chemotherapy with PCV (procarbazine [Matulane], lomustine [CeeNu], and vincristine) in addition to radiation therapy had improved progression-free survival but not overall survival compared to patients receiving radiotherapy alone, according to initial results of the Radiation Therapy Oncology Group (RTOG) 9802 trial. “On post hoc analysis, for 2-year survivors, the addition of PCV to [radiotherapy] conferred a survival advantage, suggesting a delayed benefit for chemotherapy,” the researchers reported in the Journal of Clinical Oncology.1 All patients received the same radiotherapy: 54 Gy given over 6 weeks in 30 fractions of 1.8 Gy. Patients randomly assigned to chemotherapy received six cycles of postradiation procarbazine (60 mg/m2 orally per day

on days 8 through 21 of each cycle), lomustine (110 mg/m2 orally on day 1 of each cycle), and vincristine (1.4 mg/m2 [maximum, 2 mg]) intravenously on days 8 and 29 of each cycle. Each cycle was 8 weeks.

Key Findings The median overall survival time was 7.5 years for the 126 patients allocated to the radiotherapy-only arm and more than 8.5 years but not yet reached for the radiotherapy-plus-PCV arm. The 2-year and 5-year overall survival rates were 85% and 72% for patients who received radiotherapy plus PCV vs 87% and 63% for those who received radiotherapy alone. Radiotherapy plus PCV did not improve overall survival (the primary endpoint) vs radiotherapy alone. “Therefore, the trial is negative,” the investigators concluded. “A positive trial would have required a shift in

5-year survival from 70% to 85% (a relative increase of 21%); in reality, the 5-year survival values were 63% vs 72%, a relative increase of 14%.” The median progression-free survival time was more than 6.1 years, but not yet reached for the radiotherapy-plusPCV arm vs 4.4 years for radiotherapy alone. The 2-year and 5-year progression-free survival rates were 74% and 63% for patients who received radiotherapy plus PCV vs 75% and 46% for those who received radiotherapy alone. “In the initial 2-year follow-up phase, the [overall survival] curves for the two regimens actually cross,” the researchers reported, and “a similar trend is observed for [progression-free survival].” Among the 211 patients who survived 2 years, overall and progressionfree survival rates were similar for patients in both study arms for the first 2 years, “although crossing of the curves

did occur,” the authors noted. “However, beyond 2 years, the survival curves separated significantly, with both [overall and progression-free survival] favoring patients treated with See Page 9 PCV [plus radiotherapy],” the authors stated. In a post hoc analysis of a subset, the addition of PCV to radiation “reduced the risk of death by 48% and progression by 56%, suggesting possible delayed benefits for chemotherapy.”

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Reference 1. Shaw EG, Wang M, Coons SW, et al: Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: Initial results of RTOG 9802. J Clin Oncol. July 30, 2012 (early release online).

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib 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. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. 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.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

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. 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)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 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) 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 twice daily) with dose adjustments allowed in both groups.1

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: 1.41, 3.00) 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

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.

Please see brief summary on the following page.

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.

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 regimens). 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.

AXU470817

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).

May 2012

ASCOPost.com | SEPTEMBER 1, 2012

PAGE 21

Direct from ASCO

The 2013 Gastrointestinal Cancers Symposium Will Observe the Meeting’s 10-Year Anniversary cialty who want to stay on its cutting edge.

From Bench to Bedside

Lisa Kachnic, MD

decade after its start in 2003 with a few hundred attendees, the Gastrointestinal Cancers Symposium now boasts more than 3,000 participants from all over the world. The next implementation marks the meeting’s 10th anniversary. The 3-day meeting—to be held January 24–26 in San Francisco—is designed for the exchange of the latest research and science in cancers of the pancreas, small bowel, and hepatobiliary tract; colon and rectum; and esophagus and stomach. Lisa Kachnic, MD, Symposium Program Committee Chair and Chair of the Department of Radiation Oncology at Boston Medical Center, noted that the symposium has become a mustattend event for those in the spe-

“This is really the opportunity every year where the new data from all of the research studies on prevention, detection, or treatment of GI cancers is disseminated,” Dr. Kachnic said. “It gives the opportunity for GI oncologists to learn the new data and apply it to their practice.”

look back at the triumphs, challenges, and lessons learned from the past 10 years for each disease site.

