TAP Vol 5 Issue 8 by Harborside Press LLC

Chemotherapy and Pregnancy

| Ofatumumab in CLL

157

| Ramucirumab in Gastric Cancer

167

| ASCO’s History

191–206

VOLUME 5, ISSUE 8

MAY 15, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

JCO Spotlight

ASCO Releases Guideline on Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers Society Also Adapts Guidelines on Fatigue and Anxiety/Depressive Symptoms, see pages 49 and 54

See page 45 for a clinical perspective on the new ASCO Guidelines from Harold J. Burstein, MD, PhD.

Charles Loprinzi, MD

Dawn Hershman, MD

the Mayo Clinic, Rochester, Minnesota, and Dawn Hershman, MD, of Columbia University Medical Center, New York, were the panel co-chairs. The overall incidence of the condition is estimated continued on page 45

Expert’s Corner

ASCO Develops New Strategy to Increase Value in Cancer Care

n assuming the Presidency of ASCO a year ago, I recognized that one of our greatest challenges as a professional society is helping the American public understand the value of cancer research, especially now, when scientific advances are accelerating but resources are contracting. This is partly why I chose Science and Society as the theme of my term and the 2014 Annual Meeting. To inform the public’s view of the value of research—and of science in general—we have to passionately share our stories and explain how scientific continued on page 186

Dr. Hudis is Chief of the Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center; President of the American Society of Clinical Oncology (2013–2014); and Professor of Medicine, Weill Cornell Medical College, New York.

MORE IN THIS ISSUE

A Conversation With Lowell E. Schnipper, MD By Jo Cavallo

By Clifford A. Hudis, MD, FACP

By Matthew Stenger SCO has released a clinical practice guideline on prevention and treatment of chemotherapy-induced peripheral neuropathy in adult cancer patients, published in the Journal of Clinical Oncology.1 The guidelines resulted from the efforts of an expert panel, with representation from the fields of medical oncology, community oncology, nursing, pain research, genetics, neurology, pharmacology, patient representation, and guideline methodology. Charles Loprinzi, MD, of

Reflecting on the Past Year and Looking Ahead to the Next

ast January, ASCO held a leadership summit in Washington, DC, with representatives from the pharmaceutical industry, insurance payers, patient advocates, and physicians to address the skyrocketing costs of new drugs and technologies used in the diagnosis and treatment of cancer. Although costs are rising throughout the health-care system, they are especially pronounced in cancer care, where new therapies

include 8 of the top 10 most expensive drugs covered by Medicare. And while cancer care in total is responsible for only 5% of health-care expenditures, this is expected to grow over the next 6 years, from $125 billion in 2010 to a projected $175 billion in 2020.1 The meeting, “Summit on Optimizing High Value Cancer Care: Addressing the Cost of Drugs and Novel Technologies,” was an initial step in developing a dialogue among the key stakeholders. The ultimate goal is to find solutions that will We are trying to be an honest broker in enhance value in cancer care (optimal clinical benhelping oncologists and patients make efit per unit cost) and intheir best-informed treatment decisions crease patient access, while continuing to encourage based on effectiveness and cost. innovation in drug and —Lowell E. Schnipper, MD technology development.

Oncology Meetings Coverage NCCN Annual Conference �� 3, 38 Society of Surgical Oncology ��5, 12 AACR Annual Meeting �� 14, 16, 18, 20 ASPO Annual Meeting ��26 ACCC Annual Meeting ��28 Targeted Anticancer Therapies ��29 Derek Raghavan, MD, PhD, on Treating Prostate Cancer ��82 Leonard Saltz, MD, on Optimal Treatment of Rectal Cancer �� 86 Direct From ASCO ��102–105 William Curry, MD, on Glioblastoma �� 130 Eliezer Robinson, MD, on QOL in Cancer Survivors �� 149 Eduardo Cazap, MD, on Clinical Research in South America �� 168

continued on page 98

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A Harborside Press® Publication

The ASCO Post | MAY 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Paul F. Engstrom, MD Fox Chase Cancer Center

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Samuel Silver, MD, PhD University of Michigan Health System

Associate Editors

Bishoy Morris Faltas, MD Weill Cornell Medical College

Jame Abraham, MD Cleveland Clinic

John A. Fracchia, MD New York Urological Associates

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

Alison Freifeld, MD University of Nebraska Medical Center

Jamie Von Roenn, MD American Society of Clinical Oncology

Louis B. Harrison, MD Continuum Cancer Centers of New York

Lynn D. Wilson, MD Yale University School of Medicine

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Stanley H. Winokur, MD Singer Island, Florida

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

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

Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center

International Editors

Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network 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

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 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 subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania

George W. Sledge, MD Indiana University

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

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com Sarah McGullam, Web Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Terri Caivano, Kristina O’Toole, Alyson Prete, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com Alyson@harborsidepress.com Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com Anthony Cutrone, President Anthony@harborsidepress.com John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Contributing Writers: Charlotte Bath, Alice Goodman, Caroline Helwick, Susan London, Caroline McNeil, Eileen O’Gara-Kurtis, Shalmali Pal, Ronald Piana, Susan Reckling, Matthew Stenger, Marian Wiseman

James L. Mulshine, MD Rush University Medical Center

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

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

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

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Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

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

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | MAY 15, 2014

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National Comprehensive Cancer Network Annual Conference Guidelines

NCCN Clinical Practice Guidelines in Oncology: 2014 Updates By Caroline Helwick

t the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), held recently in Hollywood, Florida, NCCN Panel members presented updates for several tumor types, briefly summarized here. For a more complete description of all updates, visit www.nccn.org.

Breast Cancer Guidelines Incorporate Pertuzumab

“In HER2-positive metastatic disease, the triplet of pertuzumab, trastuzumab, and docetaxel has become the go-to first-line therapy.” —William Gradishar, MD

The 2014 NCCN Guidelines now recommend the addition of pertuzumab (Perjeta) to a number of regimens in both the adjuvant and metastatic settings for HER2-positive disease, according to William Gradishar, MD, of Northwestern University and the Robert H. Lurie Comprehensive Cancer Center, Chicago. The Panel noted, “Considering the unprecedented improvement in overall survival in the metastatic setting and the significant improvement in pathologic complete response seen in the neoadjuvant setting, the NCCN Panel considers it reasonable to incorporate pertuzumab in … adjuvant regimens, with duration similar to that used in the neoadjuvant setting, if the patient did not receive pertuzumab as part of neoadjuvant therapy.” Pertuzumab may also be part of neoadjuvant treatment in

patients with ≥ T2 or ≥ N1 disease. The preferred adjuvant foundation is doxorubicin/cyclophosphamide followed by paclitaxel with trastuzumab (Herceptin), with pertuzumab a possible addition. In metastatic disease, the triplet of pertuzumab, trastuzumab, and docetaxel is the only category 1 option listed, based on a significant improvement in both progression-free and overall survival, compared with trastuzumab/docetaxel. Pertuzumab added to docetaxel/carboplatin/trastuzumab is also a preferred regimen, and paclitaxel can be used in place of docetaxel in these triplets. The combination of paclitaxel/bevacizumab (Avastin) remains in the Guidelines, but the Panel added a footnote to emphasize that an overall survival benefit has not been demonstrated. The Guidelines now include paclitaxel plus trastuzumab as an option for patients with low-risk, HER2-positive stage I tumors. In addition, the Guidelines have updated the principles for HER2 testing to be consistent with those of ASCO, and have added exemestane plus everolimus (Afinitor) to postmenopausal endocrine therapy regimens for systemic disease.

Cancer Survivorship Guidelines Address Two Common Side Effects

“The guidelines are an important validation of our patients’ symptomatic experience.” —Elizabeth A. Kvale, MD

The NCCN Survivorship Guidelines were expanded to include a new section on cancer-associated cognitive impairment and a greater focus on chemotherapy-induced peripheral neuropathy in the adult cancer pain section. With growing awareness of the late effects of cancer treatment, the NCCN Panel felt it was time to emphasize these topics. Susan G. Urba, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, presented recommendations for assessing and managing peripheral neuropathy. Data support the use of antidepressants and opioids, often in combination, she said. Elizabeth A. Kvale, MD, of the University of Alabama at Birmingham Comprehensive Cancer Center, presented the inaugural guidelines for cognitive impairment, a field that is still struggling from a lack of evidence.

Chemotherapy-Induced Peripheral Neuropathy

New Section on Cognitive Impairment

Updates in Non-Hodgkin Lymphoma

The Guidelines acknowledge that cancer and its treatment can disrupt “normal” cognitive function and affect function and quality of life. Of 21 longitudinal studies in breast cancer, 16 have shown that cancer-associated cognitive impairment, particularly verbal ability and thought processing, affects 20% to 30% of patients. This is usually transient but persists longterm for a subset of patients. The NCCN Guidelines recommend targeted neuropsychological testing and limit neuroimaging recommendations to those patients determined to be at high risk for central nervous system disease. Growing evidence suggests that structural and functional changes underlie the experience. Patients who present with symptoms should also be screened for potentially reversible contributing factors. Unfortunately, evidencebased treatments are lacking, but the NCCN Guidelines describe some patient-centered interventions.

At least 20% of patients develop peripheral neuropathy as a result of chemotherapy. While the NCCN Guidelines have long addressed this side effect, the expanded section focuses on long-term cancer survivors, many of whom have persistent pain. The first line of treatment is antidepressants (especially duloxetine) and anticonvulsants (gabapentin and pregabalin), combined with opioids when pain is severe or refractory. Other recommended interventions include topical agents such as 5% lidocaine patch (usually best when combined with an opioid, antidepressant, and/or anticonvulsant). Dr. Urba emphasized the need for psychosocial support as well. “These patients may be on lifelong medication, and they should learn coping skills,” she said.

“We are rapidly moving beyond R-CHOP for all patients with diffuse large B-cell lymphoma.” —Andrew D. Zelenetz, MD, PhD

Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, reviewed the updates to the NCCN Guidelines for diffuse large B-cell lymphoma and presented the inaugural guidelines in T-cell lymphomas continued on page 4

Don’t Miss These Important Reports in This Issue of The ASCO Post Phase I Study of Belinostat in Peripheral T-Cell Lymphoma and Small Cell Lung Cancer, reported by Sanjeeve Bala, MD

see page 29

ALK-Rearranged Advanced NSCLC, by Alice T. Shaw, MD, PhD see review on page 61

Visit The ASCO Post online at ASCOPost.com

Lee M. Ellis, MD, on Demanding More From Clinical Trials see page 73

The ASCO Post | MAY 15, 2014

PAGE 4

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 3

for primary cutaneous CD30-positive lymphoproliferative disorders and large granular lymphocytic leukemia. Under the diagnosis section of the Diffuse Large B-cell Lymphoma Guidelines, the immunohistochemistry panel was modified to include the MYC gene, which is now considered to be essential in the evaluation of these tumors. Some 5% to 10% of diffuse large B-cell lymphomas harbor a MYC oncogene rearrangement, which is associated with worse outcomes. Dr. Zelenetz said the Panel “revisited and keeps revisiting the role of imaging in [diffuse large B-cell lymphoma] as new data emerge.” In monitoring early-stage patients who achieve a clinical response, the updated Guidelines state that repeat computed tomography scanning should not be done routinely but only as clinically indicated—a change that reflects the limited utility of surveillance imaging in patients with localized disease. The debate about the optimal first-line therapy for diffuse large B-cell lymphoma is reflected in the 2014 Guidelines, which list three effective options for primary mediastinal B-cell lymphoma: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) followed by radiotherapy, DA-EPOCH-R (doseadjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, rituximab), and R-CHOP followed by ICE (ifosfamide, carboplatin, etoposide) with or without radiotherapy. For first-line therapy in patients with poor left-ventricular function, the attenuated immunotherapy regimen R-miniCHOP, which contains a decreased dose of CHOP and a conventional dose of rituximab for elderly patients, has been added as an option for patients older than age 80 with comorbidities.

pathways diverge depending on whether the lesions are solitary, where surgical excision with or without local radiotherapy is recommended, or multifocal, where methotrexate is the preferred treatment, although radiotherapy, systemic retinoids, pralatrexate (Folotyn), and observation (if asymptomatic) are all listed as options. Most outcomes are good, he said. T-cell large granular lymphocytic leukemia also follows a typically indolent course. Diagnosis requires peripheral blood smear analysis for cytology, flow cytometry on peripheral blood, bone marrow aspirate and biopsy, and adequate immunophenotyping. Indications for therapy include severe neutropenia, moderate neutropenia with recurrent infections, symptomatic or transfusion-dependent anemia, autoimmune disorders associated with Tcell large granular lymphocytic leukemia, and B symptoms. As with the primary cutaneous CD30-positive lymphoproliferative disorders, treatment of T-cell large granular lymphocytic leukemia depends on the presence or absence of symptoms, with observation considered reasonable for asymptomatic individuals. In patients with symptoms, first-line choices include methotrexate, cyclophosphamide, and cyclosporine, with or without corticosteroids.

New Standard of Care in Chronic Lymphocytic Leukemia

Multiple Myeloma: Support for Continued Treatment

Inaugural Guidelines in T-cell Lymphomas New Guidelines were issued for the two rare primary cutaneous CD30positive tumors—anaplastic large cell lymphoma and lymphomatoid papulosis—and for T-cell large granular lymphocytic leukemia. The treatment algorithm in the NCCN Guidelines for primary cutaneous CD30-positive T-cell lymphoproliferative disorders hinges on the presence or absence of symptoms. For lymphomatoid papulosis patients who are symptomatic and have extensive lesions, methotrexate, phototherapy, systemic retinoids, and topical steroids are listed as treatment options. For anaplastic large cell lymphoma, the treatment

versity Comprehensive Cancer Center in Columbus. Most CLL patients are diagnosed with early-stage disease, and regardless of risk factors, treatment is initiated only when patients become symptomatic. The choice of regimen is differentiated by age or functional status and by genomic features. New to the guidelines is the emphasis on del(17p), which is particularly associated with poor outcomes and requires different management. “If you treat any group, this is the one,” Dr. Byrd noted. The 2014 Guidelines have added the CD20 antibody obinutuzumab (Gazyva) plus chlorambucil (Leukeran) as a new standard of care, based on the German CLL11 study that found it superior to chlorambucil/rituximab (Rituxan) in multiple endpoints. This regimen is now indicated as first-line treatment in CLL patients without del(11q) or del(17p), both those aged < 70 (with or without comorbidities) and those aged ≥ 70; with del(17p) (any age); and with del(11q) if ≥ 70 or younger with comorbidities. Similarly, with relapsed disease, treatment is initiated based on symptoms. The NCCN Guidelines list many options, however, with the approval of ibrutinib (Imbruvica), traditional second-line therapies have largely become irrelevant, he pointed out. Ibrutinib, an inhibitor of Bruton tyrosine kinase, and idelalisib, an inhibitor of PI3K-delta, both target the BCR signaling pathway and inhibit B-cell signaling in CLL. Ibrutinib is listed as a treatment option in relapsed/refractory disease, but idelalisib is still being investigated.

“The additional cost of chlorambucil plus obinutuzumab is probably justified by more than 1 year additional PFS. For the elderly, this is a better drug, and we should incorporate it.” —John C. Byrd, MD

The treatment of chronic lymphocytic leukemia (CLL) is poised for change, thanks to the development of effective agents targeting the BCR signaling pathway, according to John C. Byrd, MD, of The Ohio State Uni-

“The future is even more promising than what we have seen so far.” —Kenneth C. Anderson, MD

In multiple myeloma, it seems that “more is better,” as studies reported in 2013 support the concept of maintenance therapy after induction and consolidation in newly diagnosed transplant patients, and continued lenalidomide (Revlimid) in nontransplant patients, said Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston. In transplant candidates, three-drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong progression-free and overall survival, and this is becoming standard practice. In nontransplant candidates, lenalidomide/dexamethasone until progression is now the standard of care. Recent studies have provided the basis for inclusion of bortezomib (Velcade) plus prednisone and bortezomib plus thalidomide (Thalomid) as options for maintenance therapy in the 2014 Guidelines. Dr. Anderson added that future updates to the NCCN Guidelines will most likely include the oral proteasome inhibitor ixazomib (MLN9708), given the very promising ongoing late-stage trials. “We are now building on the ‘len/dex’ platform, not only by adding the intravenous proteasome inhibitors bortezomib or carfilzomib, but also the oral proteasome inhibitor ixazomib, and the results are very impressive. This all-oral regimen of ixazomib, lenalidomide, and dexamethasone is very active in newly diagnosed myeloma,” he noted. The 2014 Guidelines also encourage enrollment of patients with smoldering myeloma, defined by IgG ≥ 2g/dL, IgA > 1 g/dL, or Bence-Jones protein > 1 g/24 h in the absence of clinical sequelae including hypercalcemia, renal dysfunction, anemia, or bone disease, onto clinical trials designed to delay or prevent progression to active myeloma requiring therapy.

Relapsed/Refractory Disease The NCCN Guidelines for relapsed/refractory myeloma include bortezomib, bortezomib plus liposomal doxorubicin, and lenalidomide/dexamethasone as category 1 recommendations. Among the other “preferred regimens” are now carfilzomib as a single agent and pomalidomide (Pomalyst)/ dexamethasone. Perhaps the greatest effect will be seen when carfilzomib and pomalidomide are used in combination, Dr. Anderson predicted. On the horizon are new classes of agents that are demonstrating very impressive gains in remission duration and survival: monoclonal antibodies (daratumumab, which targets CS1, and elotuzumab and SAR650984, which target continued on page 40

ASCOPost.com | MAY 15, 2014

PAGE 5

Society of Surgical Oncology Breast Cancer

Survival Analysis of Contralateral Prophylactic Mastectomy Sparks Discussion By Shalmali Pal

ontralateral prophylactic mastectomy improved breast cancer patients’ odds of overall survival by 23% compared with single mastectomy alone, according to a retrospective analysis of nearly 170,000 patients in a U.S. database, but surgical breast cancer specialists warned that the data needed to be interpreted cautiously.

or without contralateral prophylactic mastectomy, from 1998 to 2010. She explained that the contralateral prophylactic mastectomy rate increased

tion of our extremely large sample size of 28,000 patients in a matched cohort, and that the differences between the two groups were so small as to not be

The survival benefit with [contralateral prophylactic mastectomy] suggests selection bias. Future prospective studies are needed to determine whether possible cohorts of patients are likely to benefit from [this procedure] by collecting data such as comorbidities, family history of breast cancer, and lifestyle habits.

‘Potentially Harmful’ One attendee at the SSO meeting took issue with the interpretation of the differences between the two groups, especially given the large sample size. “I think you have to be really careful with the issues of causality and association with a retrospective study with

—Laura L. Kruper, MD

Rondi Kauffmann, MD

Patients with unilateral, nonmetastatic breast cancer who underwent contralateral prophylactic mastectomy had a lower risk of death (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.73–0.82) relative to patients who had single mastectomy alone, reported Rondi Kauffmann, MD, of City of Hope in Duarte, California, at the 2014 Society of Surgical Oncology (SSO) Cancer Symposium in Phoenix.1

from 4% at the beginning of the study in 1998 to 22% in 2010. Her group looked at survival differences for the whole study population and for those aged 50 and up. The total cohort consisted of 169,631 patients; 141,616 had single mastectomy alone, whereas 28,015 underwent contralateral prophylactic mastectomy. The authors performed a matched, case-control analysis with patients matched based on several factors including age, race, grade, estrogenreceptor status, and nodal status, Dr. Kauffmann explained. In terms of patient demographics,

Contralateral Prophylactic Mastectomy and Survival ■■ A retrospective, observational study of nearly 170,000 breast cancer patients in a national database demonstrated improved odds of survival with contralateral prophylactic mastectomy vs single mastectomy alone. ■■ The 3-year, 5-year, and 10-year overall survival benefits were consistently higher than those for disease-specific survival, suggesting that selection bias explains the improved survival benefit: Healthier patients are opting to undergo contralateral prophylactic mastectomy. ■■ The overall rate of contralateral breast cancer for the matched cohort was low at 2.3%, and removing these cases from analyses did not change the results, suggesting that selection bias explains the improved survival benefit, not prevention of contralateral breast cancers.

In addition, the authors reported that the hazard ratio for disease-free survival with contralateral prophylactic mastectomy was 0.85 (95% CI = 0.79– 0.92) compared to patients who had single mastectomy alone.