Great for Networking The symposium is the largest multidisciplinary GI-focused gathering in the United States, with sponsors including ASCO, the American Society of Radiation Oncology (ASTRO), the American Gastroenterological Association (AGA), and the Society of

The meeting really gives a young investigator an opportunity to network, perhaps with senior investigators or GI oncologists from other countries, to discuss potential collaboration and research opportunities. —Lisa Kachnic, MD

The symposium—attended by residents, post-docs, fellows, and all levels of faculty and private practitioners— offers a vast array of lectures, including educational sessions and abstract presentations focused on GI cancers. In observance of the meeting’s decade in existence, daily special sessions titled “A Decade in Review” will also take a

Surgical Oncology (SSO). Despite its growth, the meeting has managed to remain intimate, said Dr. Kachnic. “The GI Symposium is a smaller venue where fellows, residents, and junior attendees have the opportunity to interact with experts in GI oncology from around the world,” she said. “The meeting really gives a young in-

vestigator an opportunity to network, perhaps with senior investigators or GI oncologists from other countries, to discuss potential collaboration and research opportunities. We really don’t have these opportunities at the bigger meetings.” Abstracts are currently being accepted for submission; the deadline is September, 25, 2012, at 11:59 PM EDT. Abstracts in the following disease sites will be accepted: esophagus and stomach; pancreas, small bowel, and hepatobiliary tract; and colon and rectum. Abstracts should address one of the following topics: prevention, screening, and diagnosis; multidisciplinary treatment; and translational research. Also at the meeting, merit awards will be given to fellows who submit high-quality abstracts. Winners will receive a monetary award as well as complimentary registration for the 2013 GI Cancers Symposium and access to symposium housing reserved for ASCO. For more information about the meeting or to register, visit www.gicasym.org.

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ASCO Expert Panel Concludes Evidence Supports Physician Discussion of PSA Testing for Men with Longer Life Expectancies

SCO has issued a new evidencebased provisional clinical opinion (PCO) on the use of prostatespecific antigen (PSA) testing for prostate cancer screening. To facilitate informed decisions, ASCO also released a new, detailed decision aid to help men and their physicians understand the risks and benefits of screening, and decide if PSA testing is the appropriate choice. The PCO recommends that physicians discuss the benefits and risks of PSA testing with their asymptomatic male patients who have life expectancies of greater than 10 years, but states that the risks likely outweigh

the benefits for men with shorter life expectancies. The benefits include the identification of higher-risk prostate cancer earlier, when treatment may be more effective, while the risks include overdiagnosis, unnecessary biopsy and treatment, and treatment side effects. This guidance differs from recommendations issued in May 2012 by the U.S. Preventive Services Task Force (USPSTF), which recommends against PSA-based screening for prostate cancer. Specifically, the PCO recommends the following: ■■ In men with a life expectancy

less than or equal to 10 years, it is recommended that general screening for prostate cancer PSA testing be discouraged. For these men, the evidence of harm seems to outweigh potential benefits. ■■ In men with a life expectancy of greater than 10 years, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives for this group of men, but is also associated with harms, including complications from unneces-

sary biopsy, surgery, or radiation treatment for cancers that may be slow-growing and not ultimately life-threatening. ■■ It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. The decision aid and the guideline are available at www.asco.org/ pco/psa.

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The ASCO Post | SEPTEMBER 1, 2012

PAGE 22

Direct from ASCO

Conquer Cancer Foundation $10K Challenge: Multiply Your Donation’s Impact in September

he Foundation proudly announces its first-ever Conquer Cancer Foundation $10K Challenge. For the entire month of September, your online gift to the Conquer Cancer Foundation of the American Society of Clinical Oncology will be

matched by the generous support of Ariad Pharmaceuticals®. The Conquer Cancer Foundation’s goal is to raise at least $10,000 in online donations during the challenge. A gift this month will provide twice its value in support where it is needed most—to help fulfill the Foundation’s mission to conquer cancer by funding breakthrough re-

search, by sharing knowledge with physicians and patients worldwide, and by supporting initiatives to ensure that all people have access to high-quality cancer care. Every dollar counts! Please consider making a tax-deductible gift online to the Conquer Cancer Foundation today at www.conquercancerfoundation.org/ donate. And, thank you in advance for helping to make the Conquer Cancer Foundation $10K Challenge an overwhelming success. Help us get the word out! You can also support the Challenge by using Facebook or Twitter to share your participation with friends and colleagues and encourage them to join you.

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Save the Date Breast Cancer Symposium

Quality Care Symposium

September 13-15, 2012

November 30 December 1, 2012

Marriott Marquis San Francisco, California

Manchester Grand Hyatt San Diego, California

Markers in Cancer

Gastrointestinal Cancers Symposium

October 11-13, 2012 Westin Diplomat Hollywood, Florida

January 24-26, 2013 Moscone West Building San Francisco, California

CONQUERING

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

ConquerCancerFoundation.org

ASCOPost.com | SEPTEMBER 1, 2012

PAGE 23

Direct from ASCO

It’s Time to Get Ready for New Medicare Reporting Requirements Medicare shifting in 2013 from offering incentives to reducing reimbursement B:8.625”

s if you didn’t already have enough to worry about, now add this: If your practice doesn’t meet the requirements of the Physicians Quality Reporting System (PQRS) and Electronic Prescribing (eRx) Incentive, you don’t just miss out on the bonuses the programs offered as incentive in recent years. If you fail to successfully participate in the PQRS in 2013, the Centers for Medicare & Medicaid Services (CMS) will reduce your reimbursement in 2015. And if you don’t have an eRx system in place this year, your Medicare reimbursement drops in 2013. Further reductions are possible in 2015 due to lack of participation in CMS Electronic Health Records (EHR) Incentive Programs (“meaningful use”). So if you didn’t participate in these programs before, now is the time to start.

It is critical that oncologists and their practice staff understand the importance of participation in these CMS reporting programs.

www.asco.org/CMSreporting. In the fall, ASCO will provide a national webinar for members and their practice staff to outline CMS reporting pro-

participated in the PQRS program that year, with the average potential incentive payment totaling $3,000. continued on page 24

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA •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

—Allen S. Lichter, MD

“It is critical that oncologists and their practice staff understand the importance of participation in these CMS reporting programs,” stressed ASCO Chief Executive Officer Allen S. Lichter, MD. “Gone are the days when a failure to report resulted in the loss of a bonus payment. Now, oncologists will see their Medicare reimbursements decrease as a result of nonparticipation.”

T:7.625”

gram requirements for 2013. S:6.75” Based on 2010 PQRS data released by CMS, 30% of eligible oncologists/hematologists successfully

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

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

ASCO’s Website Can Help To get practices started with reporting if they haven’t begun already, ASCO is stepping up communications, outreach, and guidance to oncologists, including establishing a new overview page on its website offering helpful information and links,

Randomized, double-blind, controlled trial

The ASCO Post | SEPTEMBER 1, 2012

PAGE 24

Direct from ASCO

Medicare Reporting Requirements continued from page 23

Twenty-two percent of eligible radiation oncologists participated in 2010, with an average potential incentive payment of about $8,000.

Jeffery C. Ward, MD

Incentives Previously Thought Not Worth It by Some Already burdened with reams of data to input, many practices deemed those potential bonuses too low to worry about, said Jeffery C. Ward, MD, of Puget Sound Cancer Centers in Edmonds, Washington, and Chair of ASCO’s Clinical Practice Committee. “Some practices weighed the costs and benefits of PQRS participation and decided that the effort wasn’t worth the small bonus,” he said. It’s time to think again, though. Dr. Ward pointed out that when considering 2013 PQRS reporting, oncologists need to know that they will receive 1.5% less on Medicare Part B physician fee schedule reimbursement in 2015 if they do not report in 2013. “So, a decision not to report in 2013 will result in a loss of the 0.5% payment increase for that year”—paid in a lump bonus payment in 2014— in addition to the 1.5% reduction in Medicare reimbursement throughout 2015,” he added. CMS proposes a similar link between 2014 PQRS reporting and adjustments in 2016. Getting it right takes time, added Dr. Ward. “PQRS is not just a spigot you can turn on and start collecting payments whenever you want,” he said. “My practice was an early adopter of PQRS, and it took a couple of years to get a reliable reporting process in place.” As for eRx, physicians who don’t adopt a system and participate in the program this year will have 1.5% automatically deducted from their Medicare physician fee schedule–covered

charges in 2013. Next year, the incentive declines to 0.5% and the accompanying penalty will increase to 2%, to be applied in 2014. There are no incentives for 2014, making 2013 the last possible year to earn an incentive.

CMS 2013 Fee Schedule’s Proposed Changes The CMS physician fee schedule proposed rule was released in early July, suggesting several important components related to PQRS. Those included: ■■ A vision and plan to better align the reporting requirements for PQRS, the EHR Incentive Program, and other CMS programs ■■ Reduction in the number of patients for whom a measure group must be reported (from 30 to 20) ■■ Increased reporting options for group-practice participants and a reduction in the number of providers required to qualify as a group practice (from 25 to 2) ■■ A cancer measure group Kristen McNiff, MPH, Senior Advisor in ASCO’s Quality & Guidelines Department, said she’s very pleased about the cancer measure group, which should greatly facilitate PQRS participation by allowing reporting on a manageable and set number of patients. While the PQRS program has more than 200 measures, only a handful are cancer-specific or even relevant to the care provided in oncology practices, she added.

PQRS and QOPI Go Hand in Hand ASCO members who participate in the Quality Oncology Practice Initiative (QOPI) have long asked for the option to use their QOPI reporting as a way to meet PQRS requirements, Ms. McNiff said. “We have advocated for years to have a cancer measure group added to the PQRS program,” she said. “If this measure group makes it to the final rule, we will be able to move forward with integration of PQRS reporting into the QOPI program.” For more information on changes in Medicare reporting requirements and how to get your practice on board, go to ASCO’s new help page on the topic: www.asco.org/ CMSreporting.