Study Details Dr. Kauffmann and colleagues conducted a retrospective, observational study of patients identified from the Surveillance, Epidemiology, and End Results database. All subjects had newly diagnosed breast cancer and underwent mastectomy with

the authors reported a statistically significant difference for some patient and tumor characteristics, but the absolute differences were small, Dr. Kauffmann pointed out. For example, 81.9% of women who underwent single mastectomy alone were white vs 82.6% in the contralateral prophylactic mastectomy group (P = .0772). Also, 64.7% of women in the single mastectomy–only arm had node-negative status vs 65.5% in the contralateral prophylactic mastectomy arm (P = .0640). “This led us to conclude that this statistically significant P value was a func-

clinically relevant. We concluded that these groups were well matched,” Dr. Kauffmann said. The group reported that increased age, larger T classification, African American race, poorly differentiated grade, positive nodal status, and receptor-negative status were associated with an increased risk of breast cancer–specific death.

Survival Data The 3-, 5-, and 10-year overall and disease-specific survival rates were determined for patients who had contralateral prophylactic mastectomy and single mastectomy. The overall and disease-specific survival rates were higher for contralateral prophylactic mastectomy patients than for single mastectomy patients for each of the follow-up time periods, yet consistently overall survival rates were greater than diseasespecific rates. The authors then looked to see if the survival advantage persisted when excluding younger patients in whom the high-risk BRCA mutation was overrepresented. They still found a survival benefit for contralateral prophylactic mastectomy vs single mastectomy. Dr. Kauffmann highlighted the limitations of this retrospective research including a lack of data on the use of therapy other than surgery. Also, information on comorbidities and BRCA status could not be obtained. Finally, “despite the use of propensity score to match patients and distribute comorbities between the two cohorts, it is likely that some residual confounding remains,” she said. Nevertheless, these data do “contribute to the existing body of literature on contralateral prophylactic mastectomy,” she said.

Kimberly Van Zee, MD

very high statistical power,” warned Kimberly Van Zee, MD, of Memorial Sloan Kettering Cancer Center in New York. “You discounted the statistical significance of the imbalance between your two groups even after propensity matching. All the imbalance was in the direction of the contralateral prophylactic mastectomy group having lower risk.” Dr. Van Zee also pointed out that “the overall survival benefit is greater than the disease-free survival benefit, proving that your contralateral prophylactic mastectomy group was at lower risk of dying and were selected to be lower-risk patients.” Dr. Van Zee said the study’s conclusion that contralateral prophylactic mastectomy conferred a survival advantage was “potentially harmful and [a form of] misinformation if it’s based on inappropriate conclusions [from the data]…” Dr. Kauffmann conceded that that “the effect of the confounders is clearly impacting the overall survival much more heavily than the disease-free survival. Certainly, this is a difficult topic because we’ll never have a randomized controlled trial. Unfortunately, short of a multicenter study where we can control for comorbidities, chemotherapy, and other types of treatment other than just surgery, it is fraught with potential danger for interpreting overstrongly.”

Real-World Implications Monica Morrow, MD, of Memorial Sloan Kettering Cancer Center, also drew attention to the hazard of continued on page 6

The ASCO Post | MAY 15, 2014

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Society of Surgical Oncology Contralateral Prophylactic Mastectomy continued from page 5

overinterpreting the results. “I think the reason that we are all concerned about this is that, while you clearly understand the limitations of the dataset, what gets out there in the world is simply, ‘[Contralateral Prophylactic Mastectomy] Improves Survival,’” she said. “So to ask the question in a slightly different way, … What was the incidence of contralateral breast cancer in the unilateral arm?” In response to Dr. Kauffmann’s reply that the incidence was low at 3% to 5%, Dr. Morrow pointed out “you are showing 3% to 5% survival differences, which

the cohort were further investigated. Within the matched cohort of contralateral prophylactic mastectomy and single mastectomy patients, 2.3% of the patients developed a contralateral breast cancer, which is low. First, a multivariate analysis was performed with the original variables of the study now including contralateral breast

cancer as a variable. The hazard ratio for the overall survival rate with contralateral prophylactic mastectomy was 0.77 (95% CI = 0.73–0.82). When all cases of contralateral breast cancer were removed from the analysis, the hazard ratio did not change (HR = 0.77, 95% CI = 0.72–0.82). This led the authors to conclude

that the improvement in survival was not from prevention of contralateral breast cancer. “The people who would most benefit from [contralateral prophylactic mastectomy] are those who are at high risk of developing a contralateral breast cancer. However, by prevention of [contralateral breast cancer],

Redefine treatment goals with YERVOY (ipilimumab) is the ONLY metastatic melanoma therapy proven in a phase 3 study to deliver a durable long-term survival benefit1

Monica Morrow, MD

implies that every single patient who got contralateral breast cancer died of her disease in this followed-and-screened cohort, which we know is extremely unlikely. I would just join [Dr. Van Zee] in saying that I would be exceedingly careful in overinterpreting the data.” With these cautionary words by Drs. Morrow and Van Zee, senior investigator Laura L. Kruper, MD, of City of Hope, returned to the data to perform additional analyses. “One of the benefits of being able to present one’s data at a large scientific meeting is that it allows a study’s results

46% 1-YEAR survival rate*

24% 2-YEAR survival rate*

Some patients were still alive up to 4.5 years2 The overall survival curve shows 2, 1, and 0 patients were still in follow-up in the YERVOY arm at 48, 52, and 56 months at the time of study closure. *Estimate based on Kaplan-Meier analysis.1

Median overall survival was 10 months in the YERVOY arm3

YERVOY + gp100 vs gp100: HR=0.68 (95% CI: 0.55, 0.85, P=0.0004) YERVOY vs gp100: HR=0.66 (95% CI: 0.51, 0.87, P=0.0026)a YERVOY + gp100 vs YERVOY: HR=1.04 (95% CI: 0.83, 1.30, P=0.76) Not adjusted for multiple comparisons.

A phase 3, double-blind, double-dummy study that randomized 676 patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin (IL-2), dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive YERVOY 3 mg/kg in combination with an investigational gp100 peptide vaccine (gp100) (n=403), YERVOY 3 mg/kg (n=137), or gp100 (n=136). The primary endpoint was overall survival in the YERVOY + gp100 arm vs the gp100 arm.1

Laura L. Kruper, MD

to be scrutinized before publication. We greatly appreciate the comments from both Drs. Morrow and Van Zee since they are leaders in breast cancer research and understand the complexities of population-based studies,” she told The ASCO Post.

Further Analyses With the additional analyses, the cases of contralateral breast cancer in

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

ASCOPost.com | MAY 15, 2014

PAGE 7

Society of Surgical Oncology we would expect the disease-specific survival benefit to be greater than overall survival benefit, and this is not what we are seeing,” Dr. Kruper said. “In our additional analyses, we demonstrated that the low rate of [contralateral breast cancer] in the cohort has little impact on the survival rates, implying that the increased

survival seen with [contralateral prophylactic mastectomy] is from selection bias: Those who are healthier or lead healthier lifestyles are either choosing [contralateral prophylactic mastectomy] or are chosen to undergo [contralateral prophylactic mastectomy]. This selection bias also potentially explains why the overall survival

benefit was consistently greater than the disease-specific survival benefit in our study,” she concluded.

Recurrence Rates In response to another attendee’s question regarding recurrence rates, the stage at which patients presented with recurrence, and adherence to a screen-

durable long-term survival in metastatic melanoma

YERVOY is not indicated for patients under 18 years of age.

Indication

YERVOY® (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

See experts discuss redefining treatment goals for metastatic melanoma Find out at www.RedefineTreatmentGoals1.com

To learn more, visit www.YERVOY.com or call Support Services at 1-855-YERVOY1.

Please see detailed Important Safety Information, including Boxed WARNING regarding immune-mediated side effects, and brief summary of Full Prescribing Information on adjacent pages. ©2014 Bristol-Myers Squibb Company. All rights reserved. 731US13BR03586-03-01 01/14

ing schedule, Dr. Kauffmann said her group is currently analyzing the dataset for that information. Regarding those analyses, Kruper et al were subsequently able to demonstrate that the development of a contralateral breast cancer had varying effects on survival. For those who presented with a continued on page 8

The ASCO Post | MAY 15, 2014

PAGE 8

Society of Surgical Oncology Contralateral Prophylactic Mastectomy continued from page 7

“low stage” contralateral breast cancer (in situ to stage II), there was an improved survival benefit whereas those presenting with a “high stage” contralateral breast cancer (stage II to IV) had an increased risk of death. Ac-

cording to Dr. Kruper, this also demonstrates selection bias with those undergoing routine surveillance, having contralateral breast cancers detected at an earlier stage. “The improved survival is not from the [contralateral breast cancer] but from the regular health maintenance.” n Disclosure: Drs.

Kauffmann,

Morrow,

Kruper, and Van Zee reported no potential conflicts of interest.

Reference 1. Kauffmann R, Nelson R, Smith D, et al: Improved survival with contralateral prophylactic mastectomy. 2014 Society of Surgical Oncology Cancer Symposium. Abstract 12. Presented March 15, 2014.

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

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY® (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: • Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day • Failure to complete full treatment course within 16 weeks from administration of first dose • Severe or life-threatening adverse reactions, including any of the following: – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5× the upper limit of normal (ULN) or total bilirubin >3× the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients • Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis • Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids • Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms • Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients • Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Important Safety Information continued on following page.

ASCOPost.com | MAY 15, 2014

PAGE 9

FDA Update

FDA Approves Ramucirumab for Stomach Cancer

he U.S. Food and Drug Administration (FDA) has approved ramucirumab (Cyramza) to treat patients with advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with disease progression on or after prior treatment

with fluoropyrimidine- or platinumcontaining chemotherapy. Ramucirumab is a recombinant monoclonal antibody of the IgG1 class that binds to the vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks the activation of the receptor.

“Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies,” said Richard Pazdur, MD, Director of the Office of Hema-

Important Safety Information (cont’d) Immune-mediated Hepatitis: • In the pivotal Phase 3 study in YERVOY (ipilimumab)-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% • 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2) • Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution • Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids • Withhold YERVOY in patients with Grade 2 hepatotoxicity • In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) Immune-mediated Dermatitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis • There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis • Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated • Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms • Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: • In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported • Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported • Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes • Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: • In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immunemediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients Important Safety Information continued on following page.

tology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “[Ramucirumab] is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.” continued on page 10

The ASCO Post | MAY 15, 2014

PAGE 10

FDA Update Ramucirumab for Stomach Cancer continued from page 9

Improved Overall Survival The approval was based on the demonstration of improved overall survival in the REGARD trial, a multinational, randomized (2:1), double-blind, multicenter investigation. The trial evalu-

ated ramucirumab’s safety and efficacy in 355 participants with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Two-thirds of trial participants received ramucirumab plus best supportive care while the remaining participants received a placebo plus best supportive care.

Results showed patients treated with ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months in patients receiv-

ing placebo (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.60– 0.998, P = .047 on stratified log-rank test). Median progression-free survival was also longer in the ramucirumab arm compared to placebo (HR = 0.48, 95% CI = 0.38–0.62, P < .001 on stratified log-rank test). Results from a second clinical trial

Important Important Safety Safety Information Information (cont’d) (cont’d) Immune-mediated Immune-mediated Endocrinopathies Endocrinopathies (cont’d): (cont’d): – All –9 All patients 9 patients had hypopituitarism, had hypopituitarism, and some and some had additional had additional concomitant concomitant endocrinopathies endocrinopathies suchsuch as adrenal as adrenal insufficiency, insufficiency, hypogonadism, hypogonadism, and hypothyroidism and hypothyroidism – 6 of– the 6 of9the patients 9 patients werewere hospitalized hospitalized for severe for severe endocrinopathies endocrinopathies • Moderate • Moderate endocrinopathy endocrinopathy (requiring (requiring hormone hormone replacement replacement or medical or medical intervention; intervention; Grade Grade 2) 2) occurred occurred in 12in(2.3%) 12 (2.3%) YERVOY YERVOY (ipilimumab)-treated (ipilimumab)-treated patients patients and consisted and consisted of hypothyroidism, of hypothyroidism, adrenal adrenal insufficiency, insufficiency, hypopituitarism, hypopituitarism, and 1 and case 1 case eacheach of hyperthyroidism of hyperthyroidism and Cushing’s and Cushing’s syndrome syndrome • Median • Median time time to onset to onset of moderate of moderate to severe to severe immune-mediated immune-mediated endocrinopathy endocrinopathy was 11 wasweeks 11 weeks and and ranged ranged up toup 19.3 to 19.3 weeks weeks after after the initiation the initiation of YERVOY of YERVOY • Monitor • Monitor patients patients for clinical for clinical signssigns and symptoms and symptoms of hypophysitis, of hypophysitis, adrenal adrenal insufficiency insufficiency (including (including adrenal adrenal crisis), crisis), and hyperand hyperor hypothyroidism or hypothyroidism – Patients – Patients may may present present with with fatigue, fatigue, headache, headache, mental mental status status changes, changes, abdominal abdominal pain,pain, unusual unusual bowel bowel habits, habits, and hypotension, and hypotension, or nonspecific or nonspecific symptoms symptoms which which may may resemble resemble otherother causes causes suchsuch as brain as brain metastasis metastasis or underlying or underlying disease. disease. Unless Unless an alternate an alternate etiology etiology has been has been identified, identified, signssigns or symptoms or symptoms should should be considered be considered immune-mediated immune-mediated – Monitor – Monitor thyroid thyroid function function teststests and clinical and clinical chemistries chemistries at theatstart the start of treatment, of treatment, before before eacheach dose,dose, and as andclinically as clinically indicated indicated based based on symptoms. on symptoms. In a limited In a limited number number of patients, of patients, hypophysitis hypophysitis was was diagnosed diagnosed by imaging by imaging studies studies through through enlargement enlargement of theofpituitary the pituitary glandgland • Withhold • Withhold YERVOY YERVOY in symptomatic in symptomatic patients. patients. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of of prednisone prednisone or equivalent) or equivalent) and initiate and initiate appropriate appropriate hormone hormone replacement replacement therapy. therapy. Long-term Long-term hormone hormone replacement replacement therapy therapy may may be necessary be necessary OtherOther Immune-mediated Immune-mediated Adverse Adverse Reactions, Reactions, Including Including Ocular Ocular Manifestations: Manifestations: • In the • Inpivotal the pivotal Phase Phase 3 study 3 study in YERVOY-treated in YERVOY-treated patients, patients, clinically clinically significant significant immune-mediated immune-mediated adverse adverse reactions reactions seenseen in <1% in <1% were:were: nephritis, nephritis, pneumonitis, pneumonitis, meningitis, meningitis, pericarditis, pericarditis, uveitis, uveitis, iritis,iritis, and hemolytic and hemolytic anemia anemia • Across • Across the clinical the clinical development development program program for YERVOY, for YERVOY, likelylikely immune-mediated immune-mediated adverse adverse reactions reactions also also reported reported with with <1%<1% incidence incidence were:were: myocarditis, myocarditis, angiopathy, angiopathy, temporal temporal arteritis, arteritis, vasculitis, vasculitis, polymyalgia polymyalgia rheumatica, rheumatica, conjunctivitis, conjunctivitis, blepharitis, blepharitis, episcleritis, episcleritis, scleritis, scleritis, leukocytoclastic leukocytoclastic vasculitis, vasculitis, erythema erythema multiforme, multiforme, psoriasis, psoriasis, pancreatitis, pancreatitis, arthritis, arthritis, autoimmune autoimmune thyroiditis, thyroiditis, sarcoidosis, sarcoidosis, neurosensory neurosensory hypoacusis, hypoacusis, autoimmune autoimmune central central neuropathy neuropathy (encephalitis), (encephalitis), myositis, myositis, polymyositis, polymyositis, and ocular and ocular myositis myositis • Permanently • Permanently discontinue discontinue YERVOY YERVOY for clinically for clinically significant significant or severe or severe immune-mediated immune-mediated adverse adverse reactions. reactions. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of prednisone of prednisone or equivalent) or equivalent) for severe for severe immune-mediated immune-mediated adverse adverse reactions reactions • Administer • Administer corticosteroid corticosteroid eye drops eye drops for uveitis, for uveitis, iritis,iritis, or episcleritis. or episcleritis. Permanently Permanently discontinue discontinue YERVOY YERVOY for immune-mediated for immune-mediated ocular ocular disease disease unresponsive unresponsive to local to local immunosuppressive immunosuppressive therapy therapy Pregnancy Pregnancy & Nursing: & Nursing: • YERVOY • YERVOY is classified is classified as pregnancy as pregnancy category category C. There C. There are no areadequate no adequate and well-controlled and well-controlled studies studies of YERVOY of YERVOY in pregnant in pregnant women. women. Use Use YERVOY YERVOY during during pregnancy pregnancy only only if theifpotential the potential benefit benefit justifies justifies the potential the potential risk to risk thetofetus the fetus • Human • Human IgG1IgG1 is known is known to cross to cross the placental the placental barrier barrier and YERVOY and YERVOY is anisIgG1; an IgG1; therefore, therefore, YERVOY YERVOY has the haspotential the potential to betotransmitted be transmitted fromfrom the mother the mother to thetodeveloping the developing fetusfetus • It is• not It isknown not known whether whether YERVOY YERVOY is secreted is secreted in human in human milk.milk. Because Because manymany drugsdrugs are secreted are secreted in in human human milk milk and because and because of theofpotential the potential for serious for serious adverse adverse reactions reactions in nursing in nursing infants infants fromfrom YERVOY, YERVOY, a decision a decision should should be made be made whether whether to discontinue to discontinue nursing nursing or to or discontinue to discontinue YERVOY YERVOY Common Common Adverse Adverse Reactions: Reactions: • The• most The most common common adverse adverse reactions reactions (≥5%) (≥5%) in patients in patients who who received received YERVOY YERVOY at 3 mg/kg at 3 mg/kg werewere fatigue fatigue (41%), (41%), diarrhea diarrhea (32%), (32%), pruritus pruritus (31%), (31%), rash rash (29%), (29%), and colitis and colitis (8%)(8%) PleasePlease see brief seesummary brief summary of Full of Prescribing Full Prescribing Information, Information, including including Boxed Boxed WARNING WARNING regarding regarding immune-mediated immune-mediated side effects, side effects, on following on following pages.pages. References: References: 1. Hodi 1. FS,Hodi O’Day FS,SJ, O’Day McDermott SJ, McDermott DF, et al.DF,Improved et al. Improved survivalsurvival with ipilimumab with ipilimumab in patients in patients with metastatic with metastatic melanoma. melanoma. N Engl JNMed. Engl2010;363(8):711-723. J Med. 2010;363(8):711-723. 2. YERVOY 2. YERVOY packagepackage insert. Princeton, insert. Princeton, NJ: Bristol-Myers NJ: Bristol-Myers Squibb Company. Squibb Company. 3. Data 3. onData file. YERV on file.008. YERV Bristol-Myers 008. Bristol-Myers Squibb Company. Squibb Company. Princeton, Princeton, NJ. AprilNJ. 2011. April 2011.

ASCOPost.com | MAY 15, 2014

PAGE 11

FDA Update

that evaluated the efficacy of ramucirumab plus paclitaxel vs paclitaxel alone also showed an improvement in overall survival.

Safety The most common adverse events (all grades) observed in ramucirumabtreated patents were hypertension and

diarrhea. Grade 3 to 4 adverse reactions reported at a higher incidence in the ramucirumab arm included hypertension and hyponatremia. The most common serious adverse events with ramucirumab were intestinal obstruction and anemia. The FDA reviewed ramucirumab under its priority review program, which

YERVOY® (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information.] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions.] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning.] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range: 1.6–13.4) and 6.3 weeks (range: 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event. Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution. Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information.] Concurrent Administration with Vemurafenib In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous,

Yrv1213pbs731US13BR02790_0101wip3.indd 1

provides an expedited review for drugs that have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. The agent was also granted orphan product designation because it is intended to treat a rare disease or condition. Ramucirumab is marketed by Eli Lilly. n

or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY (ipilimumab)-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis. The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY. Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information.] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-mediated enterocolitis [see Warnings and Precautions]. • Immune-mediated hepatitis [see Warnings and Precautions]. • Immune-mediated dermatitis [see Warnings and Precautions]. • Immune-mediated neuropathies [see Warnings and Precautions]. • Immune-mediated endocrinopathies [see Warnings and Precautions]. • Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions].

12/13/13 1:32 PM

More on Novel Agents See pages 62–66 for more FDA updates. See pages 157 and 167 for full reports on using ofatumumab in CLL and ramucirumab in gastric cancer.