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Updated for 2012: Cancer in Older Adults

ell your patients about Cancer in Older Adults, Cancer. Net’s newly updated booklet for older adults and their family and friends. The content of the booklet is adapted from the ASCO University Module, Cancer Care for Older Patients. It provides information on the physical and emotional changes that are associated with aging and

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

cancer, including recommendations for coping with daily life, cancer treatment, coexisting conditions, and caregiving needs. Find it online at www.cancer.net/olderadults, and order copies at www. cancer.net/estore.

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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

Learn about our commitment to patients at BioOncologyAccessSolutions.com/support

Taking a broader view — charting a unique course in cancer care

At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community. A commitment to patients — We created Genentech BioOncology™ Access Solutions®, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care. Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card and ongoing charitable donations to various co-pay assistance foundations. A commitment to care — Since 1985, when our first product was approved, we have donated $2.85* billion in free medicine through the Genentech® Access to Care Foundation (GATCF) and other product donation programs. Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care. *GATCF donation value is based on the most current forecast.

The ASCO Post | SEPTEMBER 1, 2012

PAGE 26

2012 Oncology Meetings September 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

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

British Association for Cancer Research: Chasing Cancer Stem-like Cells September 12 • Harrogate, North Yorkshire, United Kingdom For more information: www.bacr.org.uk 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org Modern Principles of Treatment of Neurooncology Diseases: Prospects for Functional Neurosurgery September 15-16 • Yalta, Ukraine For more information: http://nbscience.com

1st 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

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

American College of Surgeons Annual Clinical Congress September 30-October 4 • Chicago, Illinois For more information: www.facs.org

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

October

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

2nd Annual Next Generation Sequencing Asia Congress October 1-2 • Singapore For more information: www. discoveryontarget.com/HDACInhibitors 6th Next-Generation Histone Deacetylase Inhibitors October 1-2 • Boston, Massachusetts For more information: www. discoveryontarget.com/HDACInhibitors

Congress of Oncologists

Targeting the Ubiquitin Pathway: Discovery and Development of Novel Inhibitors

September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists

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

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

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

Ninth International Conference of the Society for Integrative Oncology October 8-10, 2012 • Albuquerque, New Mexico For more information: www.integrativeonc.org

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

Oncology Clinical Development Congress October 10-11 • Manchester, Cheshire, United Kingdom For more information: www.oncologyclinicaldevelopmentcongress.com

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

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

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

ASCOPost.com | SEPTEMBER 1, 2012

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In the Literature

Emerging Clinical Data on Cancer Management DRUG TOXICITIES New Agents That Improve Efficacy Can Also Increase Morbidity and Treatmentrelated Mortality Newly approved anticancer drugs that lead to improvements in efficacy can also lead to increased morbidity and treatment-related mortality, according to a study in the Journal of Clinical Oncology. The investigators conducted a meta-analysis of 38 randomized controlled trials evaluating agents approved by the FDA for the treatment of solid tumors. “Our analysis shows that most newly approved anticancer drugs are associated with increased odds of toxic death, treatment discontinuation, and severe adverse events compared with the standard treatment received by controls,” the authors reported. Treatment-related toxicities from these new agents are even more likely to occur in clinical practice than in clinical trials because patients seen in clinical trials are “generally selected for good performance status and few comorbidities,” the authors pointed out. “It is therefore not possible to predict the real-life outcomes and extent of such toxicities with the data generated by [randomized controlled trials].” Use of new targeted agents and chemotherapy among less selected patients in general oncologic practice should take into consideration the health status of the individual patient. The investigators support large population-based outcome studies to quantify real-life efficacy and toxicity and identify variations among

different populations. “Our analysis showed no correlation between the end points of efficacy and toxicity,” the investigators reported. “Efficacy of treatment is determined by a variety of disease-related factors such as the intrinsic sensitivity of tumor cells, which in turn depends on the molecular properties of the tumor and the tumor microenvironment. Toxicity is dependent more on drug metabolism and clearance and is influenced by biologic characteristics of the host including performance status, comorbidities, drug-metabolizing enzymes, organ function, and concurrent medications. Therefore, it is not surprising that, in general, efficacy and toxicity of a drug are independent of each other. Although there have been reports relating toxicities of some targeted agents to their efficacy, this is likely to occur when inhibition of the same targets is responsible for producing both efficacy and toxicity.”

Niraula S, et al: J Clin Oncol. July 16, 2012 (early release online).