The ASCO Post | MAY 15, 2014

PAGE 12

Society of Surgical Oncology Breast Cancer

Lymphedema Lingers Long After Sentinel Lymph Node Dissection for Early Breast Cancer By Shalmali Pal

atients with early-stage breast cancer who underwent sentinel lymph node dissection experienced

lymphedema with increasing incidence over time, according to a presentation at the 2014 Society of Surgical Oncology

(SSO) Cancer Symposium in Phoenix.1 In women who took part in the American College of Surgeons Oncol-

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information.] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1–4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY (ipilimumab) with the incidences of antibodies to other products may be misleading.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

DRUG INTERACTIONS

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

USE IN SPECIFIC POPULATIONS

Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patientsa

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3–5

Any Grade

Grade 3–5

Any Grade

Grade 3–5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls. [See Nonclinical Toxicology (13.2) in Full Prescribing Information.] Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:

Pregnancy Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No dose adjustment is needed for patients with renal impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 × to 1.5 × the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. •

Inform patients of the potential risk of immune-mediated adverse reactions.

• • •

Advise patients to read the YERVOY Medication Guide before each YERVOY infusion. Advise women that YERVOY may cause fetal harm. Advise nursing mothers not to breastfeed while taking YERVOY.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321675A0

Rev December 2013 731US13BR02790-01-01

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Yrv1213pbs731US13BR02790_0101wip3.indd 2

12/13/13

ogy Group (ACOSOG) Z0010 trial, the cumulative incidence of lymphedema after sentinel lymph node dissection was 10.5% at 1 year, 17.4% at 3 years, and 24.1% at 5 years based on objective measurements, reported Mediget Teshome, MD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues. Based on subjective assessments, the cumulative incidence of lymphedema was 3.7% at 1 year, 8.9% at 3 years, and 11.9% at 5 years. Sentinel lymph node dissection is a minimally invasive approach to axillary staging in early-stage breast cancer, and “when compared to traditional axillary lymph node dissection, many studies have demonstrated decreased morbidity with this approach,” Dr. Teshome said during her presentation at an SSO Plenary Session. However, a potential complication of sentinel lymph node dissection is lymphedema, and long-term studies on this outcome have been lacking, she explained. The results of ACOSOG Z0010, which was conducted from 1999 to 2003, showed no difference in overall survival, locoregional recurrence, or distant metastasis in patients with occult sentinel lymph node micrometastases by immunohistochemistry.2,3

Current Study For the current follow-up study, eligible patients were women from ACOSOG Z0010 with clinical T1-2, N0, M0 disease. Of eligibile patients, 4,865 women underwent arm measurement assessment at baseline and at least one other time point. All underwent sentinel lymph node dissection, with 3,966 in the sentinel lymph node dissection–only group and 899 who underwent completion axillary lymph node dissection. The vast majority of women underwent wholebreast irradiation (89.7%), more than half received chemotherapy (56.5%), and about two-thirds had hormonal therapy (66.9%). Lymphedema was evaluated objectively as an increase of 2 cm from the preoperative arm measurement vs the contralateral arm, corresponding with a 10% increase in arm volume, Dr. Teshome said. Subjective measurement consisted of ipsilateral arm swelling as 1:32 PM reported by the patient.

ASCOPost.com | MAY 15, 2014

PAGE 13

Society of Surgical Oncology Assessments were performed before sentinel lymph node dissection and then again at 30 days, 6 months, and annually for 5 years after surgery. The median number of assessments was four,

axillary lymph node dissection. When comparing the two techniques, the 5-year incidence rate by subjective assessment was 41.2% for axillary lymph node dissection compared

Looking specifically at women undergoing sentinel lymph node dissection, there appears to be a plateau effect over time with regard to the subjective determination of lymphedema, while the cumulative incidence by objective arm measurements seems to slowly increase over time. —Mediget Teshome, MD

and the median follow-up time was 9.9 years, although arm measurements were only done to 5 years. Dr. Teshome pointed out that there was attrition of arm measurements over time, with 69.9% of women undergoing assessment at 1 year, 51.5% at 3 years, and 27.6% at 5 years, but the authors were still able to analyze data in over 1,000 patients.

Outcomes In the sentinel lymph node dissection–only group who experienced lymphedema, the authors found that patients were older (age 58 vs 56, P < .0001), had a body mass index of 30 kg/m2 and higher (40.9% vs 25.5%, P < .0001), and had a lower percentage of medially located tumors (17.2% vs 21.2%, P = .016). Although the authors reported that lymphedema after sentinel lymph node dissection “occurs more frequently than clinically suspected and with increasing incidence over time,” they also noted that women who had only sentinel lymph node dissection fared better than those who required

with 11.9% for sentinel lymph node dissection, while the 5-year incidence rate by objective assessment was 40.3% vs 24.1%. This is compared to the prevalance of lymphedema after sentinel lymph node dissection at each measurement point, which varied from 6.5% to 9.2% for objective assessment and 2.1% to 3.7% for subjective assessment. Additionally, patients undergoing axillary lymph node dissection had a greater cumulative incidence of decreased range of motion and axillary paresthesia at 5 years (51.3% and 76.3%, respectively) compared with sentinel lymph node dissection patients (22.1% and 29.1%).

Both increasing age (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.01–l.02, P < .003) and obesity (HR = 1.89, 95% CI = 1.61–2.22, P < .0001) were predictors of lymphedema after sentinel lymph node dissection. However, increasing age, presence of axillary seroma, and African American race were predictors of decreased range of motion and axillary paresthesia following axillary lymph node dissection.

Study Discrepancies and Limitations Dr. Teshome called attention to some “notable and interesting points” in the study results. “First, as expected, there is an increased incidence of lymphedema after axillary lymph node dissection as compared to sentinel lymph node dissection,” she said. “Second, looking specifically at women undergoing sentinel lymph node dissection, there appears to be a plateau effect over time with regard to the subjective determination of lymphedema, while the cumulative incidence by objective arm measurements seems to slowly increase over time. Lastly, there is discrepancy between the subjective and objective reports of lymphedema, with approximately twice as many cases by objective measures.” But the latter was not true in the axillary lymph node dissection group, where

Lymphedema After Lymph Node Dissection ■■ Lymphedema occurred more frequently than clinically suspected and with increasing incidence over time in women with early-stage breast cancer who undergo sentinel lymph node dissection. ■■ Increasing age and obesity were predictors of lymphedema after sentinel lymph node dissection. ■■ Women who underwent sentinel lymph node dissection and axillary lymph node dissection had a greater cumulative incidence of decreased range of motion and axillary paresthesia at 5 years postprocedure.

cumulative subjective and objective data were essentially the same, she said. She added that the discrepancy in patients undergoing sentinel lymph node dissection may be explained by improvement in lymphedema symptoms over time secondary to interventions. That said, there was limited follow-up on lymphedema treatment or symptom improvement, Dr. Teshome noted. Other limitations were the lack of randomization, and attrition in arm measurements during the study period, which meant that every patient did not have a complete assessment profile. “Lastly, the majority of our patients received radiation therapy, and although there was no association in our analysis, this may have impacted the findings,” she said. Dr. Teshome said future areas of research would include the evaluation of severity of lymphedema after sentinel lymph node dissection, assessment of patient education on post–sentinel lymph node dissection symptoms, and lymphedema prevention efforts. n

Disclosure: This study was funded by the National Cancer Institute. Dr. Teshome reported no potential conflicts of interest.

References 1. Teshome M, Ballman KV, McCall LM, et al: Long-term incidence of lymphedema after sentinel lymph node dissection for early stage breast cancer: ACOSOG Z0010 (Alliance). 2014 SSO Cancer Symposium. Abstract 3. Presented March 14, 2014. 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569575, 2011. 3. Hunt KK, Ballman KV, McCall LM, et al: Factors associate with localregional recurrence after a negative sentinel lymph node dissection: Results of the ACOSOG Z0010 trial. Ann Surg 256:428-436, 2012.

Visit The ASCO Post at the ASCO Annual Meeting May 30 - June 3, 2014 The ASCO Post BOOTH 24091 • Harborside Press BOOTH 24092

The ASCO Post | MAY 15, 2014

PAGE 14

American Association for Cancer Research Annual Meeting Genitourinary Oncology

Blood Test Can Identify Prostate Cancer Patients Who Are Not Likely to Respond to Enzalutamide By Alice Goodman

simple blood test may be able to identify men with castration-resistant prostate cancer who will not respond to enzalutamide (Xtandi). The presence of the splice variant androgen receptor (AR) V7 in circulating tumor cells identified men who were unlikely to respond to

“[Castration-resistant prostate cancer] may be a misnomer, because a number of men with this disease continue to benefit from a variety of [androgen receptor]-directed therapies. This implies that [castration-resistant prostate cancer] remains androgen-driven. Enzalutamide inhibits

We believe these data have immediate clinical implications in that we can steer patients who test positive for this splice variant away from enzalutamide and offer them chemotherapy and/or radiation. —Emmanuel Antonarakis, MBBCh

enzalutamide and whose disease would progress more quickly, according to an early study presented at the 2014 Annual Meeting of the American Association for Cancer Research (AACR) in San Diego.1 This was the first presentation of these data. “AR-V7 is detectable in [circulating tumor cells] in a subset of [castration-resistant prostate cancer] patients and seems to predict resistance to enzalutamide. We believe these data have immediate clinical implications in that we can steer patients who test positive for this splice variant away from enzalutamide and offer them chemotherapy and/or radiation,” said Emmanuel S. Antonarakis, MD, Assistant Professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. “Further, the availability of a blood biomarker for AR-V7 could fuel the development of novel therapies targeting this aberrant version of the androgen receptor.”

Multiple Mechanisms During the discussion following this presentation, Dr. Antonarakis said that there are multiple potential mechanisms responsible for resistance. “We are not postulating that AR-V7 is the only mechanism of resistance to enzalutamide in [castration-resistant prostate cancer] patients,” he noted.

the binding of androgens to the androgen receptor and inhibits nuclear translocation of the androgen receptor. It has been hailed as a miracle drug for some patients, but a significant proportion of patients do not benefit from this agent,” he said. Use of enzalutamide for castration-resistant prostate cancer in the predocetaxel setting is off-label. However, U.S. Food and Drug Administration (FDA) approval for this indication may soon be forthcoming. In the phase III AFFIRM study that led to initial FDA approval of enzalutamide, 21% of patients failed to respond, based on no appreciable decline in prostate-specific antigen (PSA) levels. Although many potential reasons for resistance to the drug have been proposed, Dr. Antonarakis and his colleagues have focused on splice variants of the androgen receptor as one mechanism of resistance. To date, 18 different androgen receptor splice variants have been described. “We believe AR-V7 is the most important variant. These variants are missing the ligand binding domain, which is the direct target of enzalutamide,” he continued.

Key Data The study employed a circulating tumor cell–based AR-V7 assay that has two parts: the Adna Test Prostate Cancer Select

Fine-Tuning Selection for Prostate Cancer Therapy ■■ A preliminary study suggests that the presence of a splice variant of the androgen receptor (AR) gene—AR-V7—can identify patients with castration-resistant prostate cancer who will not respond to enzalutamide. ■■ If confirmed, this simple blood test will be immediately clinically applicable. ■■ Use of this test has the potential to avoid wasted resources and to direct patients to therapies that have a better chance of success

and the Adna Test Prostate Cancer Detect kits (Adna Gen, Langenhagen, Germany). A total of 31 men with castration-resistant prostate cancer about to start treatment with enzalutamide were prospectively enrolled. They provided circulating tumor cell samples at baseline, at the time of response, and at the time of resistance. At the AACR meeting, Dr. Antonarakis presented data only on the baseline samples. Of the 31 patients, 12 (39%) had detectable AR-V7 in their circulating tumor cells; 61% did not. Among patients previously treated with abiraterone (Zytiga), the incidence of detectable AR-V7 increased to 55%, whereas it was detectable in only 9% of those who were abiraterone-naive. None of the patients with detectable AR-V7 responded to enzalutamide according to RECIST criteria or PSA criteria. Every patient who had a prostate-specific antigen (PSA) response had wild-type AR,

although presence of wild-type AR only did not guarantee a response. In addition, the presence of detectable AR-V7 was associated with a 7.4-fold risk of PSA progression and an 8.5-fold risk of clinical/radiographic progression, compared to patients with wild-type AR only. In a multivariate model for response, three factors were independently associated with inferior response: detectable AR-V7, baseline PSA level, and previous abiraterone treatment. In another multivariate assessment, two factors were associated with progression-free survival: the presence of AR-V7 and previous abiraterone therapy. n

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

Reference 1. Antonarakis E, Lu C, Wang H, et al: 2014 AACR Annual Meeting. Abstract 2910. Presented April 7, 2014.

EXPERT POINT OF VIEW

his is an extremely important study,” said Daniel Petrylak, MD, Professor of Medicine and Urology at the Yale School of Medicine in New Haven, Connecticut. “This work needs to be replicated prospectively in a larger group of patients. Right now we have no way to select appropriate first-line therapy for these patients other than clinical parameters,” Dr. Petrylak continued. “None of the patients with the AR-V7 variant responded to enzalutamide. This blood test, if replicated, will give us a way to differentiate patients for therapy.”

None of the patients with the AR-V7 variant responded to enzalutamide. This blood test, if replicated, will give us a way to differentiate patients for therapy. —Daniel Petrylak, MD

Possible FDA Approval Dr. Petrylak said that enzalutamide may be approved by the U.S. Food and Drug Administration (FDA) within the next year for the prechemotherapy setting based on results of the PREVAIL trial, which means that the clinician would have four options for treatment in this clinical state (including abiraterone [Zytiga]/prednisone, radium-223 [Xofigo], and sipuleucelT [Provenge]) in addition to enzalutamide (Xtandi). “Although the data will not help select for the latter three agents, it would seem as if a positive AR-V7 test would exclude enzalutamide as a therapeutic option. This has the potential to save resources and prevent delay of other therapies, which are potentially more effective. It makes no sense to give a drug that you know is not going to work,” Dr. Petrylak commented. Dr. Petrylak said there are several hurdles to obtaining approval for this test, but if approved, “it will be very useful.” This study is a first step. n Disclosure: Dr. Petrylak reported no potential conflicts of interest.

NOW ENROLLING – A RANDOMIZED PHASE III STUDY

A phase III study of the CDK4/6 inhibitor LEE011 in combination with letrozole for the treatment of postmenopausal women with advanced breast cancer Screening assessments

Postmenopausal women with HR+/HER2– advanced breast cancer No prior systemic anticancer therapy for advanced disease

Randomization (1:1)

ECOG performance status 0 or 1 Additional inclusion/exclusion criteria apply.

Letrozole 2.5 mg QD + LEE011 600 mg QD

For more information • Contact your local Novartis medical representative • Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

Letrozole 2.5 mg QD + placebo QD

Primary end point: Progression-free survival Key secondary end point: Overall survival

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

• Visit www.clinicaltrials.gov (NCT01958021)

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available. MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

Novartis Pharma AG CH-4002 Basel, Switzerland

March 2014

G-PIP-1084431

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

The ASCO Post | MAY 15, 2014

PAGE 16

American Association for Cancer Research Annual Meeting Hematology

Early Data for AG-221 Show Unprecedented Activity in Acute Myeloid Leukemia and Myelodysplastic Syndrome By Alice Goodman

lthough the data are preliminary, experts were impressed with responses to a novel IDH2 inhibitor called AG-221 in patients with hematologic malignancies. In the first clinical trial of AG-221, there were three complete remissions,

Eytan Stein, MD

two complete remissions with incomplete platelet count recovery (where platelets had not yet reached 100,000/μL), and one partial remission in patients with re-

lapsed, refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) whose tumors harbored mutated isocitrate dehydrogenase (IDH2).1 These were all patients with limited treatment options and a very poor prognosis. “This is kind of unheard of, but it is very early clinical data and it is an extremely exciting result. These data provide early validation of future directions. We plan to study mutant IDH2 further as a therapeutic target in AML and MDS,” said lead author Eytan Stein, MD, Memorial Sloan Kettering Cancer Center, New York. “These patients have no good treatment options. We give them chemotherapy, but it is not very effective and has substantial toxicity,” he noted. “These complete responses in refractory AML with a drug not nearly as toxic as chemotherapy—one in a patient who

EXPERT POINT OF VIEW

ormal discussant of the AG-221 study presented at the 2014 American Association for Cancer Research meeting, John C. Byrd, MD, of The Ohio State University, Columbus, said, “Congratulations to Dr. Stein for bringing this drug forth.” He continued, “Acute myeloid leukemia (AML) is challenging to treat. The initial introduction of therapies is done in relapsed AML, where secondary aberrations often predominate, with lower likelihood of clinical benefit. AML is often proliferative, and virtually all AML patients have cytopenias.”

The study shows that AML with IDH2 mutations is therapeutically targetable with AG-221. This is a patient-friendly therapy, and it can be moved to combination therapy. —John C. Byrd, MD

About 10% of all adult AML patients have IDH2 mutations, and these occur more frequently with age, Dr. Byrd said. IDH2 levels correlate with progression-free survival and are a good surrogate endpoint.

Impressive Data “We would not expect relapsed AML patients to do very well. It is impressive that 16 patients remain on study. The complete response rate is notable, and there are no dose-limiting toxicities,” he noted. “The study shows that AML with IDH2 mutations is therapeutically targetable with AG-221. This is a patient-friendly therapy, and it can be moved to combination therapy. There are some questions, including the durability of the remissions, how well the drug works for the aggressive IDH2 172 mutation, and whether there are latent side effects. Combinations and sequences will be studied. The future looks interesting for this compound,” Dr. Byrd stated. n Disclosure: Dr. Byrd reported no potential conflicts of interest.

These complete responses in refractory AML with a drug not nearly as toxic as chemotherapy—one in a patient who showed disease progression on bone marrow transplant—are exciting. —Patricia LoRusso, DO

showed disease progression on bone marrow transplant—are exciting,” commented Patricia LoRusso, DO, Karmanos Cancer Institute, Detroit. Dr. LoRusso moderated a press conference at the 2014 Annual Meeting of the American Association for Cancer Research (AACR), where these data were presented. “It is only a phase I trial, and we don’t yet know what these complete responses mean,” she added.

Novel Mechanism In a separate interview, Dr. Stein explained that this study validates the concept that blocking mutant IDH2 dramatically reduces production of the oncometabolite 2-hydroxyglutarate (2HG), which is an abnormal substance produced by mutant IGH2 that interferes with maturation of bone marrow cells. IDH2 mutations have been identified in several solid tumors and hematologic malignancies, including AML and MDS. “We thought that if you blocked IDH2 this would allow the myeloblast to mature into a healthy infection-fighting neutrophil,” he explained. AG-221 (developed by Agios) is an orally available, selective potent inhibitor of the mutated IDH protein. The phase I dose-escalation study enrolled 22 patients with AML or MDS whose cancers were positive for mutated IDH2. Patient cohorts were treated with AG-221 administered in 28-day cycles as follows: 30 mg twice daily, 50 mg twice daily, 75 mg twice daily, or 100 mg/d. The cutoff date for data presentation was March 2014. The regimens of 75 mg twice daily and 100 mg/d are still being evaluated and will continue to be escalated

until a maximum tolerated dose is indentified, Dr. Stein said. The data presented at the AACR meeting were based on 10 patients from the 30-mg and 50-mg cohorts. Patients had progressive or refractory disease after one to four prior therapies; one patient had undergone bone marrow transplantation. Median age was 62.5 years, and all patients had documented IDH2 mutations. Of these 10 patients, 7 were evaluable for efficacy. Of these, six had objective responses as assessed by the investigator, including three complete responses and two complete responses with incomplete platelet recovery. Responding patients are continuing to receive the drug.

Toxicity Findings Thus far, the treatment has been well tolerated. Two patients had severe adverse events, one with elevated white blood cell count and one with confusion and respiratory failure due to disease-related infection. Four patients died within 30 days of study drug termination, all due to disease-related sepsis occurring in cycle 1. Thus far, no dose-limiting toxicities have been identified. Dose escalation is continuing in additional patient cohorts, and cohort expansion is planned for later in the year. n

Disclosure: Drs. Stein and LoRusso reported no potential conflicts of interest.

Reference 1. Stein EM, Tallman M, Pollyea DA, et al. 2014 American Association for Cancer Research Annual Meeting. Abstract CT103. Presented April 6, 2014.

AG-221 in Hematologic Malignancies ■■ A novel therapy directed to the IDH2 mutation holds promise in AML and MDS in patients whose tumors harbor this mutation. ■■ Although preliminary, complete or near-complete responses were obtained in five of seven patients with a poor prognosis. No dose-limiting toxicities have been identified.

The ASCO Post | MAY 15, 2014

PAGE 18

American Association for Cancer Research Annual Meeting Novel Agents

FGFR Inhibitors of Interest in Bladder and Lung Cancer By Alice Goodman

ibroblast growth factor receptor (FGFR) inhibitors are an emerging area of interest in cancer therapeutics. Studies presented at the 2014 American Association for Cancer Research (AACR) Annual Meeting in San Diego provided early encouraging data for two investigational pan-FGFR inhibitors for the treatment of advanced solid tumors driven by FGFR alterations—notably, bladder and lung cancer. Both drugs are oral agents that inhibit FGFR1, FGFR2, FGFR3, and FGFR4, and both are moving into further development for several types of cancer.

JNJ-42756493 The first study showed that the FGFR inhibitor JNJ-42756493 had excellent activity in patients with advanced solid tumors. This phase I trial enrolled 41 patients with various tumor types that had progressed despite previous therapies. All patients enrolled in the trial had normal phosphate levels at baseline. Increased phosphate levels are an on-target effect of FGFR inhibition. As expected, hyperphosphatemia was the most frequent adverse event, occurring in 58% of patients. Other commonly reported adverse events were asthenia (20%), fatigue (60%), and gastrointestinal effects (20%). No cardiotoxicity was observed in these patients. The dose-finding phase of the trial identified 9 mg as the recommended dose for phase II trials. At the 9-mg dose

Rodrigo Dienstmann, MD

level, 7 of 8 patients developed hyperphosphatemia, said lead author Rodrigo Dienstmann, MD, Vall d’Hebron Hospital, Barcelona, Spain. Dr. Dienstmann and colleagues instituted a detailed management approach for hyperphosphatemia that included dose reductions. This approach seemed to reduce the occurrence of hyperphosphatemia. Maximal RECIST responses were seen in patients treated at 6 mg or higher. Responses were observed in patients with FGFR amplification and translocation. Ongoing studies of JNJ-42756493 include efforts to optimize dose and schedule and to analyze biomarkers. Expansion

cohorts are currently enrolling patients with FGFR-aberrant tumors, including lung and breast cancer.

BGJ398 The second study evaluated a panFGFR inhibitor called BGJ398 in patients with solid tumors that expressed FGFR abnormalities. Study results suggested that bladder cancer and lung cancer are particularly susceptible to FGFR inhibition. “About 15% of bladder cancer patients have FGFR mutations, and an additional 6% have an FGFR translocation. About 21% of non–small cell lung cancer patients have FGFR abnor-

EXPERT POINT OF VIEW

“F

GFR abnormalities have been reported in many cancers, including breast, lung, and bladder cancers. While the types of events that occur in these cancers are different, preclinical evidence supports a role for oncogenesis in each of these types,” said formal discussant of the FGFR inhibitor studies presented at the American Association for Cancer Research Annual Meeting, Paul K. Paik, MD, of Memorial Sloan Kettering Cancer Center, New York. Paul K. Paik, MD “However, there is not a 100% correlation in preclinical models between response to FGFR inhibitors and FGFR abnormalities.” Both abstracts showed that the respective drugs have good selectivity and potency as kinase inhibitors, and both study designs were similar, Dr. Paik said.

Early Data

Lecia Sequist, MD

malities,” explained lead author Lecia Sequist, MD, of Dana-Farber Cancer Institute, Boston. “We specifically enrolled only patients with FGFR genetic alterations in their tumors because we predicted that these patients would have the greatest chance of benefiting from the drug,” she said. Dr. Sequist commented that the results in patients with bladder cancer were “exciting” because these patients have few treatment options. The phase I study she reported included dose-escalation and dose-expansion phases. In the dose-escalation phase, patients were treated with oral BGJ398 once or twice a day in a 28-day cycle. The maximum tolerated dose was defined as 125 mg. Ongoing dose-expansion cohorts include squamous cell NSCLC and bladder cancer. Of 95 bladder cancer patients

“Overall, these studies provide an early signal of promising activity in bladder cancer and outlier activity in lung and breast cancer,” Dr. Paik said. These are early data, he emphasized, and there are several outstanding issues related to response, including whether FGFR amplification alone is a sufficient driver event, whether drug concentration sufficient for FGFR1 inhibition in the amplified setting is being attained, and whether there is a role for ligand binding inhibition or alternative pathway activation. “Mutation and fusion events appear to have a higher predictive value, and gene amplification less so. Future research will tell us more about these compounds and the subtleties involved in targeting them,” Dr. Paik said. n Disclosure: Dr. Paik has received research funding from AstraZeneca and GlaxoSmithKline.

59 years. Thirty-eight percent had breast cancer, 34% had lung cancer, and 9% had bladder cancer. Eight patients remain on treatment at the time of the AACR meeting. Most withdrawals were due to disease progression. At the maximum tolerated dose, 87% of patients developed hyperphosphatemia, 43% had stomatitis, 34% had decreased appetite, 23% had fatigue, 30% had alopecia, and 15% had nausea. These adverse events were mainly mild to moderate. “Hyperphosphatemia is an on-target expected effect that is manageable with dietary restriction, phosphate-lowering therapy, and dose interruptions. We found that an intermittent dosing schedule reduced

FGFR Inhibitors in Cancer Therapy ■■ FGFR inhibitors appear to have good activity in cancers driven by FGFR3 mutations and other FGFR alterations. ■■ Side effects are predictable and mainly include hyperphosphatemia, stomatitis, alopecia, decreased appetite, and fatigue. ■■ Two novel pan-FGFR inhibitors are moving into phase II testing.

screened, 7 (7%) had an FGFR3 mutation; of 147 lung cancer patients screened, 14 (9%) had FGFR1 amplification. The results Dr. Sequist presented were based on 107 patients with a mean age of

hyperphosphatemia, so going forward, 3 weeks on and 1 week off will be our preferred dosing schema,” Dr. Sequist said. A waterfall plot showed tumor shrinkage by RECIST criteria in patients

treated at doses > 100 mg/d, with the most notable responses seen in bladder and lung cancer. In her presentation at AACR, Dr. Sequist focused on the bladder cancer patients. She said the lung cancer data will be presented at this year’s ASCO Annual Meeting. Of six patients with bladder cancer, five with a driver mutation of FGFR3 did very well. Overall response rate was 40%, and disease control rate was 100% in these five patients. The sixth patient had FGFR1 amplification and very aggressive disease. “The key feature [of effective therapy] seems to be selection of patients based on FGFR abnormalities,” she said. n

Disclosure: Drs. Sequist and Dienstmann reported no potential conflicts of interest.

References 1. Dienstmann R, Bahleda R, Adamo B, et al: First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. 2014 AACR Annual Meeting. Abstract CT325. Presented April 8, 2014. 2. Sequist LV, Cassier P, Varga A, et al: Phase I study of BGJ398, a selective panFGFR inhibitor in genetically preselected advanced solid tumors. 2014 AACR Annual Meeting. Abstract CT326. Presented April 8, 2014.

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The ASCO Post | MAY 15, 2014

PAGE 20

American Association for Cancer Research Annual Meeting Breast Cancer

I-SPY 2 Trial ‘Graduates’ Neratinib to Phase III Study in HER2-Positive, Hormone Receptor–Negative Breast Cancer By Alice Goodman

n the targeted-therapy era, it is important to identify subsets of patients who can benefit from novel agents and combinations as quickly as possible. The I-SPY 2 trial is designed to expedite this goal and to change the way that targeted agents are studied and approved. This innovative adaptive trial design evaluates new therapies in specific biomarker- designed subsets of patients, and identifies “graduates” that deserve phase III study. The first results of I-SPY 2, presented at the 2013 San Antonio Breast Cancer Symposium, identified veliparib/carboplatin added to standard neoadjuvant therapy as the first regimen to graduate for the signature of triple-negative breast cancer.1 The second graduate—neratinib (a small-molecule inhibitor of HER2) plus standard neoadjuvant therapy in HER2-positive, hormone receptor–negative breast cancer—was announced at the 2014 Annual Meeting of the American Association for Cancer Research (AACR) in San Diego.2 That combination will now move to phase III testing in HER2-positive, hormone receptor–negative breast cancer.

56% vs 33% among patients treated with chemotherapy alone. Researchers found that the regimen had a 95% probability of superiority vs standard therapy and a 79% likelihood of success vs trastuzumab (Herceptin) plus paclitaxel in a phase III trial. Neratinib did not show promise in any of the other biomarker-defined subsets of breast cancer evaluated in I-SPY 2, and the drug was associated with a high frequency of diarrhea, which was often severe and required supportive care. I-SPY 2 uses a prespecified and automated algorithm, and randomization probabilities are updated as the study proceeds, according to biomarker signature, magnetic resonance imaging, and pathologic complete response results. Randomization is based on performance of regimens within eight biomarker subtypes/signatures. Theoretically, an agent is eligible for graduation in 10 clinically relevant signatures.

Study Details

EXPERT POINT OF VIEW

ommenting on the I-SPY 2 neratinib results presented at the 2014 American Association for Cancer Research Annual Meeting, Edith Perez, MD, Deputy Director at Large, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, said that results were consistent with other data. “Testing for HER2 is important. These data corroborate that there is a higher chance of response [to neratinib] in the neoadjuvant setting in patients with estrogen reEdith Perez, MD ceptor–negative breast cancer,” she said. The issue of toxicity with neratinib is of concern, Dr. Perez continued. “There is a very high degree of diarrhea with paclitaxel/neratinib, and this will make it difficult for this regimen to compete with other HER2-directed agents like lapatinib [Tykerb],” she said. “In spite of prophylaxis, a significant number of patients still suffered from grade 3 diarrhea, consistent with at least seven episodes in a day or need for intravenous fluids for ≥ 24 hours.” “It is important to conduct these types of trials,” she said. “It would also be important to look at subsets of patients with brain metastases to see if these drugs are of benefit. Another interesting triplet to study in phase III would be pertuzumab [Perjeta], trastuzumab, and neratinib.” n Disclosure: Dr. Perez has received research funding from Genentech and GlaxoSmithKline.

rector of the Carol Frank Buck Breast Care Center at USCF Helen Diller Family Comprehensive Cancer Center, San Francisco, and Donald A. Berry, PhD, Professor of Biostatistics at The University of Texas MD Anderson Cancer Center and founder of Berry Consultants, Houston.

The study enrolls patients with stage II breast cancer and tumor size of a least 2.5 cm considered at high risk for early recurrence according to MammaPrint results. The algorithm randomly assigned 116 patients to the Key Findings arm of the trial testing neratinib, a pan“I-SPY 2 is designed to accelerate HER inhibitor. the process of identifying drugs that Pathologic complete response rates Need for Biostatistical Support Thomas J. Lynch, MD, who modon the neratinib arm were compared with those of 78 pa- erated a press conference where these tients concurrently random- data were presented, said that this ized to the control arm treated approach promises to be more effiwith standard chemotherapy, cient than previous models of clinifor all 10 predefined biomark- cal trials. “This approach reduces the er signatures. The probability number of patients treated with older of superiority to control and therapies and increases the number success in a phase III trial are of patients who will be treated with calculated by a specially de- more innovative therapies,” he said. Donald A. Berry, PhD Laura J. Esserman, MD He noted that the adaptive randomsigned model for this trial. are effective for breast cancer subtypes Principal investigators for I-SPY 2 ization design depends on adequate and to reduce the cost, time, and num- are Laura J. Esserman, MD, Profes- biostatistical support, which could bers of patients needed to get effective sor of Surgery and Radiology and Di- be a limitation. Dr. Lynch is Director drugs to market,” stated John W. Park, MD, Professor of Medicine at the Neratinib Advances in I-SPY 2 USCF Helen Diller Family Comprehensive Cancer Center in San Francis■■ An innovative adaptive trial called I-SPY 2 promises to accelerate the co. Dr. Park presented results of I-SPY process of identifying predefined subsets of patients who can benefit 2 at the AACR meeting. from targeted therapies. Results of I-SPY 2 showed that the ■■ Using this innovative approach, neratinib was deemed worthy of phase III combination of neratinib plus stantesting in HER2-positive, hormone receptor–negative breast cancer. dard neoadjuvant therapy achieved a ■■ Neratinib causes severe diarrhea. pathologic complete response rate of

Thomas J. Lynch, MD

of the Yale Cancer Center in New Haven, Connecticut. n

Disclosure: I-SPY 2 is sponsored by Quantum Leap Healthcare Collaborative, a 501(3)C charitable foundation. Dr. Berry is co-owner of Berry Consultants, LLC. Berry Consultants designs adaptive clinical trials—including some in oncology—for pharmaceutical companies, medical companies, and NIH cooperative groups. Drs. Esserman and Park reported no potential conflicts of interest.

References 1. Rugo HS, Olapade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the ISPY 2 trial. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013. 2. Park JW, Liu MC, Yee D, et al: Neratinib plus standard neoadjuvant therapy for highrisk breast cancer: Efficacy results from the I-SPY 2 trial. 2014 AACR Annual Meeting. Abstract CT227. Presented April 7, 2014.

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The ASCO Post | MAY 15, 2014

PAGE 26

American SocietyNational of Preventive Oncology Annual Meeting ACCC Annual Meeting Survivorship

Promoting Health Behaviors Among Cancer Survivors New model of survivorship care needed, experts say By Caroline McNeil

romoting healthy behaviors among cancer survivors is associated with improved quality of life according to many studies. But how to translate that evidence into community practice remains a huge question, and the need for answers is growing.

Catherine Alfano, PhD

It’s not only the lack of consensus on how to help cancer survivors adopt and maintain healthy behaviors—the who, what, and where—that make this an urgent problem, said Catherine Alfano, PhD, of the National Cancer Institute (NCI), speaking at the annual meeting of the American Society of Preventive Oncology (ASPO) in March. Other factors include the burgeoning number of cancer survivors (including older survivors); the expectations of the baby boom generation for returning to active lifestyles with high quality of life; and the projected shortage of oncologists, primary care providers, and nurses. “We are facing a perfect storm,” she said. “From my perspective at the National Cancer Institute, there is only one way out of it: We must create a new model of survivorship care that focuses on helping cancer survivors manage their own health after cancer—preventing or alleviating problems through healthy behaviors such as exercise, a healthy diet, and maintaining a healthy body weight.” Dr. Alfano and other speakers emphasized that the traditional medical model, in which oncologists ask about health behaviors during routine followup appointments, has had limited impact. New models have emerged within

the survivorship programs of some major cancer centers. But there is a need to know what works outside these major centers, in communities where most cancer survivors live, she said.

Traditional Model The traditional model has potential advantages but also significant barriers. On the plus side, physicians and other health providers are seen as credible sources, noted Bernadine Pinto, PhD, of The Miriam Hospital and W. Alpert Medical School of Brown University, Providence, Rhode Island. And followup oncology visits, which typically continue for about 5 years, seem to provide a ready-made opportunity to discuss lifestyle issues and health behavior change. Yet health behavior counseling is often not provided. The lack of office systems to incorporate this kind of counseling is one barrier, Dr. Pinto said. Moreover, many oncologists have the perception that patients don’t want and won’t accept suggestions for lifestyle change. She cited one survey in which fewer than 10% of survivors said a physician had asked about lifestyle issues.

Bernadine Pinto, PhD

More focused health provider efforts may have some benefit, but it is not clear how much. One recent randomized trial among breast cancer survivors compared extended advice about exercise (personal counseling plus follow-up phone calls) to brief advice (counseling alone).1 While extended advice was effective in the short-term, and brief advice was also found to have some ben-

Cancer Survivorship: Research Into Practice ■■ There is an urgent need to translate what we know about health promotion programs for cancer survivors into community practice. ■■ Community-based programs and those that support self-management are promising new models. ■■ Research is urgently needed on these and other policy and implementation issues.

efit, it was “not enough to conclude that provider advice alone was sufficient to change behaviors,” Dr. Pinto said. Some comprehensive cancer centers have developed more comprehensive programs. Both The University of Texas MD Anderson Cancer Center in Hous-

Well With Chronic Illness.2 The report addresses models for long-term management of arthritis, diabetes, and other conditions, including those common in cancer survivors, such as lymphedema and fatigue. Support for communitybased efforts and for self-management

We have the models, we know the science. Now the question is, how do we move these models of care into the community in successful ways? —Karen Syrjala, PhD

ton and Memorial Sloan Kettering Cancer Center in New York, for instance, offer disease-specific survivorship clinics, which include medical assessments and health behavior recommendations. The Fred Hutchinson Cancer Research Center, Seattle, refers patients to a survivorship clinic at the Seattle Cancer Care Alliance and provides educational and supportive programs. But in most clinical settings, survivorship care is still medically and symptom focused, said Karen Syrjala, PhD, of Fred Hutchinson. Reimbursement for more extended programs is problematic, and there are few standards and guidelines for such programs (although she noted that the National Comprehensive Cancer Network and the American Society for Bone Marrow Transplant have issued guidelines recently.)

Community-Based Programs In one emerging model, community organizations and programs are playing a significant role. The YMCA’s LIVESTRONG program, for instance, has fitness instructors trained in the elements of cancer, post-rehab exercise, and supportive cancer care and who work with individual survivors to tailor a program to their needs. These have many advantages she said, especially for the majority of cancer survivors who live far from major cancer centers. “This is what I really want to recommend today,” Dr. Syrjala said. Community-based programs are a strong theme in a 2012 report from the Institute of Medicine (IOM), Living

is among its recommendations. The cancer community can learn from these, said Karen BasenEngquist, PhD, MPH, of MD Anderson, who served on the IOM committee that prepared the report. For example, we know that there is often poor adherence to recommendations, and that reimbursement is limited.

More Research One conclusion of the IOM report was that more research is needed on how to implement such programs. Symposium speakers agreed: “We have the models, we know the science. Now the question is, how do we move these models of care into the community in successful ways?” Dr. Syrjala said. “We need more of the right kind of evidence,” added Dr. Alfano. It’s important to know the benefits and costs at multiple levels—those of the survivor,

Karen Basen-Engquist, PhD, MPH

family, provider, and the health-care system, she said. Dr. Alfano, the appointed discussant of the symposium, also stressed the need to recognize and work within continued on page 28

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The ASCO Post | MAY 15, 2014

PAGE 28

ACCC Annual National Meeting Clinical Trials

Workshops Train Community Cancer Center Nurses and Administrators to Implement Clinical Trials

series of new workshops are teaching nurses and administrators from community hospital cancer programs how to promote, run, and improve their institutions’ clinical trials. The training focuses on specific skills and tasks, offers postcourse support and aims for longterm, measurable outcomes, including an increase in accruals. Although 85% of cancer patients are treated at the community level, many patients have to travel to a major cancer center to participate in a clinical trial. This was part of the rationale behind the training, said Regina Cunningham, RN, PhD, Chief Nursing Executive at the Hospital of the University of Pennsylvania and one of the designers of the workshops. Distance is a known barrier to participation in trials, she said, speaking at the Annual Meeting of the Association of Community Cancer Centers (ACCC) in March. Only 5% of cancer patients in the United States participate in cancer clinical trials.

Regina Cunningham, RN, PhD

Promoting Health Behaviors continued from page 26

the “diverse places people can get survivorship care in our system.” Other major issues that need to be addressed, she said, are reimbursement for lifestyle interventions, promoting maintenance of lifestyle change (an issue that might influence reimbursement), and health behavior change in families that would support survivors’ health behaviors over time. What is it going to take to get all of

NCI-Funded Program Training Community Nurses and Administrators to Implement Cancer Clinical Trials is funded through a

The workshops focus on practicalities, including billing and financial issues, data management, regulatory and legal issues, working with clinical trial sponsors, and ensuring quality. grant from the National Cancer Institute. The principal investigators, in addition to Dr. Cunningham, are Marcia Grant, RN, DNSc, at City of Hope in Duarte, California, and William Redd, PhD, of Mount Sinai in New York. The workshops focus on practicalities, including billing and financial issues, data management, regulatory and legal issues, working with clinical trial sponsors, and ensuring quality. Over the course of 2 days, experts in cancer clinical trials provide small-group training on specific skills, such as marketing, recruitment, and developing an infrastructure to support clinical trials. this done? A March 2014 paper from NCI stresses the need for collaboration.3 Authored by Dr. Alfano and others, it focuses on physical activity, but its conclusions could apply to other health behaviors in the context of survivorship care: “Overall, we recommend that physical activity and cancer survivorship research employ additional study designs, include relevant stakeholders and be more collaborative, integrated, contextual, and representative in terms of both setting and participants.”