BREAST CANCER Taxane-induced Neuropathy Does Not Correlate with Improved Outcomes in Operable Breast Cancer An analysis of 4,554 patients who received adjuvant weekly paclitaxel and other taxane-based regimens in the E1199 trial “demonstrated that taxaneinduced peripheral neuropathy does not correlate with improved outcomes in patients with operable breast cancer,” investigators reported in the Journal of Clinical Oncology. A control arm from a previous

study, the N9831 trial, had shown a link between paclitaxel-related neuropathy and improved 3-year disease-free survival. The objective of the recently reported analysis was to “determine whether there was a relationship between taxane-induced neuropathy and outcomes in patients treated in the E1199 trial.” The women in that study had axillary node-positive or high-risk node-negative breast cancer. They received up to four cycles of doxorubicin and cyclophosphamide every 3 weeks and then were randomly assigned to receive one of four further treatments: paclitaxel at 175 mg/m2 every 3 weeks for 4 cycles (P3); paclitaxel at 80 mg/m2 weekly for 12 cycles (P1); docetaxel at 100 mg/m2 every 3 weeks for 4 cycles (D3); or docetaxel at 35 mg/m2 weekly for 12 cycles (D1). A total of 770 patients (16.9%) experienced grade 2 to 4 neuropathy after the initiation of adjuvant taxane therapy. Grade 2 neuropathy was the most common, at 71.8%, followed by grade 3 at 27.5%, and grade 4 at 0.7%. The highest percentage of grade 2 to 4 neuropathy, 22%, occurred in the P1 arm, followed by 17.5% in the P3 arm, 14.7% in the D3 arm, and 13.4% in the D1 arm. “There was a decreased risk of neuropathy in premenopausal compared with postmenopausal patients,” the researchers reported, and a trend for a higher risk of neuropathy in blacks compared with other races and obese vs nonobese patients. “There was a significant association between hyperglycemia and neuropathy,” the authors added, “that remained significant after adjustment for age, race, obesity, and menopausal status.” There was, however, no association between neuropathy and clinical outcomes, including overall, disease-free, and relapse-free survival. Schneider BP, et al: J Clin Oncol July 30, 2012 (early release online).

SQUAMOUS CELL CARCINOMA Kidney Transplant Recipients Switching to Sirolimus Had Lower Risk of Secondary Squamous Cell Carcinomas

Kidney transplant recipients with at least one previous cutaneous squamous cell carcinoma decreased their risk of developing new cutaneous squamous cell carcinomas by switching from calcineurin inhibitors (cyclosporine or tacrolimus) to sirolimus (Rapamune) in a multicenter phase III study. New squamous cell carcinomas developed in 14 of the 64

patients (22%) randomly assigned to receive sirolimus and 22 of the 56 patients (39%) who maintained their initial treatment with calcineurin inhibitors. The median time to onset was 15 months in the sirolimus group vs 7 months in the calcineurin group (P = .02) “Several studies have shown that after a first cutaneous squamous-cell carcinoma, multiple subsequent skin cancers develop in 60% to 80% of kidney-transplant recipients within 3 years. Transplant recipients share common risk factors with the nonimmunosuppressed population, but the specific tumor burden of such patients is linked to the immunosuppressive medications used,” the authors of the Efficacy of Rapamycin in Secondary Prevention of Skin See Page 9 Cancers in Kidney Transplant Recipients (TUMORAPA) study noted in the introduction to their report published in The New England Journal of Medicine. “We speculate that there may be a specific antineoplastic activity of sirolimus that explains the decrease in new skin cancers rather than a lower amount of immunosuppression,” they added after reporting their results.

Risks and Benefits There were many more serious adverse events in the sirolimus group—60 compared to 14 in the calcineurin group. “Almost all sirolimus-treated patients had at least one adverse event that was considered to be related to the study drug,” the researchers stated. “Although serious adverse events were significantly more frequent (0.94 per patient) in the sirolimus group than in the calcineurin-inhibitor group (0.25 per patient), the number of cutaneous squamous cell carcinomas was lower by a factor of 3.4,” the investigators noted. “The benefit–risk ratio appeared to increase with lower doses of sirolimus (as compared with higher doses) and with progressive conversion from calcineurin inhibitors to sirolimus (as compared with rapid conversion),” the authors added. “This apparent antitumoral effect was more pronounced when sirolimus was introduced after the first occurrence of a cutaneous squamous-cell carcinoma, as compared with introduction after the occurrence of multiple cutaneous squamous-cell carcinomas.”

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Euvrard S, et al: N Engl J Med 367:329339, 2012.

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 | SEPTEMBER 1, 2012

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In the News Supportive Care

Adolescent and Young Adult Patients Report Unmet Needs for Cancer Information and Psychosocial Support Services 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.

sychosocial care needs are not being met in substantial proportions of adolescents and young adults (AYAs) with cancer, according to a study among patients aged 14 to 39 years at the time of diagnosis with invasive cancer. The study was published in the journal Cancer1 and reported in the health and consumer media.