Participants develop specific goals for 6, 12, and 18 months. Goals are task-oriented; for instance under infrastructure, a goal might be to refine or create a patient tracking form or develop a computed tomography screening form. Under communication, a goal might specify developing a poster and/or a brochure for physicians’ offices.

Eligibility Requirements

Program Evaluation Evaluation of the training will include “hardcore outcomes,” said Dr. Cunningham, including the number of clinical trials opened, the number of patients screened, and the number of patients accrued at specified intervals after the training is completed. Baseline data are collected during the application process. Participant evaluations of the curriculum and its usefulness specifically to administrators and nurses will also be collected. The workshops, each of which can accommodate about 40 people,

Nurses and administrators from programs accredited by the American College of Surgeon’s Commission on Cancer may apply to attend the free workshops, with preference given to nurses and administrators who apply as a team. The Commission on Cancer recently revised its accreditation standards, requiring that cancer programs recruit at least 2% of their patients into clinical trials—anMarcia Grant, RN, DNSc William Redd, PhD other reason behind the creation of the training program, said Dr. will take place twice a year through Cunningham. 2017. The first two workshops were Following the workshop, trainees held last year at City of Hope and at review their goals in monthly phone Mount Sinai. Future workshops incalls led by faculty who also present a clude one in Monrovia, California, topic, answer questions, and address June 5–6, 2014. A fall workshop will problems. Trainees also have ongoing be held on the East Coast. For adaccess to faculty via email and to other ditional information, visit http:// resources on a discussion board. clinical-trials-training.org. n At the ASPO symposium, Dr. Alfano echoed that conclusion, referring to an old African proverb: If you want to go fast, go alone; if you want to go far, go together. n Disclosure: Drs. Pinto, Alfano, Syrjala, and Basen-Enquist reported no potential conflicts of interest.

References 1. Pinto BM, Papandonatos GD, Goldstein MG: A randomized trial to promote physical activity among breast cancer pa-

tients. Health Psychol 32:616-626, 2013. 2. Institute of Medicine: Living Well With Chronic Illness: A Call for Public Health Action. Washington, DC, National Academies Press, 2012. Available at www. iom.edu. 3. Phillips SM, Alfano CM, Perna FM, et al: Accelerating translation of physical activity and cancer survivorship research into practice: Recommendations for a more integrated and collaborative approach. Cancer Epidemiol Biomarkers Prev. April 4, 2014 (early release online).

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | MAY 15, 2014

PAGE 29

Targeted Anticancer Therapies International Congress ACCC Annual National Meeting Targeted Therapy

Belinostat Moves Forward in Trials for Two Aggressive Cancers By Caroline McNeil

n February, the U.S. Food and Drug Administration (FDA) granted belinostat (Beleodaq), a targeted histone deacetylase (HDAC) inhibitor, priority review status based on a pivotal phase II trial in peripheral T-cell lymphoma. Just 1 month later, researchers at the National Cancer Institute (NCI) in Bethesda, Maryland, reported that belinostat combined with simultaneous chemotherapy in a phase I trial had produced partial responses in solid tumors, including small cell lung cancer. Plans for a multicenter, randomized phase II trial are now under discussion, according to Sanjeeve Bala, MD, a staff clinician in the Developmental Therapeutics Branch at NCI’s Center for Cancer Research, who reported the phase I results at the 12th International Congress on Targeted Anticancer Therapies,1 hosted by Georgetown’s Lombardi Cancer Center in Washington, DC, March 5–7.

Sanjeeve Bala, MD

Both peripheral T-cell lymphoma, which is a type of non-Hodgkin lymphoma, and small cell lung cancer are aggressive, hard-to-treat cancers that, although rare, are (when considered together) diagnosed in tens of thousands of patients each year in the United States. Belinostat is being studied in small cell lung cancer for its ability to synergize with combination chemotherapy and in peripheral T-cell lymphoma as a single agent. Its success in early trials has raised hope that patients may soon have expanded treatment options. In the case of peripheral T-cell lymphoma, that could be very soon; the FDA’s decision, under the priority review process, is due August 9.

though it was a phase I, dose-finding trial in relapsed or advanced disease, partial responses were seen in 7 of 26 participants, 13 of whom completed six cycles. Three of the four patients with

Susan Bates, MD

small cell lung cancer who completed six cycles had partial responses. The availability of a continuous infusional regimen for this agent may be the key to its success in this setting, said Dr. Bala. Continuous intravenous administration allows the targeted agent to be given simultaneously with chemotherapy. And that appeared to be more effective than sequential administration in preclinical studies, which were conducted by the laboratory of Susan Bates, MD, Head of Molecular Therapeutics in the Medical Oncology Branch at NCI, who developed the current research protocol. The effectiveness of simultaneous rather than sequential administration is plausible in light of what is known about how HDAC inhibitors work, Dr. Bala noted. Inhibitors like belinostat block HDAC, thereby increasing transcription and making more cancer cell DNA available for destruction by the

addition to increasing transcription, could influence various other functions that lead to cell death. One aspect that lent further support to the trial, he said, was the observation that small cell lung cancer cells were also very sensitive to belinostat alone. The next step for belinostat in small cell lung cancer is still under discussion but will probably be a randomized phase II trial comparing simultaneous intravenous belinostat and chemotherapy to chemotherapy alone. “We are still in the process of thinking through these plans,” Dr. Bala said, “but it will need to be a multicenter trial.” Such a

Owen A. O’Connor, MD, PhD

trial is expected to enroll relapsed patients with small cell lung cancer and perhaps patients with small cell cancers from other primary sites.

Peripheral T-Cell Lymphoma Belinostat was used as a single agent in the peripheral T-cell lymphoma trial, a randomized phase II study involving 129 patients with recurrent or relapsed disease, first reported at the 2013 ASCO Annual Meeting.2 Known as the BELIEF trial, this investigation was led by Owen

Belinostat in Development ■■ Belinostat (Beleodaq) is in development as a targeted HDAC inhibitor that is being studied in small cell lung cancer for its ability to synergize with combination chemotherapy, and in peripheral T-cell lymphoma as a single agent. ■■ The studies in peripheral T-cell lymphoma have opened the way for possible approval by the Food and Drug Administration within 6 months. ■■ Both peripheral T-cell lymphoma and small cell lung cancer are aggressive and hard-to-treat cancers that, although rare, are (when considered together) diagnosed in tens of thousands of patients each year in the United States.

Small Cell Lung Cancer For small cell lung cancer, the NCI researchers used an infusional form of belinostat and delivered it simultaneously with the standard chemotherapy drugs etoposide and cisplatin. Al-

chemotherapy drugs. Simultaneous administration of chemotherapy and belinostat could optimize this synergy. Other mechanisms may also be at play, Dr. Bala added, as blocking HDAC, in

A. O’Connor, MD, PhD, Professor of Medicine and Experimental Therapeutics, and Director of the Center for Lymphoid Malignancies at Columbia University Medical Center in New York.

The BELIEF trial showed an overall response rate of 26% to 28% among all participants. In patients with platelet counts above 100,000/μL, the rate was 28%, and in patients with a subtype of peripheral T-cell lymphoma called angioimmunoblastic T-cell lymphoma, it was 45.5%. In this study, belinostat was administered as an intravenous infusion on a daily-for-5-days schedule. One advantage to belinostat in this setting may be its low toxicity. Compared to other agents with activity in peripheral T-cell lymphoma, it is less toxic to bone marrow, an advantage especially in previously treated patients who may have poor bone marrow reserve. Its safety profile also makes it potentially easier to combine with chemotherapy, according to Topotarget A/S, the Scandinavian-based company that is developing the drug along with its U.S. partner, Spectrum Pharmaceuticals. While the FDA has granted belinostat priority review, the company has also moved ahead to lay the groundwork for a phase III trial that would confirm and extend the findings in the BELIEF trial. The plan is to study belinostat combined with the quartet of chemotherapy drugs known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). The combination (BelCHOP) will be compared to a control group treated with CHOP alone. The peripheral T-cell lymphoma phase III trial is expected to begin in 2015, TopoTarget said in a statement. n Disclosure: Drs. Bala, Bates, and O’Connor reported no potential conflicts of interest.

References 1. Bala S, Bryla C, Redon C, et al: Phase I trial of belinostat, a potent histone deacetylase inhibitor (HDI), in combination with cisplatin (Cis) and etoposide (Etop). International Congress on Targeted Anticancer Therapies. Abstract O3.4. Presented March 5, 2014. 2. O’Connor OA, Masszi T, Savage KJ, et al: Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial. 2013 ASCO Annual Meeting. Abstract 8507. Presented June 1, 2013.

The ASCO Post | MAY 15, 2014

PAGE 30

National Comprehensive Cancer Network Annual Conference Hematology

Andrew D. Zelenetz, MD, PhD, on Treating the Elderly Lymphoma Patient With Elevated Bilirubin By Caroline Helwick

t the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), lymphoma expert and NCCN Panel Chair on Lymphoma, Andrew D. Zelenetz, MD, PhD, fielded questions from oncologists. The ASCO Post was there to capture his recommendations for a common clinical scenario—treating the elderly patient with elevated bilirubin. Dr. Zelenetz is Vice Chair of the Department of Medicine and former Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York.

sonable chemotherapy option in a patient with suitable cardiac function is Rmini-CHOP [prednisone at 40 mg/m2 on days 1–5, rituximab at 375 mg/m2 on day 1, doxorubicin at 25 mg/m2 on day 1, cyclophosphamide at 400 mg/

dose-adjusted EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab). “Because of the dosing of the drugs by continuous infusion over 96 hours, you can give full doses and

While the older patient with large cell lymphoma and elevated bilirubin may have a somewhat worse prognosis that some, he still has the potential for a curative outcome. —Andrew D. Zelenetz, MD, PhD

Clinical Scenario

with this regimen. In fact, R-GemOx has become my go-to treatment for relapsed or refractory disease in the older patient who is not a transplant candidate,” he said. R-GemOx is now included in the NCCN Guidelines, he added, and there are no problems with reimbursement now that oxaliplatin is available generically. Dr. Zelenetz said he gives this regimen to any patient who is not a transplant candidate, “which at Memorial is a patient age 70 or older, but we have given this to patients in their 90s,” he added.

Not Recommended

The patient is an 80-year-old who presented with monoclonal gammopathy. At 3 months’ follow-up, he had weight loss and jaundice, with splenic and liver lesions, a bilirubin of 10 mg/dL and climbing, and an ejection fraction of 40%. The biopsy revealed large cell lymphoma that was CD20-positive. How would you treat this patient? “For the older patient with elevated bilirubin, you have a few good options, some of them rather surprising,” Dr. Zelenetz said. The obvious option, “which is easy,” he added, is to give rituximab [Rituxan] (375 mg/m2), high-dose prednisone (100 mg), and cyclophosphamide (1.0–1.2 g/m2). “Don’t worry that this dose of cyclophosphamide is too high; you are not giving an anthracycline. The goal for this cycle is not to provide definitive therapy but to get adequate cytoreduction to reduce the bilirubin and permit definitive treatment,” he explained. Once the bilirubin has dropped (it need not completely normalize), a rea-

m2 on day 1, vincristine at 1 mg/m2 on day 1]. “R-mini-CHOP has been used in patients with ejection fractions as low as 45% and the results are remarkably good, so this is a reasonable option for older patients,” he maintained.

Less Conventional Options A new and “surprising” option is to substitute gemcitabine for the anthracycline in R-CHOP, according to Dr. Zelenetz. This involves gemcitabine at 750 mg/m2 for the first cycle, increasing to 875 mg/m2, then to 1,000 mg/ m2 by the third cycle if tolerated, for six cycles; all cycles are supported by growth factors. The results in terms of progression-free and overall survival are similar to those seen with R-miniCHOP, and, importantly, outcomes are not diminished in patients with low ejection fractions, making this a good choice for elderly patients, he indicated. The third approach is rather unconventional, Dr. Zelenetz acknowledged. The patient is treated from day 1 with

you never get to a very high Cmax. The ejection fraction is maintained so you don’t get cardiac toxicity, and you do not have issues with drug clearance,” he pointed out. “We give dose-adjusted EPOCH-R from the get-go, with doses based on nadir counts. You can use either pegfilgrastim [Neulasta] or filgrastim [Neupogen]; they are associated with the same rate of dose adjustments,” he said. “The other regimen that is remarkably good in older patients—even patients over the age of 90—is rituximab/ gemcitabine/oxaliplatin (R-GemOx),” he continued. R-GemOx (rituximab at 375 mg/m2 on day 1, gemcitabine at 1,000 mg/m2 on day 2, oxaliplatin at 100 mg/m2 on day 2) is very well tolerated in older patients, which Dr. Zelenetz acknowledged is somewhat unexpected. “I was nervous the first time I gave this to a patient, but he flew through it without a problem, and since then I have treated a series of older patients

One regimen that is being used by some clinicians but is not recommended by Dr. Zelenetz is bendamustine (Treanda)/ rituximab. “According to market research, this regimen began to be commonly used in older patients with large cell lymphoma in the relapsed/refractory setting, in the absence of published data. But now there have been two studies in de novo large cell lymphoma, and while the overall response rates are pretty good, the response duration is miserably short,” he said. “While the older patient with large cell lymphoma and elevated bilirubin may have a somewhat worse prognosis that some, he still has the potential for a curative outcome,” he emphasized. “I would not recommend bendamustine/rituximab. I would use one of the three curative regimens I described.” n Disclosure: Dr. Zelenetz has received research support from Genentech/Roche, Gilead, Janssen/Pharmacyclics, and BristolMyers Squibb, is a consultant for Genentech/ Roche, Gilead, Sanofi-Aventis, Hospira, and Dr. Reddy Laboratories, and is on the scientific advisory board for Lymphoma Research Foundation and Cancer Genetics Institute.

Don’t Miss These Important Reports in This Issue of The ASCO Post Leonard Saltz, MD, on Rectal Cancer see page 86

Martin J. Heslin, MD, MSHA, on Pursuing a Business Degree after a Medical Degree see page 175

Visit The ASCO Post online at ASCOPost.com

Walter F. Baile, on Breaking Bad News to Patients see page 211

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a doselimiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non– small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non–Small Cell Lung Cancer (NSCLC) Study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase 3 MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the pancreatic adenocarcinoma study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

ABRAXANE is also indicated in MBC and NSCLC ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. • The primary end point in the metastatic breast cancer (MBC) phase 3 trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. • The primary end point in the NSCLC phase 3 trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms.

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 100 800 1st dose reduction 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 8 4 Severe Symptomsd Asthenia Any Symptoms 47 39 8 3 Severe Symptomsd Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

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

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 2 25 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral 227 (54%) 70 (17%) 51 (13%) 3 (1%) neuropathya Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract 47 (11%) 10 (2%) 20 (5%) 1 (<1%) infectionsb Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_ALL_HCP_BSv007 10_2013

The ASCO Post | MAY 15, 2014

PAGE 38

National Comprehensive Cancer Network Annual Conference Health-Care Policy

The Affordable Care Act: NCCN Panelists Rate It ‘Average’ By Caroline Helwick and Susan Reckling

ncologists and third-party payers are already experiencing changes as a result of the Affordable Care Act, which earned an “average” rating by a panel of providers, payers, and patients assembled at the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida. In an NCCN Roundtable titled, The Affordable Care Act: Where Are We Now? they shared their perspectives about the Affordable Care Act’s successes and failures, its impact on contemporary oncology practices, and the potential for the newly insured population to shake up the economics of cancer care. The panelists rendered the Affordable Care Act a grade of 5 on a scale of 0 (“a flop”) to 10 (“the most effective program ever”), when asked to rate it by Round oodman, table moderator Clifford G PhD, who is Senior Vice President and Principal at The Lewin Group, Falls

Medical Director of Oncology Services at the University of Colorado Hospital.

New Risk Pools

John C. Winkelmann, MD

and undergoing routine cancer screenings. In turn, oncologists are seeing an influx of these new patients, many of whom present with complex cases due to delayed diagnosis, according to John C. Winkelmann, MD, of Oncology Hematology Care, Cincinnati.

Dr. Fowler explained that this poses risk in oncology because, when the Affordable Care Act was first implemented, healthy patients younger than 35 were expected to sign up in droves. Instead, the current enrollee is middleaged, a population more likely to have cancer and comorbidities and to require more expensive treatment. With more patients potentially requiring more expensive cancer care, Dr. Goodman asked the payer representatives how they assess their risk pools. Both acknowledged that at this early point in time, the necessary claims data are not available to adjust premiums, and may not be available for a while. “You do what you can to manage your risk,” said Lee N. Newcomer, MD, MHA, Senior Vice President of UnitedHealthCare. “You start slow and learn,

W. Thomas Purcell, MD, MBA

Clifford Goodman, PhD

Church, Virginia. The ASCO Post has summarized the discussion below.

Has the Profile of Cancer Patients Changed? Enrollees of the Affordable Care Act–associated insurance programs appear to be previously uninsured or underinsured, and somewhat older and sicker than typical oncology patients, panelists noted. “The hope was that 40% of the enrollment would be in the younger population, under 35, but what we are seeing is that it is closer to 25% to 27%,” said Elizabeth J. Fowler, PhD, JD, Vice President of Global Health Policy at Johnson & Johnson. Dr. Fowler previously served as Special Assistant to the President for Health Care and Economic Policy at the National Economic Council and played a role in developing the Senate version of health reform. In Kentucky, due to the well-run state exchange and Medicaid expansion, many adult patients are seeing a primary care physician for the first time

At the University of Colorado Cancer Center, Aurora, physicians are seeing more medically indigent adults and newly underinsured patients, now being insured within a narrow network and therefore lacking the access to comprehensive care that was previously available through employer-sponsored programs. These groups qualify for Medicaid or have purchased “bronze packages” with large copays or deductibles, noted W. Thomas Purcell, MD, MBA, Executive

The intent of the [Affordable Care Act] was to move us from a fee-for-service system that rewards volume to a system that rewards value and looks at outcomes and quality. —Elizabeth J. Fowler, PhD, JD

Better coverage for more Americans, especially with certain provisions like screening, is good for people. —Michael Kolodziej, MD

network is defined by cost, the decision is based purely on cost, and the quality aspect may be an issue,” he added.

What Are the Problem Areas? “I hear from patients all the time about difficulties signing up,” said Mohammed S. Ogaily, MD, Medical Director of the Oakwood Center for Hematology and Oncology in Detroit, and President of the Michigan Society of Hematology and Oncology. Dr. Newcomer flagged the unintended consequence of making quick deci-

Lee N. Newcomer, MD, MHA

like with any other new process…. We will be ready to get fully committed and expand as soon as we understand how it’s going to work.” Michael Kolodziej, MD, National Medical Director of Oncology Strategy for Aetna, agreed, commenting, “Given the uncertainty, you manage what you can manage. Many of the strategies to manage the risk of this unknown pool are the same strategies we use to manage the risk in the pool that we do know about.” According to the panel, risk is not only on the horizon for payers and providers, but also for patients. Those who should be particularly concerned are patients with rare cancers, since they require state-of-the-art treatment that is not always available in the community setting. They seek care at larger, academic centers that are not within their narrow network and are forced to pay for their care out of pocket, noted Dr. Purcell. “What worries me is that the narrow

Mohammed S. Ogaily, MD

sions in the design of the bill, and commented on the need to reprogram or reverse initial regulations and policies, which had financial consequences for insurers. “Getting to that point of stability, where decisions are made and we can move forward, will be a good thing for consumers, payers, and the government,” he suggested. “What’s missing from the [Affordable Care Act]?” Dr. Goodman asked. Dr. Winkelmann suggested that oncology societies such as ASCO would prefer more explicit provisions for clinical trial enrollment, so that interested patients would not be financially penalized. Dr. Newcomer said he would add

ASCOPost.com | MAY 15, 2014

PAGE 39

National Comprehensive Cancer Network Annual Conference a “medical necessity clause” that would create incentives for choosing the most cost-effective option from among the many offered in the NCCN guidelines.

Shift Toward Rewarding Value Dr. Newcomer’s suggestion that cost-effectiveness be a part of any new health-care model led to a larger discussion of the need to move away from the current reimbursement system. “The intent of the [Affordable Care Act] was to move us from a fee-for-

service system that rewards volume to a system that rewards value and looks at outcomes and quality,” explained Dr. Fowler. “Financial incentives keep us locked into old models,” added Dr. Newcomer. His suggestion was for the expanded use of advanced nurse practitioners and physician assistants, who could cost-effectively administer the treatment plan that oncologists develop, especially given the anticipated shortage of oncologists. This is one

example of the need to think outside the box, he said. “If we rethink it, we can solve the problem,” Dr. Newcomer proposed. Panel participants acknowledged that just 90 days into the implementation of the Affordable Care Act, it is too soon to tell what the ultimate benefits of this aspect of health-care reform will be. However, their consensus was that several factors will be important for its success: integrated care, payment reform, and an increased fo-

cus on value and quality. And regardless of the final makeup of the newly insured population, the experts agreed that the expansion of health-care coverage is inherently a good thing, and the Affordable Care Act can be credited for that. “Better coverage for more Americans, especially with certain provisions like screening,” said Dr. Kolodziej, “is good for people.” n Disclosure: visit http://www.nccn.org/ disclosures/default.asp.

Issues in Oncology Guidelines

Challenges in Creating and Promoting Clinical Practice Guidelines By Caroline Helwick

ith regard to clinical practice guidelines, clinicians want an authoritative resource that will clearly and concisely instruct them in most clinical scenarios. Guideline developers want to give them this, “but producing guidelines is not as straightforward as it might seem,” according to David Garcia, MD, Professor of Medicine at the University of Washington in Seattle, who has been involved in developing guidelines in hematology. At the 2013 ASH Annual Meeting, Dr. Garcia cited several challenges that must be addressed during the development of guidelines: the participation of parties with conflicts of interest, the difficulty of calculating net clinical benefit, and the danger of including recommendations not based on high-quality evidence.

tality of the evidence and come up with a recommendation going against his or her own hypothesis,” he suggested. But it’s impossible to completely eliminate “conflicted authors,” since these tend to be the experts in the field, he pointed out. “If we exclude them,

The strongest recommendations are based on high-quality evidence that (1) the intervention impacts an important clinical outcome, rather than a surrogate outcome that may not matter

We need to maintain transparency regarding the evidence and methods used to create the guidelines, and any possible conflicts of interest. And we also need to provide key recommendations for use at the bedside, as a summary, checklist, or algorithm, with the strengths clearly labeled. —David Garcia , MD

Conflicts of Interest Cannot Be Avoided Potential conflicts of interest may be not only financial but intellectual, and not only real but perceived. Financial conflicts of interest are well recognized and can affect both the direction and strength of the guidelines. Even the perception of a financial conflict of interest can challenge the credibility of the guidelines, he pointed out, but intellectual conflicts of interest may be even more important, he contended. “Writers of guidelines may have powerful intellectual conflicts of interest. If you consider that an expert in a field spends his or her career writing grants, and conducting trials to prove that treatment A is better than treatment B in a certain situation, it may be hard for this person to consider the to-

How Strong Are the Recommendations?

it’s possible the guidelines will miss the mark and fail to address key real-world dilemmas,” he said. “World authorities” who find themselves excluded may, in turn, “find occasion to criticize the guidelines and call their validity into question,” he suggested. “This would likely lead to poor uptake of the guidelines in clinical practice.” Dr. Garcia suggested these solutions: Include authors with potential conflicts of interest but disclose all conflicts of interest (financial and intellectual), restrict financial conflicts of interest (ie, set a dollar-peryear threshold), limit voting or discussion by authors with selected conflicts of interest, and include nonconflicted persons as independent safeguards (ie, methodologists trained in interpreting evidence).

to the patient, and (2) that the benefits likely outweigh any risks. While these may seem obvious, physicians and patients often differ on these points. Future guideline writers need to focus on patient-important (not surrogate) outcomes whenever possible, he suggested, and be equipped with better knowledge about how patients view the tradeoffs associated with treatment options. Even when there is high-quality evidence, individual patient preferences as well as resource considerations (eg, widely varying treatment settings) may reduce the strength of a recommendation, he added. “So, for those asking why the strength of so many guidelines is weak, there are many reasons,” Dr. Garcia said.

Perils of ‘Expert Consensus’ “When I am in a clinical situation where the evidence is inconclusive, I pick up the phone and call someone with practical experience in this situation,” he said. “Experiential recommendations are important to me in the hallway, but publishing expert opinions can lead to unintended consequences.” While they sometimes cannot be avoided, guidelines based on expert consensus can be “unjustified, unreasonable, and stifling of future clinical research,” Dr. Garcia maintained. “Once a group of experts makes a recommendation, even if it is labeled weak, the tendency of practicing doctors who just want the answer to what they should do is to adopt the practice—sometimes with such fervor that convincing them to enroll a patient in a clinical trial to definitively answer the question can be challenging, and even unethical,” Dr. Garcia suggested. “Sometimes, we recommend things that turn out to be harmful, such as hormone replacement therapy in postmenopausal women.” Some of the weaknesses in guidelines can be ameliorated, he said, through transparency and by the way they are used. “We need to maintain transparency regarding the evidence and methods used to create the guidelines, and any possible conflicts of interest,” he said. “And we also need to provide key recommendations for use at the bedside, as a summary, checklist, or algorithm, with the strengths clearly labeled.” Disclosure: Dr. Garcia reported no potential conflicts of interest.

The ASCO Post | MAY 15, 2014

PAGE 40

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 4

Non–Small Cell Lung Cancer: Treatment Growing Ever More Targeted

“For primary disease, treatment recommendations have been modified according to nodal status and tumor size, and mutational testing recommendations have been refined.” — Leora Horn, MD, MSc

The treatment of advanced non–small cell lung cancer (NSCLC) is increasingly centered on tumor histology and molecular driver mutations, according to Leora Horn, MD, MSc, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Recent studies have demonstrated an improved response rate and progressionfree survival in patients with epidermal growth factor receptor (EGFR) mutation– positive lung cancer treated with a first-line EGFR tyrosine kinase inhibitor compared to chemotherapy. However, all patients eventually develop acquired resistance, about half of which are due to acquisition in resistant tumors of a second site (T790M) mutation. Newer tyrosine kinase inhibitors and combinations of targeted agents appear capable of overcoming acquired resistance based on phase I data, including afatinib (Gilotrif) and cetuximab (Erbitux), which has been incorporated into the 2014 Guidelines for first- and second-line treatDisclosure Information

ment, and the investigational third-generation tyrosine kinase inhibitors AZD9291 and CO01686. The ALK/MET inhibitor crizotinib (Xalkori), which is so effective in ALKpositive lung cancer, is being evaluated in the first-line setting, and another investigational ALK inhibitor, ceritinib, is showing promise in patients with acquired resistance to crizotinib. According to the 2014 NCCN Guidelines, maintenance therapy is an option for select patients with tumor response or stable disease and is not considered the standard of care for all patients. Category 1 options in continuation maintenance therapy include single-agent bevacizumab and single-agent cetuximab, although the latter agent is rarely used. For primary disease, treatment recommendations have been modified according to nodal status and tumor size, and mutational testing recommendations have been refined.

Metastatic Melanoma: A Whole New Ballgame

regimens, a testament to the wealth of new effective agents against what used to be a rapidly fatal disease. The extensive list of treatments forms the key update to the Melanoma Guidelines, according to John A. Thompson, MD, of the Seattle Cancer Care Alliance. The effective new agents include anti-CTLA4 antibodies, antibodies targeting the programmed death protein and its ligand—anti–PD-1 and anti–PD-L1 agents—and drugs targeting the BRAF and MEK mutations. The Guidelines list as preferred regimens: single-agent ipilimumab (Yervoy), vemurafenib (Zelboraf), and dabrafenib (Tafinlar) (all category 1), as well as dabrafenib plus trametinib (Mekinist), highdose interleukin-2 (Proleukin), and enrollment on a clinical trial (not ranked). Among the eight “other active regimens,” only the new MEK inhibitor trametinib earned a category 1 recommendation. The novel agents are producing durable remissions that can persist for many years. “More and more, we are pulling from this list of preferred drugs rather than using the ‘other’ category,” said Dr. Thompson.

Immunomodulatory and Targeted Agents

“Metastatic melanoma is a bad disease, but with new agents we hope we can move the survival curve.” —John A. Thompson, MD

The NCCN’s list of preferred regimens for metastatic melanoma now tops half a dozen, most being category 1 recommendations. There are eight additional active

Drs. Kvale and Byrd reported no potential conflicts of interest. Dr. Urba has served on advisory boards, speakers bureaus, and as an expert witness or consultant for Eisai and Helsinn. Dr. Gradishar has served on an advisory board, speakers bureau, and as expert witness or consultant for Bayer HealthCare, Eisai, Genentech, Genomic Health, Myriad Genetic Laboratories, and Onyx Pharmaceuticals. Dr. Carroll has received or participated in clinical research support/data safety monitoring board for Genomic Health, Myriad Genetic Laboratories, National Cancer Institute, and Department of Defense. He has served on an advisory board, speakers bureau, or as an expert witness or consultant for Genomic Health. Ms. Hampel has received or participated in clinical research support/data safety monitoring board for Myriad Genetic Laboratories and University of Washington. Dr. Zelenetz has received or participated in clinical research support/data safety monitoring board for Abbott Laboratories, Boehringer Ingelheim GmbH, Celgene, Cephalon, Genentech, GlaxoSmithKline, Janssen, Millennium, Novartis, Onyx, Infinity, and Seattle Genetics. Dr. Zelenetz has also served on an advisory board, speakers bureau, or as an expert witness, or consultant for Celgene, Genentech, GlaxoSmithKline, Onyx, Bullet Bio Technology, Cancer Genetics, Dr. Reddy`s Laboratories,

With the anti-CTLA4 agent ipilimumab, the survival curve ultimately plateaus, and about 20% of patients are surviving out to 5 years. Enthusiasm is even greater for the anti-PD-1 and anti–PD-L1 agents, to which 30% to 50% of patients with metastatic disease respond, and virtually all responders are alive at 1 year. In combination, these two immunomodulatory classes produce “a striking degree of tumor suppression and responses in the majority of patients,” he observed. The targeting of the BRAF mutation with vemurafenib and dabrafenib has also changed the treatment landscape, but resistance develops rapidly to these drugs. Much of the resistance is attributed to the action of MEK; therefore, blocking MEK with drugs such as trametinib is now among the recommendations. Combined

BRAF and MEK inhibition has proven to be an even better approach, both for efficacy and safety.

Colorectal Cancer: New Guidelines for Assessing Genetic Risk

“We felt the information about the genetic and familial colorectal cancer syndromes had grown, and this is not where clinicians were looking for it.” —Heather Hampel, MS, CGC

New features within the NCCN Guidelines for Detection, Prevention, and Risk Reduction include recommendations for the assessment of high-risk familial and genetic colorectal cancer syndromes. These guidelines now exist under their own cover, paralleling those previously established for the assessment of genetic and familial breast cancer. Prior to 2014, the detection and management of hereditary colorectal cancer fell under the NCCN Colorectal Cancer Screening Guidelines. The Panel recommends that all colorectal cancer patients be screened for Lynch syndrome. Such screening could be universal (ie, all tumors would be genetically tested) or universal for colorectal cancer patients under the age of 70 and for selected patients older than 70 who meet certain clinical criteria, according to Heather Hampel, MS, CGC, a genetics counselor at The Ohio State University Comprehencontinued on page 42

Emergent Biosolutions, Foundation Medicine, Gilead, Hospira, Roche, and sanofi-aventis U.S. Dr. Horn has received or participated in clinical research support/data safety monitoring board for Boehringer Ingelheim GmbH, OSI Pharmaceuticals. She has also served on an advisory board, speakers bureau, or as an expert witness or consultant for Bristol-Myers Squibb. Dr. Anderson has served on an advisory board, speakers bureau, or as an expert witness or consultant for Celgene, Millennium, Onyx Pharmaceuticials, Gilead, and sanofi-aventis U.S. Dr. Anderson also reported potential conflicts of interest with Acetylon and OncoPep. Dr. Thompson has received or participated in clinical research support/data safety monitoring board for Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone, Novartis, and Altor Bioscience. He has also served on an advisory board, speakers bureau, or as an expert witness, or consultant for Amgen and Bristol-Myers Squibb. Dr. Vickers is named as a co-inventor on a patent application for a statistical method for predicting the result of a prostate cancer biopsy, commercialized by Opko; Dr. Vickers has stock options in Opko and is due to receive royalty payments from sales of the test. For more information visit http://www.nccn.org/disclosures/default.asp.

Another treatment opportunity FDA-approved MARQIBO

(vinCRIStine sulfate LIPOSOME injection) For the treatment of adult patients with Philadelphia chromosome– negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies. This indication is based on overall response rate. Clinical beneﬁt such as improvement in overall survival has not been veriﬁed.

• 15.4% (10/65) overall response rate in patients who received multiple prior therapies (4.6% CR + 10.8% CRi) (95% CI 7.6–26.5)1 − 100% had previously received non-liposomal (standard) vincristine − 48% had undergone prior hematopoietic stem cell transplant (HSCT) − 51% had received 3 or more prior therapies − 45% were refractory to their immediate prior therapy − 85% had precursor B-cell ALL and 15% had precursor T-cell ALL − 100% were ineligible for immediate HSCT at enrollment − 34% had not received asparaginase products • Median duration of CR or CRi1 − 28 days (95% CI 7, 36) based on the first date of CR or CRi to the date of the last available histologic assessment of the same response (n=8) − 56 days (95% CI 9, 65) based on the first date of CR or CRi to the date of documented relapse, death, or subsequent chemotherapies, including HSCT (n=10) • MARQIBO is sphingomyelin/cholesterol-based liposome–encapsulated vincristine1 − Plasma clearance of MARQIBO is slow, 345 mL/h, at a dose of 2.25 mg/m2. This is in comparison to the rapid clearance of non-liposomal vincristine sulfate at 189 mL/min/m2 (11,340 mL/h) − Slow clearance of MARQIBO contributes to a much higher area under the curve (AUC) for MARQIBO relative to non-liposomal vincristine sulfate • The recommended dose of MARQIBO is 2.25 mg/m2 intravenously over 1 hour every 7 days.1 A dose of MARQIBO is calculated based on the patient’s actual body surface area

Important Safety Information WARNING • For Intravenous Use Only—Fatal if Given by Other Routes • Death has occurred with intrathecal administration • MARQIBO (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage Contraindications • MARQIBO is contraindicated in patients with demyelinating conditions, including Charcot-Marie-Tooth syndrome; in patients with hypersensitivity to vincristine sulfate or any of the other components of MARQIBO; and for intrathecal administration

• Neutropenia, thrombocytopenia, or anemia may occur. Monitor blood counts prior to each dose. Consider dose modification or reduction as well as supportive care measures if Grade 3 or 4 myelosuppression develops • Anticipate, monitor for, and manage tumor lysis syndrome • A prophylactic bowel regimen should be instituted with MARQIBO to prevent constipation, bowel obstruction, and/or paralytic ileus • Severe fatigue can occur requiring dose delay, reduction, or discontinuation of MARQIBO • Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Monitor liver function and modify or interrupt dosing for hepatic toxicity • MARQIBO can cause fetal harm. Advise women of potential risk to fetus Adverse Events • The most commonly reported adverse reactions (incidence >30%) in clinical studies include constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%) • A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%) • Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%) • Deaths occurred in 23% of patients in study 1. The nonleukemia-related causes of death were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multisystem organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1) Drug Interactions • MARQIBO is expected to interact with drugs known to interact with non-liposomal vincristine sulfate, therefore the concomitant use of strong CYP3A inhibitors or the use of potent P-glycoprotein inhibitors or inducers should be avoided Use in Specific Populations • The safety and effectiveness of MARQIBO in pediatric patients have not been established • It is not known whether MARQIBO is excreted in human milk

Please see Brief Summary of Prescribing Information, including the BOXED WARNINGS, for MARQIBO on adjacent pages. Please see Prescribing Information at MARQIBO.com. 1. MARQIBO [prescribing information]. October 2012.

Warnings and Precautions • MARQIBO is for intravenous use only—fatal if given by other routes. Intrathecal use is fatal • Extravasation causes tissue injury. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures • Sensory and motor neuropathy are common and cumulative. Monitor patients for peripheral motor and sensory, central and autonomic neuropathy and reduce, interrupt, or discontinue dosing. Patients with preexisting severe neuropathy should be treated with MARQIBO only after careful risk-benefit assessment

TALON

©2014 Spectrum Pharmaceuticals, Inc. MARQIBO is a registered trademark of Talon Therapeutics, Inc. a wholly owned subsidiary of Spectrum Pharmaceuticals, Inc. All rights reserved. February 2014. Printed in the USA. 0111-084701 www.sppirx.com

The ASCO Post | MAY 15, 2014

PAGE 42

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 40

sive Cancer Center, Columbus. Universal screening for Lynch syndrome has been a topic of discussion in oncology and gastroenterology circles for several years, but a formal recommendation by the NCCN moves the concept forward, Ms. Hampel said. Almost three-

fourths of NCCN centers have begun conducting universal screening for all new colorectal cancer patients. In the 2014 guidelines, testing for Lynch syndrome is separated into two sections: clinical testing criteria based on personal and family history, and routine tumor testing criteria. Screening the colorectal cancer patient is also a robust cancer prevention

strategy among their relatives. The Panel also refined the recommendations for evaluating, treating, and monitoring familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and colonic adenomatous polyposis of unknown etiology.

Marqibo® (vinCRIStine sulfate LIPOSOME injection) BRIEF SUMMARY Please see the Marqibo package insert for full Prescribing Information. WARNING • For Intravenous Use Only—Fatal if Given by Other Routes. • Death has occurred with intrathecal administration. • Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. INDICATIONS AND USAGE Adult ALL in Second or Greater Relapse Marqibo® is indicated for the treatment of adult patients with Philadelphia chromosomenegative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified. DOSAGE AND ADMINISTRATION For Intravenous Use Only—Fatal if Given by Other Routes. Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. Recommended Dosage The recommended dose of Marqibo is 2.25 mg/m2 intravenously over 1 hour once every 7 days. Marqibo is liposome-encapsulated vincristine. Dose Modifications: Peripheral Neuropathy Marqibo is contraindicated in patients with demyelinating conditions including CharcotMarie-Tooth syndrome [see Contraindications]. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment [see Warnings and Precautions]. For dose or schedule modifications guidelines for patients who experience peripheral neuropathy, see Table 1. Table 1. Recommended Dose Modifications for Marqibo-related Peripheral Neuropathy Severity of Peripheral Neuropathy Signs and Symptomsa

Modification of Dose and Regimen

If the patient develops Grade 3 (severe symptoms; limiting self-care activities of daily living [ADL]b) or persistent Grade 2 (moderate symptoms; limiting instrumental ADLc) peripheral neuropathy:

Interrupt Marqibo. If the peripheral neuropathy remains at Grade 3 or 4, discontinue Marqibo. If the peripheral neuropathy recovers to Grade 1 or 2, reduce the Marqibo dose to 2 mg/m2.

If the patient has persistent Grade 2 Interrupt Marqibo for up to 7 days. If the peripheral neuropathy after the first dose peripheral neuropathy increases to Grade 3 reduction to 2 mg/m2: or 4, discontinue Marqibo. If the peripheral neuropathy recovers to Grade 1, reduce the Marqibo dose to 1.825 mg/m2. If the patient has persistent Grade 2 peripheral neuropathy after the second dose reduction to 1.825 mg/m2:

Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 or 4, discontinue Marqibo. If the toxicity recovers to Grade 1, reduce the Marqibo dose to 1.5 mg/m2.

Grading based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. c Instrumental ADL: refers to preparing meals, shopping for groceries and clothes, using telephone, managing money, etc. a

Preparation and Handling Items Required by the Pharmacy to Prepare Marqibo • Marqibo Kit • Water batha • Calibrated thermometera (0°C to 100°C) • Calibrated electronic timera • Sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter • 1 mL or 3 mL sterile syringe with needle, and • 5 mL sterile syringe with needle. a

The manufacturer will provide the water bath, calibrated thermometer, and calibrated electronic timer to the medical facility at the initial order of Marqibo and will replace them every 2 years.