Bradley Zebrack, PhD, MSW, MPH

Within 4 months of diagnosis, 215 patients were assessed for whether they wanted to use and had used cancer information resources, emotional support services, and practical support services, such as infertility treatment, complementary and alternative health care, and help with understanding health insurance. The percentages of patients with unmet needs varied according to the specific need and age subset. Among those reporting unmet needs for cancer information, the percentages ranged from 10.3% of those aged 14 to 19, to 28.3% of 20- to 29-year-olds. Reports of unmet needs for mental health counseling ranged from 13.4% of 14to 19-year-olds, to 38.5% of 30- to 39-year-olds. Those aged 20 to 29 had See Page 9 the highest percentage of unmet needs for fertility services, 30.4%, compared to 14.4% for younger and 13.8% for older adolescent and young adult patients.

Treated in Adult and Pediatric Settings The most commonly diagnosed cancers among the study participants were leukemia (48 patients, 23.1%), bone tumors (24 patients, 11.5%), Hodgkin disease (23 patients, 11.1%), and softtissue sarcoma (21 patients, 10.1%). Compared to patients with cancer in the U.S. population, patients diagnosed with cancers that had relatively low survival rates were overrepresented in the study—81.7% had cancers with 40% to 75% 5-year survival rates. The study’s lead author, Bradley Zebrack, PhD, MSW, MPH, Associate Professor of Social Work at the University of Michigan, Ann Arbor, said that finding could be attributed to patients being recruited only from tertiary care hospitals, the three participating pediatric care institutions and the two participating universityaffiliated adult care medical institutions. Findings suggested that wanting or using a service varied “depending on sociodemographic characteristics and clinical conditions, but rarely according to the type or severity of cancer,” the study report noted. “I find that really fascinating,” Dr. Zebrack said in an interview with The ASCO Post. “It doesn’t matter if the doctor says, ‘You have Hodgkin disease, but we are going to cure this; you have a 90% to 95% chance of survival.’ That patient is just as likely to report the need for support-

Don’t Expect Questions: Be Proactive with Younger Patients

t is unrealistic to expect adolescents and young adults with cancer to initiate questions about disease-related or or treatment-related issues that are troubling them, according to Bradley Zebrack, PhD, MSW, MPH, Associate Professor of Social Work at the University of Michigan, Ann Arbor. Oncologists need to repeatedly ask their adolescent and young adult patients how they are coping with cancer, pain, treatment-related side effects, and emotional and sexual issues. If cancer or its treatment may impact a patient’s ability to have children in the future, the oncologist should not only proactively raise the issue, but also discuss specific fertility preservation methods, such as cryopreservation and sperm-banking. “If doctors are not offering that up, the young people certainly are not going to ask about it,” Dr. Zebrack said. “If they hear about fertility issues later, they may wonder why their doctor didn’t address them.” Another way oncologists can help meet the psychosocial needs of adolescents and young adults is to “have a small cadre of veteran young adult patients who they can connect with their newly diagnosed patients. At the very least, new patients can be connected with an organization like Imerman Angels,” Dr. Zebrack said. This organization matches cancer patients, as well as survivors and caregivers, with Mentor Angels, for one-on-one support. “A Mentor Angel is a cancer survivor or caregiver who is of the same age, same gender, and most importantly, who has beaten the same type of cancer,” according to the Imerman Angels website (www.imermanangels.com). The service is free and connects people worldwide.

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settings—whether an adult care hospital or even a small group oncology practice that sees mostly adults—are disease-focused,” Dr. Zebrack explained. “Teens and young adults benefit from a more family-oriented approach.”

Teens and young adults [with cancer] benefit from a more family-oriented approach. —Bradley Zebrack, PhD, MSW, MPH

ive care services as the patient who has been told, ‘You’ve got a really nasty cancer; you have less than a 50% chance of survival.’ The assumption had been that if we can cure you, you have no reason to need support services, like counseling from a mental health professional, but in fact that is not the case.” Adolescents and young adults treated in adult facilities were more likely to report unmet needs for mental health and some other services. “Some people characterize the difference between the pediatric hospitals and the adult hospitals in this way: The pediatric settings are family-centered, whereas the adult

Nutrition and Diet Nearly half of the adolescents and young adults in the study indicated unmet needs for information and counseling specific to diet and exercise, and those who had received chemotherapy were more likely to use exercise, diet, and nutrition information. This “suggests that chemotherapy likely disrupts AYAs’ routine fitness and/or dietary regimens, thus making them more desiring of and amenable to recommendations related to how they can incorporate exercise and healthful eating into their lives to the extent possible,” according to the study report.