Preparation Instructions for Marqibo (vinCRIStine sulfate LIPOSOME injection), 5 mg/31 mL (0.16 mg/mL) Procedures for handling and disposal of anticancer drugs should be followed [see References]. Call [1 888 292 9617] if you have questions about the preparation of Marqibo. Marqibo takes approximately 60 to 90 minutes to prepare. The preparer should have dedicated uninterrupted time to prepare Marqibo due to the extensive monitoring of temperature and time required for the preparation. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Marqibo. The preparation steps of Marqibo that involve mixing the Sodium Phosphate Injection, Sphingomyelin/Cholesterol Liposome Injection, and VinCRIStine

Prostate Cancer “We had to make the Guidelines more streamlined, more readable, and more actionable.” —Peter R. Carroll, MD, MPH

Peter R. Carroll, MD, MPH, and

Sulfate Injection must be done in a biological safety cabinet or by established pharmacy safety procedures for the preparation of sterile injectable formulations and hazardous drugs. However, the preparation steps that involve placement of the vial in the water bath must be done outside of the sterile area. Do not use with in-line filters. Do not mix with other drugs. 1. Fill a water bath with water to a level of at least 8 cm (3.2 inches) measured from the bottom and maintain this minimum water level throughout the procedure. The water bath must remain outside of the sterile area. 2. Place a calibrated thermometer in the water bath to monitor water temperature and leave it in the water bath until the procedure has been completed. 3. Preheat water bath to 63°C to 67°C. Maintain this water temperature until completion of the procedure using the calibrated thermometer. 4. Visually inspect each vial in the Marqibo Kit for particulate matter and discoloration prior to preparation, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. 5. Remove all the caps on the vials and swab the vials with sterile alcohol pads. 6. Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding Sphingomyelin/ Cholesterol Liposome Injection and VinCRIStine Sulfate Injection. 7. Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection. 8. Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial. 9. Withdraw 5 mL of VinCRIStine Sulfate Injection. 10. Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial. 11. Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE. 12. Fit Flotation Ring around the neck of the Sodium Phosphate Injection vial. 13. Confirm that the water bath temperature is at 63°C to 67°C using the calibrated thermometer. Remove the Sodium Phosphate Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is maintained at 63°C to 67°C. 14. IMMEDIATELY after placing the Sodium Phosphate Injection vial into the water bath, record the constitution start time and water temperature on the Marqibo Overlabel. 15. At the end of the 10 minutes, confirm that the water temperature is 63°C to 67°C using the calibrated thermometer. Remove the vial from the water bath (use tongs to prevent burns) and remove the Flotation Ring. 16. Record the final constitution time and the water temperature on the Marqibo Overlabel. 17. Dry the exterior of the Sodium Phosphate Injection vial with a clean paper towel, affix Marqibo (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE. 18. Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F to 86°F). 19. Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE PREPARED, STORE AT CONTROLLED ROOM TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS. 20. Swab the top of the vial now containing Marqibo with a sterile alcohol pad and return the vial back into the biological safety cabinet. 21. Calculate the patient’s Marqibo dose based on the patient’s actual body surface area (BSA) and remove the volume corresponding to the patient’s Marqibo dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. 22. Inject the dose of Marqibo into the infusion bag to result in a final volume of 100 mL. 23. Complete the information required on the Infusion Bag Label and apply to the infusion bag. 24. Finish administration of the diluted product within 12 hours of the initiation of Marqibo preparation. 25. Empty, clean, and dry the water bath after each use. 26. Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit should be discarded and a new kit should be used to prepare the dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. CONTRAINDICATIONS Marqibo is contraindicated in patients with demyelinating conditions including CharcotMarie-Tooth syndrome. Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection). Marqibo is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS For Intravenous Use Only Fatal if Given by Other Routes. Death has occurred with intrathecal use.

ASCOPost.com | MAY 15, 2014

PAGE 43

National Comprehensive Cancer Network Annual Conference

Peter R. Carroll, MD, MPH

Andrew J. Vickers, PhD

Andrew J. Vickers, PhD, debated the value of prostate-specific antigen (PSA) testing and presented the new, streamlined NCCN Guidelines for Early Detection of Prostate Cancer, which emphasize selective early detection and treatment and are tightly aligned with the treat-

Extravasation Tissue Injury Only administer through a secure and free-flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures. Neurologic Toxicity Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness, both before and during treatment. Orthostatic hypotension may occur. The risk of neurologic toxicity is greater if Marqibo is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. In the studies of relapsed and/ or refractory adult ALL patients, Grade ≥3 neuropathy events occurred in 32.5% of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo [see Dosage and Administration]. Myelosuppression Monitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anemia develops, consider Marqibo dose modification or reduction as well as supportive care measures. Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage. Constipation and Bowel Obstruction Ileus, bowel obstruction, and colonic pseudo-obstruction have occurred. Marqibo can cause constipation [see Adverse Reactions]. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners, such as docusate. Additional treatments, such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered. Fatigue Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary. Hepatic Toxicity Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade ≥3 occurred in 6-11% of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity. Embryofetal Toxicity Marqibo can cause fetal harm when administered to a pregnant woman. Vincristine sulfate liposome injection was teratogenic or caused embryo-fetal death in animals. Women of childbearing potential should avoid becoming pregnant while being treated with Marqibo. There are no adequate and well-controlled studies of Marqibo in pregnant women and there were no reports of pregnancy in any of the clinical studies in the Marqibo clinical development program. 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]. ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: • For intravenous use only [see Warnings and Precautions] • Extravasation tissue injury [see Warnings and Precautions] • Peripheral Neuropathy [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Tumor lysis syndrome [see Warnings and Precautions] • Constipation and bowel obstruction [see Warnings and Precautions] • Fatigue [see Warnings and Precautions] • Hepatic toxicity [see Warnings and Precautions] Clinical Trials Safety 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. Integrated Summary of Safety in Relapsed and/or Refractory Ph- Adult Acute Lymphoblastic Leukemia Marqibo, at a dose of 2.25 mg/m2 weekly, was studied in a total of 83 patients in two trials: study 1 and study 2. Adverse reactions were observed in 100% of patients. The most common adverse reactions (>30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%) Adverse reactions of Grade 3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or greater and occurring in ≥5% of patients are summarized in Table 2.

ment Guidelines for prostate cancer. Although prostate cancer mortality may be reduced with prostate cancer screening, the risk of overdiagnosis with this approach is substantial, they acknowledged. “Screening for prostate cancer has been a public health disaster,” noted Dr. Vickers, of Memorial Sloan Kettering Cancer Center, New York.

Table 2. Most Commonly Reported (>5%) Gradea 3 or Greater Adverse Reactions among 83 Patients Receiving the Clinical Dosing Regimen Adverse Reactions ≥3 Blood and Lymphatic System Disorders Febrile Neutropenia Neutropenia Anemia Thrombocytopenia Infections Pneumonia Septic Shock Staphylococcal Bacteremia Neuropathyb Peripheral Sensory and Motor Neuropathy Constipation Ileus, Colonic Pseudo-Obstruction Asthenia Muscular Weakness Respiratory Thoracic and Mediastinal Disorders Respiratory Distress Respiratory Failure General Disorders and Administration Site Condition Pyrexia Fatigue Pain Gastrointestinal Disorders Abdominal Pain Investigations Aspartate Aminotransferase Increased Vascular Disorders Hypotension Psychiatric Disorders Mental Status Changes Cardiac Disorders Cardiac Arrest Renal and Urinary Disorders Musculoskeletal and Connective Tissue Disorders a b

Study 1 and 2 (N=83) n (%) 47 (56.6) 26 (31.3) 15 (18.1) 14 (16.9) 14 (16.9) 33 (39.8) 7 (8.4) 5 (6.0) 5 (6.0) 27 (32.5) 14 (16.7) 4 (4.8) 5 (6.0) 4 (4.8) 1 (1.2) 17 (20.5) 5 (6.0) 4 (4.8) 31 (37.3) 12 (14.5) 10 (12.0) 7 (8.4) 21 (25.3) 7 (8.4) 20 (24.1) 6 (7.2) 8 (9.6) 5 (6.0) 9 (10.8) 3 (3.6) 9 (10.8) 5 (6.0) 6 (7.2) 7 (8.4)

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Including neuropathy-associated adverse reactions.

A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%). Dose reduction, delay, or omission occurred in 53% of patients during the treatment. Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%). Adverse reactions related to neuropathy and leading to treatment discontinuation were decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain, each reported in at least 1 patient. Deaths occurred in 23% of patients in study 1. The nonleukemia-related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1). DRUG INTERACTIONS No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate. Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. CYP3A Interactions Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). P-glycoprotein Interactions Vincristine sulfate, the active agent in Marqibo, is also a substrate for P-glycoprotein (P-gp). The effect of concomitant use of potent P-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P-gp inhibitors or inducers should be avoided.

In the past, the NCCN Guidelines focused on screening early and often for prostate cancer and using biopsy liberally, but this was “a lengthy, circuitous path that we felt needed to be changed,” said Dr. Carroll, of the University of California, San Francisco. The new screening strategy centers continued on page 44

The ASCO Post | MAY 15, 2014

PAGE 44

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 43

on several key criteria: a younger target population of healthy men, more explicit indications for selective use of biopsy in men with high PSA levels, and selective treatment of men based on the extent and grade of disease identified. The Panel’s goal was to limit, as much

as possible, the problem of overdetection—detecting a cancer which would not lead to death or disability if left undiagnosed—without reversing any positive impact on mortality.

Target Population The updated Guidelines define the target population for screening as be-

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to 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. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug-related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and postimplantation losses, and decreased maternal body weights. Malformations were observed at doses ≥0.044 mg/kg/day in animals at systemic exposures approximately 20-40% of those reported in patients at the recommended dose. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Marqibo in pediatric patients have not been established. Geriatric Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated. Hepatic Impairment Non-liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated. The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child-Pugh B) secondary to melanoma liver metastases. The dose-adjusted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function. OVERDOSAGE When Marqibo (vinCRIStine sulfate LIPOSOME injection) was administered at a dose of 2.4 mg/m2, severe toxicities including motor neuropathy of Grade 3, grand mal seizure of Grade 4, and elevated aspartate aminotransferase and hyperbilirubinemia of Grade 4 were reported in 1 patient each. There is no known antidote for overdosage. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with Marqibo or non-liposomal vincristine sulfate. Based on the mechanism of action and genotoxicity findings in nonclinical studies conducted with non-liposomal vincristine sulfate, Marqibo may be carcinogenic. No genotoxicity studies have been conducted with Marqibo. Non-liposomal vincristine was genotoxic in some in vitro and in vivo studies. The single- and repeat-dose animal toxicology study results indicate that Marqibo can impair male fertility, consistent with the literature on non-liposomal vincristine sulfate. Administration of vincristine liposome injection causes testicular degeneration and atrophy, and epididymal aspermia in rats. Gonadal dysfunction has been reported in both male and female post-pubertal patients who received multi-agent chemotherapy including non-liposomal vincristine sulfate. The degree to which testicular or ovarian functions are affected is age-, dose-, and agentdependent. Recovery may occur in some but not all patients. Animal Toxicology and/or Pharmacology In a repeat-dose comparative toxicology study in rats, vincristine sulfate liposome injection or non-liposomal vincristine sulfate was administered to animals intravenously once per week for 6 weeks. Clinical signs of toxicity consistent with neurotoxicity were greater with vincristine sulfate liposome injection than with non-liposomal vincristine sulfate at equal vincristine sulfate doses of 2 mg/m2 /week and included uncoordinated movements, weakness, reduced muscle tone, and limited usage of the limbs. Neurological testing indicated drug-induced peripheral neurotoxicity with both drugs. Based on the histopathology examination after 6 weekly doses, vincristine sulfate liposome injection induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy than the equal dose of non-liposomal vincristine sulfate. In a separate

tween 50 and 70 years old, with baseline testing of men aged 45 to 50. Repeat testing is then based on the PSA level: 1- to 2-year intervals for those with a PSA > 1.0 ng/mL. (Previous guidelines stipulated annual screening.) For younger men with a normal digital rectal exam and a PSA level ≤ 1 ng/mL, testing should be repeated at age 50.

tissue distribution study in rats, administration of 2 mg/m2 of intravenous liposomal or non-liposomal vincristine sulfate showed greater accumulation of vincristine sulfate in sciatic and tibial nerves (as well as the lymph nodes, spleen, and bone marrow) of the animals following vincristine sulfate liposome injection. PATIENT COUNSELING INFORMATION Physicians are advised to discuss the following with patients prior to treatment with Marqibo: Extravasation Tissue Injury: Advise patients to report immediately any burning or local irritation during or after the infusion [see Warnings and Precautions]. Ability to Drive or Operate Machinery or Impairment of Mental Ability: Marqibo may cause fatigue and symptoms of peripheral neuropathy. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions]. Gastrointestinal/Constipation: Patients receiving Marqibo may experience constipation. Advise patients how to avoid constipation by a diet high in bulk fiber, fruits and vegetables, and adequate fluid intake as well as use of a stool softener, such as docusate. Instruct patients to seek medical advice if they experience symptoms of constipation such bowel movement infrequency, abdominal pain, bloating, diarrhea, nausea, or vomiting [see Warnings and Precautions]. Pregnancy/Nursing: Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with Marqibo [see Warnings and Precautions]. Instruct patients to report pregnancy to their physicians immediately. Advise patients that they should not receive Marqibo while pregnant or breastfeeding. If a patient wishes to re-start breastfeeding after treatment, she should be advised to discuss the appropriate timing with her physician [see Use in Specific Populations]. Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking [see Drug Interactions]. Peripheral Neuropathy: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the feet or hands [see Warnings and Precautions]. Other: Instruct patients to notify their physicians if they experience fever, productive cough, or decreased appetite [see Warnings and Precautions].

Testing in men older than age 70 should be done cautiously. Regardless of age, men should be screened based on overall health and life expectancy. The 2014 Guidelines provide more explicit indications for biopsy and allow for less frequent testing. Biopsy can be considered when the PSA exceeds 3.0 ng/mL and may be considered in those with other PSA values based on other risk factors such as age, family history, ethnicity, PSA kinetics, etc. PSA velocity alone at a low PSA level is no longer an indication for biopsy. “The use of PSA velocity at low levels may have little independent value and can lead to overdetection,” Dr. Carroll said. n Disclosure: See sidebar on page 40 or visit ww.nccn.org/disclosures/default.asp.

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

REFERENCES 1. NIOSH Alert: Preventing occupational exposure to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/ otm_vi/otm_vi_2.html. 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172-1193. 4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Distributed by: Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Talon Therapeutics, Inc., 11500 South Eastern Ave., Suite 240, Henderson, NV 89052 ©2014 Spectrum Pharmaceuticals, Inc. MARQIBO is a registered trademark of Talon Therapeutics, Inc. a wholly owned subsidiary of Spectrum Pharmaceuticals, Inc. All rights reserved. January 2014. Printed in the USA. 0125-080401 www.sppirx.com

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ASCOPost.com | MAY 15, 2014

PAGE 45

JCO Spotlight Survivorship

Neuropathy Guideline continued from page 1

at close to 40% in patients treated with multiple agents, with reported rates varying according to chemotherapy regimens, duration of exposure, and assessment methods. Regimens associated with higher risk are those including platinum drugs, vinca alkaloids, bor tezomib (Velcade), and taxanes.

Clinical Question The clinical question addressed by the guideline is: What are the optimum prevention and treatment approaches in the management of chemotherapyinduced neuropathies in adult cancer survivors? Guideline development involved a systematic literature search to identify randomized controlled trials in management of chemotherapy-induced peripheral neuropathy. The search identified 1,252 potentially relevant citations, of which 250 were examined in detail, with 48 trials meeting eligibility criteria for use as the evidentiary basis for guideline recommendations. The trials were reported between 1990 and 2013. A total of 42 studies provided information on 19 different interventions for the prevention of chemotherapy-

induced peripheral neuropathy; 6 studies provided information on 6 different agents evaluated in treatment of established neuropathy. The outcomes of interest in analysis of evidence were the incidence and severity of neuropathy, neurophysiologic measures, patientreported outcomes, and quality of life. The trials generally were small and heterogeneous, often with sample sizes not sufficiently large to detect clinically important differences in outcomes, and usually were not directly comparable due to use of different outcomes and measurements.

moderate against, with intermediate strength of evidence, low evidence of efficacy, and moderate evidence of harm) • Amitriptyline (recommendation = moderate against, with intermediate strength of evidence, no evidence of efficacy, and moderate evidence of harm)

ficacy and harm) • Nimodipine (recommendation = strong against, with low strength of evidence, no evidence of efficacy, and moderate evidence of harm) • Org 2766 (recommendation = moderate against, with intermediate strength of evidence and low evidence of efficacy and harm)

The clinical question addressed by the guideline is: What are the optimum prevention and treatment approaches in the management of chemotherapyinduced neuropathies in adult cancer survivors?

Prevention Recommendations Due to lack of high-quality, consistent evidence, the guidelines do not recommend any agents for use in prevention of chemotherapy-induced peripheral neuropathy. The guidelines specify that clinicians should not offer the following agents for prevention of peripheral neuropathy in cancer patients undergoing treatment with neurotoxic agents: • Acetyl-L-carnitine (recommendation = strong against, with high strength of evidence, no evidence of efficacy, and high evidence of harm) • Amifostine (recommendation =

• Calcium and magnesium for patients receiving oxaliplatin-based chemotherapy (recommendation = moderate against, with high strength of evidence and low evidence of efficacy and harm) • Diethyldithio-carbamate (recommendation = strong against, with low strength of evidence, no evidence of efficacy, and high evidence of harm • Glutathione for patients receiving paclitaxel/carboplatin chemotherapy (recommendation = moderate against, with intermediate strength of evidence and low evidence of ef-

• Retinoic acid (recommendation = moderate against, with low strength of evidence, low evidence of efficacy, and moderate evidence of harm) • rhuLIF, or emfilermin (recommendation = moderate against, with low strength of evidence, no evidence of efficacy, and low evidence of harm) • Vitamin E (recommendation = moderate against, with intermediate strength of evidence and low evidence of efficacy and harm. • Venlafaxine (insufficient information for recommendation, with intermecontinued on page 48

Guidelines for Chemotherapy-Induced Neuropathy: The Known Unknowns By Harold J. Burstein, MD, PhD

t is a tribute to the advances in supportive care that peripheral neuropathy, along with fatigue, has become the most vexing management challenge in cancer patients receiving chemotherapy. The successes of modern antiemetic regimens and white blood cell growth factor support have radically altered the shortterm side-effect profiles of chemotherapy. Vomiting and neutropenic fever have become far less frequent as major complications for patients receiving chemotherapy, and a variety of interventions are available to minimize the symptoms. Instead, the subacute and chronic syndromes of chemotherapy-induced fatigue and peripheral neuropathy have become the most challenging, and frequently, treatment-limiting, consequences. Dr. Burstein is Associate Professor of Medicine at Harvard Medical School, staff physician at Brigham and Women’s Hospital, and a medical oncologist at Dana-Farber Cancer Institute, Boston.

Unrelenting Problem Many of the most common chemotherapy agents used in the treatment of the most common cancers— eg, taxanes for breast, lung, prostate, and gynecologic tumors, oxaliplatin

certain lymphomas, can also cause neuropathy. Neuropathy can be an unrelenting problem that ranges from annoying discomfort to major impediment to daily activities, and can last long be-

The tools exist, the problem [of chemotherapy-induced neuropathy] is prevalent, and it is time to insist upon a robust series of clinical investigations to rapidly sort out promising agents and strategies to minimize this burden in the cancer community. —Harold J. Burstein, MD, PhD

for colon cancer, platinum-based chemotherapy for lung and gynecologic cancers—are strongly associated with risks of peripheral neuropathy. Newer agents such as bortezomib (Velcade), used in multiple myeloma, and brentuximab vedotin (Adcetris) used in

yond actual treatment. Neuropathy often prompts oncologists to modify treatment dosing or scheduling when it is brought to their attention. There is, of course, no x-ray or lab test for neuropathy, and the strong suspicion is that the prevalence and serious-

ness of neuropathy—like so many patient-reported outcomes—is underappreciated by clinicians caring for cancer patients.