“I think the message to providers is that chemotherapy increases this potential for life disruption,” Dr. Zebrack said. “A lot of young people are naturally involved in sports and fitness and attending to diet.” They may just be learning how to live on their own and care for themselves, including preparing healthy meals and eating well, Dr. Zebrack pointed out. Now they have to learn to do all these things while feeling sick from chemotherapy. Physical activity may not only minimize treatment-related side effects, but it can also promote social involvement and reduce isolation. “If you can get yourself involved in physical activity or physical fitness programs, it puts you into contact with people,” Dr. Zebrack said. “That’s really what these young people need, because they get so isolated.”

More Unmet Needs Among Those in Their 20s “AYAs aged 20 to 29 were significantly less likely than teens and older patients ages 30 to 39 to report using continued on page 33

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In the News

Adolescent and Young Adult Patients continued from page 31

professional mental health services and were significantly more likely to report an unmet need with regard to cancer information, infertility information, and diet/nutrition information,” the report noted. Is there something about the 20- to 29-year-olds that makes them more reluctant to seek help? “I think they are still at that stage of life when they are hesitant to trust authority figures,” Dr. Zebrack said. In addition, some of these young people who had been reporting pains or other symptoms prior to their cancer diagnosis were told not to worry. While it is understandable from the physician’s point of view that not every pain should be considered an indication of cancer, Dr. Zebrack said, for the young people who are later diagnosed with cancer, “their natural reluctance to turn to authority figures is now reinforced—from their point of view—by having been misinformed over time. They are now even more mistrusting of doctors and authority figures.”

Conflict with Independence These 20-somethings are also in the natural phase of their development when they are trying to become independent. “Turning to adults is indicative of regressing, having to become dependent on their parents again, when they really want to go out and live life on their own,” Dr. Zebrack explained. “Some young adults won’t even tell their parents that they have been diagnosed with cancer, because they want to do it on their own. So what happens? They are reluctant to see the psychologist, because that is the authority figure. They are not getting support from their friends, because their friends don’t understand what it is like to be 25 years old and have cancer. So they are reporting unmet needs, because they are not getting what they need from those whom they elect to be around,” he added.

g Cominn Soo

“I can understand a lot of these comments through my own experience,” said Dr. Zebrack, who at age 26 was diagnosed with Hodgkin lymphoma. “My family was very supportive, but I was living alone in San Francisco and had to move back into my parents’ house, into my old bedroom.” The 20- to 29-year-olds were also more likely to report an unmet need for complementary and alternative medical services. Part of the willing-

a minority of these recently diagnosed patients use the Internet for cancerrelated information and support,” according to the study report. “It’s a curious finding because we are all assuming that young people are turning to the Internet for information and support,” Dr. Zebrack said. “Have we been overestimating the value of the Internet?” The study report also notes that “cancer information can exacerbate

Dating among Adolescents and Young Adults with Cancer

ow do you tell somebody you are dating that you have cancer or that you may not be able to have children? These are among the issues explored in “Dating and Disclosure for the Cancer Patient,” part of a new book, Sexuality and Cancer, scheduled for release in the fall by Springer, New York. “The threats to the end of a relationship are high,” said Bradley Zebrack, PhD, MSW, MPH, Associate Professor of Social Work at the University of Michigan, Ann Arbor, who wrote the chapter on dating issues faced by adolescents and young adults with cancer. “The young people are thinking ‘I am tainted goods. Who is going to want to go out with me?’” Dr. Zebrack said. “If they have lost their hair from chemotherapy, a lot of young people don’t feel attractive. They don’t feel sexy. That just contributes to their sense of isolation.”

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ness to use complementary and alternative services is the thinking, “I am going to be open to anything that seems helpful,” but that thinking is a “double-edge sword,” Dr. Zebrack said. “Sure, many complementary and alternative therapies can be beneficial, but there is a lot of stuff out there that is like snake oil. Preparing these patients to be able to critically evaluate what is available and to go to reputable sources for that kind of support is important,” he added.

Is the Internet Overvalued? “The relatively low use of age-appropriate, Internet-based resources among teenagers in the current study (15.5%) suggests that, although teens may be heavy users of computers and social media in general, perhaps only

anxiety and distress, particularly for young people.” Counseling teens on accessing and properly interpreting Internet information about cancer “is a need that has not been well addressed yet,” according to Dr. Zebrack. “Some people need all the information right upfront,” he stated. From the providers’ standpoint, we need to ask on a case-by-case basis in our communication with these young adult patients, ‘How much information do you want now? Tell me when you want me to stop.’ We need to be really clear in articulating that. Social workers are trained in how to have that conversation and attuned to how to talk with individual patients. They know when the anxiety level is starting to get too high, and they stop and return to that conversation later.”

Impact of NCCN Guidelines Dr. Zebrack serves on the National Comprehensive Cancer Network (NCCN) Adolescent and Young Adult Oncology Panel that developed clinical practice guidelines for AYA oncology.2 The guidelines address the critical issues that adolescents and young adults with cancer (and their caregivers) encounter at diagnosis, during treatment, and after therapy, including psychosocial issues. Issued earlier this year, the guidelines are still too new to have had a significant impact, Dr. Zebrack said. “The big impact is going to come from the next effort, which is to package the guidelines for patients and families. Putting this information into the hands of patients and families is going to give them the armamentarium to go to their doctors and say, ‘You know you haven’t asked me about infertility yet,’ or to ask ‘Do you have experience treating other young adults with cancer? Are you going to give me a treatment used in older adults, or are you giving me a treatment intended for pediatric patients, because I am looking at the research that says I am better served by the pediatric protocol,’” Dr. Zebrack explained. “People really need to be armed with as much information as possible, because our health-care system is overburdened.” Dr. Zebrack said that the committee already has a draft of the patient and family information and expects that it will be available “in the next year or so.”

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Disclosure: Dr. Zebrack and his coauthors on the Cancer article reported no potential conflicts of interest.

References 1. Zebrack BJ, Block R, Hayes-Lattin B, et al: Psychosocial service use and unmet need among recently diagnosed adolescent and young adult cancer patients. Cancer June 28, 2012 (early release online). 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Adolescent and Young Adult (AYA) Oncology. Version 1.2012. Available at www.nccn. org/professionals/physician_gls/pdf/aya. pdf. Accessed August 7, 2012.

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Perspective

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patients in remission. In a cost-conscious world, how do we strike the right balance between follow-up visits with associated investigations for asymptomatic patients, vs waiting for the signs and symptoms of recurrence? “Cost” is more than financial; there are important emotional factors to consider as well. Routine reviews and tests are a source of comfort and reassurance to some patients but a source of great anxiety to others, as fear of relapse is virtually universal. Leaving aside the issue of financial cost, in an ideal world you would probably choose to design a specific follow-up program for each individual, based on prognosis, age, background, level of anxiety, need for reassurance, support network, etc. But when designing health-care protocols at the institutional level, we need to create disease-oriented programs that are applied more or less in the same way to every patient. Assessing the financial costs of different monitoring programs is relatively easy, but evaluating the emotional cost of different intensities of surveillance is much harder. Here, a balance must be struck between the

doctor’s needs and those of the patient. The doctor has a professional responsibility for monitoring a patient’s health, but in some countries there is also fear of criticism, or possibly even legal action for any suggestion of negligence. In this situation, there is a risk (or tendency) to overinvestigate to the detriment of the patient, since this inevitably creates additional anxiety.

As the oncologist, you understand the therapeutic necessity of identifying asymptomatic relapse if second- or third-line treatments are available and genuinely useful. In that setting, I recommend that explanations about the purpose of monitoring during remission be explained at the outset of planning treatment. This subsequently justifies the emotional “spend” involved

My take-home message for routine patient care is to suggest that monitoring should be personalized as much as is possible. We have to try to strike that balance between what we need to know as physicians and what is best for the individual patient. —John F. Smyth, MD

In my experience, patients vary greatly in their attitude toward surveillance, especially those who are better educated and well informed. Some patients crave information— frequent scans, blood tests, and so forth—but others want to minimize intrusion, lest bad news adversely affect their emotional equilibrium. As with so much in oncology, the best approach is through explanation— talking and, above all, listening.

in investigations. However, if the therapeutic options at relapse are marginal, you should do everything possible to allow patients to decide how much monitoring is optimal for them, during periods of asymptomatic remission.

Striking a Balance As we develop more specific bloodborne biomarkers of cancer activity, it may eventually be possible to monitor

patients during remission in a continuous fashion. Patients may find that both acceptable and much less threatening, since you reduce the sudden anxiety associated with intermittent scans or invasive tests. But the tools we have today are of limited value. For example, research has shown that elevation of CA125 can anticipate clinical signs and symptoms of ovarian cancer relapse by 3 to 4 months, but introducing further treatment at that time does not affect survival. Hence, the monitoring only gives the patient several months of added anxiety together with the side effects of returning to anticancer treatment. Of course, when research protocols are involved, monitoring and documentation of relapse is essential, and patients understand that. My take-home message for routine patient care is to suggest that monitoring should be personalized as much as is possible. We have to try to strike that balance between what we need to know as physicians and what is best for the individual patient. The patient needs to find his or her own equilibrium between reassurance and anxiety. That’s not easy—but this is oncology, after all.

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

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