Valuable Document Given the significance and prevalence of chemotherapy-induced neuropathy, it is important for clinicians to understand how they might prevent or treat the condition so as to reduce suffering among our patients receiving chemotherapy. The new ASCO guideline on chemotherapy-induced peripheral neuropathy,1 published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, is a valuable document that brings together the known information on how to manage neuropathy in cancer patients. Alas, what we mostly know about managing chemotherapy-induced neuropathy is how little we know. The evidence for treatment recommendations? “Small” trials with “insufficient sample sizes,” inconsistent definitions continued on page 48

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The ThePD-1 PD-1immune immunecheckpoint checkpointpathway: pathway:ananinnovative innovativetarget targetfor forcancer cancerresearch research 1-3,8 1-3,8 • By • By exploiting exploiting the the PD-1 PD-1 immune immune checkpoint checkpoint pathway, pathway, cancer cancer cells cells can can evade evade the the normal normal immune immune response response and and continue continue toto proliferate proliferate • Understanding • Understanding the the PD-1 PD-1 pathway pathway has has the the potential potential toto change change the the way way wewe approach approach certain certain cancers cancers

Learn more at www.pd1pathway.com • Experience the PD-1 checkpoint pathway through an immersive video • Hear a leading oncologist answer questions about the PD-1 checkpoint pathway • Learn more about how Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology

PD-1=programmed PD-1=programmed death death 1; PD-L1=PD-1 1; PD-L1=PD-1 ligand ligand 1; PD-L2=PD-1 1; PD-L2=PD-1 ligand ligand 2. 2. References: References: 1. Pardoll 1. Pardoll D, Drake D, Drake C. Immunotherapy C. Immunotherapy earns earns its spot its spot in the in the ranks ranks of cancer of cancer therapy. therapy. J Exp J Exp Med. Med. 2012;209(2):201-209. 2012;209(2):201-209. 2. Freeman 2. Freeman GJ, GJ, Long Long AJ, AJ, IwaiIwai Y, etY,al. etEngagement al. Engagement of the of the PD-1 PD-1 immunoinhibitory immunoinhibitory receptor receptor by abynovel a novel B7 family B7 family member member leads leads to negative to negative regulation regulation of lymphocyte of lymphocyte activation. activation. J Exp J Exp Med. Med. 2000;192(7):1027-1034. 2000;192(7):1027-1034. 3. Dong 3. Dong H, Strome H, Strome SE, SE, Salomao Salomao DR,DR, et al. etTumor-associated al. Tumor-associated B7-H1 B7-H1 promotes promotes T-cell T-cell apoptosis: apoptosis: a potential a potential mechanism mechanism of immune of immune evasion. evasion. NatNat Med. Med. 2002;8(8):793-800. 2002;8(8):793-800. 4. Hanahan 4. Hanahan D, Weinberg D, Weinberg RA.RA. Hallmarks Hallmarks of cancer: of cancer: thethe next next generation. generation. Cell.Cell. 2011;144(3):646-674. 2011;144(3):646-674. 5. Finn 5. Finn OJ. OJ. Cancer Cancer immunology. immunology. N Engl N Engl J Med. J Med. 2008;358(25):2704-2715. 2008;358(25):2704-2715. 6. Mellman 6. Mellman I, Coukos I, Coukos G, Dranoff G, Dranoff G. Cancer G. Cancer immunotherapy immunotherapy comes comes of age. of age. Nature. Nature. 2011;480(7378):480-489. 2011;480(7378):480-489. 7. Trapani 7. Trapani JA, JA, Smyth Smyth MJ.MJ. Functional Functional signifi signifi cance cance of the of the perforin/granzyme perforin/granzyme cellcell death death pathway. pathway. NatNat RevRev Immunol. Immunol. 2002;2(10):735-747. 2002;2(10):735-747. 8. Azuma 8. Azuma T, Yao T, Yao S, Zhu S, Zhu G, et G,al. etB7-H1 al. B7-H1 is aisubiquitous a ubiquitous antiapoptotic antiapoptotic receptor receptor on cancer on cancer cells. cells. Blood. Blood. 2008;111(7):3635-3643. 2008;111(7):3635-3643. 9. Latchman 9. Latchman Y, Wood Y, Wood CR, CR, Chernova Chernova T, etT,al. etPD-L2 al. PD-L2 is second is second ligand ligand for PD-1 for PD-1 andand inhibits inhibits T cell T cell activation. activation. NatNat Immunol. Immunol. 2001;2(3):261-268. 2001;2(3):261-268. 10.10. IwaiIwai Y, Ishida Y, Ishida M, Tanaka M, Tanaka Y, etY,al. etInvolvement al. Involvement of PD-L1 of PD-L1 on tumor on tumor cellscells in the in the escape escape from from hosthost immune immune system system andand tumor tumor immunotherapy immunotherapy by PD-L1 by PD-L1 blockade. blockade. ProcProc NatlNatl Acad Acad Sci U SciS U A.S2002;99(19):12293-12297. A. 2002;99(19):12293-12297.

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JCO Spotlight Neuropathy Guideline continued from page 45

diate strength of evidence and moderate evidence of efficacy and harm) is not recommended for routine clinical use. Although the available data support its potential utility, its use cannot be recommended until additional supporting data become available. No recommendations (recommendation = inconclusive, with low strength of evidence and low evidence of efficacy and harm for all) could be made on the use of acetylcysteine, carbamazepine/ oxycarbazepine, glutamate, or glutathione for patients receiving cisplatin or oxaliplatin-based chemotherapy, goshajinkigan, or omega-3 fatty acids due to inconclusive evidence of low strength.

Treatment Recommendations The guidelines provide a moderate strength recommendation for treatment of chemotherapy-induced peripheral neuropathy with duloxetine (intermediate strength of evidence, moderate evidence of efficacy, and low evidence of harm). No recommendations (recommendation = inconclusive) could be made on the use of the following agents, although the guidelines consider it reasonable to try tricyclic antidepressants, gabapentin, and a topical gel treatment

Harold J. Burstein, MD, PhD continued from page 45

of outcomes and treatment endpoints, and a scientific foundation for pathophysiology and pharmacology that is disappointing. In the end, not a single agent could be recommended for preventing chemotherapy-induced neuropathy, and only one (duloxetine) could be recommended as treatment based on a single randomized trial. One purpose of a guideline is to articulate the “don’ts” along with the “dos” and for this reason, the ASCO guideline is quite helpful. Given the lack of compelling data for preventing or treating peripheral neuropathy due to chemotherapy, patients often try a lot of different interventions based on anecdotes, claims made in

containing baclofen, amitriptyline, and ketamine in select patients: • Acetyl-L-carnitine (low strength of evidence, low evidence of efficacy, moderate evidence of harm). The guidelines note that an abstract for a phase III trial supported its value, but the trial has yet to be published in a peer-reviewed journal, and a prevention trial suggested worse outcomes with this agent. • Tricyclic antidepressants (eg, nortryp-

• Gabapentin (intermediate strength of evidence, low evidence of efficacy and harm). The guidelines state that it is reasonable to try this agent in select patients with chemotherapy-induced peripheral neuropathic pain, based on the fact that only one negative randomized trial for this agent was completed and given the efficacy of gabapentin and pregabalin in other forms of neuropathic pain. • Topical gel treatment containing ba-

Chemotherapy-Induced Peripheral Neuropathy ■■ No drug treatments are recommended in prevention of chemotherapyinduced peripheral neuropathy, and there are recommendations against use of several agents. ■■ Duloxetine is recommended for treatment of the condition. Although routine use is not recommended due to inadequate evidence, tricyclic antidepressants, gabapentin, and a topical gel containing baclofen, amitriptyline, and ketamine may be tried.

tyline/amitriptyline; intermediate strength of evidence, low evidence of efficacy and harm). The guidelines state that given limited options in chemotherapy-induced peripheral neuropathy and efficacy of these drugs in other neuropathic pain conditions, it is reasonable to try a tricyclic antidepressant (eg, nortriptyline or desipramine) in treatment. health stores, and other incomplete sources of information. The guideline is forceful in recommending against a number of such agents, including nutritional supplements like acetylL-carnitine and glutathione, various vitamins and minerals, and a variety of prescription medicines. The guideline appropriately cautions clinicians and patients about the limited roles for gabapentin and tricyclic antidepressants, agents with relatively small benefits and substantial potential side effects, in the treatment of chemotherapy-induced neuropathy.

Clear Message There is a clear message that it is time to take the gloves off in the battle against chemotherapy-induced

clofen (10 mg), amitriptyline (40 mg), and ketamine (20 mg) (intermediate strength of evidence, moderate evidence of efficacy, and low evidence of harm). The guidelines note that a single trial supported a reduction in chemotherapy-induced peripheral neuropathic symptoms with this treatment and that it is reasonable to try the treatment in select patients neuropathy. As the guideline makes apparent, there are appropriate, clinically validated methods for assessing the impact of treatments for neuropathy in cancer patients. The tools exist, the problem is prevalent, and it is time to insist upon a robust series of clinical investigations to rapidly sort out promising agents and strategies to minimize this burden in the cancer community. The ASCO guideline has mapped out for us the “known unknowns.” Hopefully, it will also create a commitment among patient advocates, clinical investigators, foundations and support groups, and pharmaceutical partners to transform this domain of supportive care in the same way that antiemetic and growth

with neuropathic pain. For tricyclic antidepressants, gabapentin, and the compounded topical gel, use should occur after discussion with patients about the limited evidence of efficacy in chemotherapy-induced peripheral neuropathy, potential harms and benefits, cost, and patient preferences. The guidelines state that further research on use of these agents in chemotherapy-induced peripheral neuropathy is warranted. The guidelines make a moderate recommendation against use of lamotrigine (intermediate strength of evidence, no evidence of efficacy, low evidence of harm) in treatment of chemotherapyinduced peripheral neuropathy. n

Disclosure: For full disclosures of the authors, visit jco.ascopubs.org.

Editor’s note: ASCO has recently adapted guidelines on screening, assessment, and care of anxiety and depressive symptoms, and fatigue. See pages 49–50 and 54–55 in this issue for more on the newly released guidelines. Reference 1. Hershman DL, Lacchetti C, Dworkin RH, et al: Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. April 17, 2014 (early release online).

factor innovations tackled nausea/ vomiting and neutropenia. When the updated ASCO guideline comes forward in a few years, we will expect that there will be a lot fewer unknowns and a lot more knowns in management of chemotherapyinduced neuropathy. n

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

Reference 1. Hershman DL, Lacchetti C, Dworkin RH, et al: Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. April 14, 2014 (early release online).

ASCO Issues Two New Guidelines on Treating Patients With Advanced, HER2-Positive Breast Cancer, see page 218

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JCO Spotlight Psychosocial Oncology

ASCO Releases Adapted Guideline on Screening, Assessment, and Care of Anxiety and Depressive Symptoms in Adults With Cancer By Matthew Stenger

etection of depression is suboptimal, and its severity is underestimated in the general population, but it is known psychiatric disorders are more common in patients with cancer than in those with any other chronic illness. Although studies in cancer patients have yielded varying figures, it is estimated that point prevalences among cancer patients are 20.7% for any mood disorder, 10.3% for anxiety disorder, and 19.4% for any adjustment disorder. ASCO has adapted the Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer1 for use in the screening, assessment, and care of anxiety and depressive symptoms in adults with cancer.2 The adapted guideline, reported in the Journal of Clinical Oncology, applies to patients aged ≥ 18 years at any phase of the cancer continuum and regardless of cancer type, disease stage, or treatment mo-

jectory of care. Assessment should be performed using validated measures. Depending on levels of symptoms, different treatment pathways are recommended (see below). Failure to identify and treat anxiety and depression in cancer patients increases the risk of poor quality of life and, potentially, risk of disease-related morbidity and mortality. • Health-care practitioners implementing the guideline recommendations should first identify the available resources in their institution and community for the treatment of depressive and anxiety symptoms. The availability and accessibility of supportive care services are important in preventing or reducing the severity of symptoms of psychopathology. It is recommended that patients be screened for depression and anxiety at diagnosis, at regular intervals thereafter, and as needed. Assessments should be a shared responsibility of a clinical team. Concerns such as risk of harm to self and/or others, severe depression or agitation, or the presence of psychosis or confusion warrant immediate referral to a Julia Howe Rowland, PhD Barbara L. Andersen, PhD psychiatrist, psychologist, dality, and it is targeted to professional physician, or equivalently trained health-care providers including medical, professional. surgical, and radiation oncologists, psyThe recommended assessment inchiatrists, psychologists, primary care struments are the nine-item Personal providers, nurses, and others involved in Health Questionnaire (PHQ)-9 for care, as well as to patients, family mem- depression and the seven-item Genbers, and caregivers. eralized Anxiety Disorder (GAD)-7 The pan-Canadian guideline un- scale for anxiety. The adapted guidederwent methodologic review by line lists other assessment instruASCO senior guideline staff members ments that can be used. and content review by an ASCO ad hoc panel including multidisciplinary Depression Initial assessment should be perrepresentation. The expert panel was co-chaired by Barbara L. Andersen, formed with two items from the PHQPhD, The Ohio State University, Co- 9 regarding whether the patient has lumbus, and Julia Howe Rowland, felt little interest or pleasure in activiPhD, of the National Cancer Institute. ties (anhedonia) and has felt down,

Guideline Principles The final recommendations of the adapted guideline are as follows: • All patients with cancer and cancer survivors should be evaluated for symptoms of depression and anxiety periodically across the tra-

ASCO Panel for Guideline on Psychosocial Distress ■■ Barbara l. Andersen, PhD, The Ohio State University, Columbus ■■ Robert J. DeRubeis, MD, University of Pennsylvania, Philadelphia ■■ Barry S. Berman, MD, Broward Health Medical Center, Fort Lauderdale ■■ Jessie Gruman, PhD, Center for Advancing Health, Washington, DC ■■ Victoria L. Champion, PhD, RN, Indiana University, Indianapolis ■■ Mary Jane Massie, MD, Memorial Sloan Kettering Cancer Center, New York ■■ Jimmie Holland, MD, Memorial Sloan Kettering Cancer Center, New York ■■ Ann H. Partridge, MD, Dana-Farber Cancer Institute, Boston ■■ Kate Bak, MSc, American Society of Clinical Oncology ■■ Mark R. Somerfield, PhD, American Society of Clinical Oncology ■■ Julia H. Rowland, PhD, National Cancer Institute, Bethesda

depressed, or helpless (depressed mood). Patients with scores indicating presence of anhedonia or depressed mood should complete the remainder of the PHQ-9. Other patients require no further screening. Scores on the PHQ-9 categorize patients as having no/mild symptoms (1–7), moderate symptoms (8–14), or moderate-to-severe (15–19) or severe (20–27) symptoms. Patients with moderate or greater symptomatology should have further diagnostic assessment to identify the nature and extent of the depressive symptoms and the presence or absence of a mood disorder. Patients with no/mild symptoms should enter Care Pathway 1—supportive care and prevention—and be offered referral to supportive care services (see below). Patients with moderate symptoms should enter Care Pathway 2—psychological (group) or psychosocial intervention. Low-intensity intervention options for these patients include individually guided self-help based on cognitive-behavioral therapy (including behavioral activation and problemsolving), group-based cognitive-behavioral therapy for depression, group psychosocial intervention, and phar-

Anxiety and Depression in Patients With Cancer ■■ All patients with cancer and cancer survivors should be evaluated for symptoms of depression and anxiety periodically across the trajectory of care. ■■ Adequate care requires supportive care services and ongoing follow-up and assessment.

macologic treatment (as appropriate). Patients with moderate-to-severe or severe symptomatology should enter Care Pathway 3, consisting of individual psychological or psychiatric intervention. The high-intensity interventions in this setting include individual cognitive-behavioral therapy or interpersonal therapy, pharmacologic treatment, or both. All patients with moderate or worse symptoms should be referred to supportive care services.

Anxiety Patients should initially be assessed with the GAD-7 scale. Scores on GAD-7 categorize patients as having no/mild symptoms (0–9), moderate symptoms (10–14), or moderate-to-severe or severe symptoms (15–21). Those with no/mild symptoms should be offered referral to supportive care. Low-intensity interventions in those with moderate symptoms include education and active monitoring, nonfacilitated or guided self-help based on cognitivebehavioral therapy, group psychosocial intervention, and pharmacologic intervention (as appropriate). High-intensity interventions in those with moderate-to-severe or severe symptoms include individual psychologic treatment with cognitive-behavioral therapy or applied relaxation, pharmacologic treatment, or both. All patients with moderate or worse symptoms should be referred to supportive care services. continued on page 50

The ASCO Post | MAY 15, 2014

PAGE 50

Perspective

One Step Forward By Jimmie C. Holland, MD

SCO has taken the field of psychosocial oncology a step forward in the right direction by providing guidelines for oncologists to direct care of the two most common emotional symptoms that patients experience: anxiety and depression.1 It is fair to say that all patients experience these symptoms—as well as their families—somewhere along the roller coaster ride of cancer. Anxiety is probably the more ubiquitous, coming in all levels of severity; depression occurs most commonly with sadness, diminished pleasure and zest for living, though it only rarely reaches the level of major or severe depression. The important point of the guidelines is that they take away the guesswork of asking oneself, “is this patient having serious trouble”—by recommending that all patients receive an assessment routinely for both anxiJimmie C. Holland, MD, is the Wayne E. Chapman Chair in Psychiatric Oncology and Attending Psychiatrist in the Department of Psychiatry & Behavioral Sciences at Memorial Sloan-Kettering Cancer Center in New York. Dr. Holland was a member of the ASCO Panel that adapted the guidelines for psychosocial distress.

Anxiety/Depressive Symptoms Guideline continued from page 49

Supportive Care Services Education and information should be provided for the patient and family regarding: • Normalcy of stress in the context of cancer • Specific stress-reduction strategies (eg, progressive muscle relaxation) • Sources of informational support/ resources (patient library, reliable Internet sites) • Availability of supportive care services (eg, professionally led groups, informational lectures, volunteer organizations) at the institution or in the community • Availability of financial support (eg, accommodations, transportation, health/drug benefits) • Information about signs and symptoms of depression if stress or distress worsen and avenues for depression care, or information about signs and symptoms of anxiety disorders

ety and depression, initially and at particularly vulnerable periods in the illness: around diagnosis, awaiting a decision about treatment, managing troublesome side effects either during treatment or as a survivor, and

office staff. However, the screening tool is simply a device to red flag the patient with distress. This must be followed by a conversation in which the oncologist, nurse, or social worker listens carefully to the patient’s problem

The guidelines take away the guess work of asking oneself, “is this patient having serious trouble”—by recommending that all patients receive an assessment routinely for both anxiety and depression. —Jimmie C. Holland, MD

the transition from curative to palliative care. I was honored to serve on the ASCO panel that modified the Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer,2 which have worked so well in Canada.

The Next Step The tools for screening for both anxiety and depression are simple, short, and can be applied rapidly by and their treatment • Information on sleep hygiene and self-management of fatigue • Information on other nonpharmacologic interventions (physical activity, nutrition)

Follow-up and Ongoing Assessment As noted in the adapted guideline, it is common for persons with depressive symptoms to lack the motivation needed to follow through on referrals or to comply with treatment recommendations. Similar considerations apply to persons with anxiety, since cautiousness and tendency to avoid threatening stimuli are primary features of the pathology. Thus, it is recommended that the following measures be taken on a biweekly or monthly basis or until symptoms have remitted in patients with depressive symptoms and on a monthly basis or until symptoms have subsided in those with anxiety: • Assessment of follow-through and compliance with individual or group

and then determines the appropriate referral. Often this might mean receiving more support by the primary team, but it could also require referral to a social worker, mental health resource, or at times, a chaplain. There is no substitute for the personal interaction as the “human” and critical second step. Screening does nothing more than identifying the vulnerable. It is up to the astute and caring staff to take the second step that assures patients that the care they

•

psychological/psychosocial referrals, as well as satisfaction with these services Assessment of compliance with pharmacologic treatment, patient’s concerns about side effects, and satisfaction with the symptom relief If compliance is poor, assessment and construction of a plan to circumvent obstacles to compliance, or discussion of alternative interventions that present fewer obstacles Change in the treatment course (eg, addition of psychological or pharmacologic intervention, change of specific medication, referral to individual psychotherapy if group therapy has not proved helpful) if symptom reduction and satisfaction with treatment are poor, despite good compliance, after 8 weeks of treatment For patients with anxiety, consideration of tapering from antidepressant medications if anxiety symptoms are under control and if the primary environmental sources of anxiety are no longer present

receive is based on genuine concern for them as individuals. The secret to the care of the patient is “caring for the patient,” written by Peabody in 1927 in JAMA3 when he deplored that medical students were getting too much science and not enough about “caring” for patients. How much the treatments change, but how little the “human” issues change. n

Disclosure: Dr. Holland reported no potential conflict of interest.

References 1. Andersen BL, DeRubeis RJ, Berman BS, et al: Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: An American Society of Clinical Oncology Guideline Adaptation. J Clin Oncol. April 14, 2014 (early release online). 2. Howell D, Keller-Olaman S, Oliver T, et al: A pan-Canadian practice guideline: Screening, assessment and care of psychosocial distress (depression, anxiety) in adults with cancer. Canadian Partnership Against Cancer (Cancer Journey Action Group) and the Canadian Association of Psychosocial Oncology, 2010. Available at www.capo.ca. 3. Peabody FW: The Care of the Patient. JAMA 88(12):877-882, 1927.

The panel stated, “Although clinicians may not be able to prevent some of the chronic or late medical effects of cancer, they have a vital role in mitigating the negative emotional and behavioral sequelae. Recognizing and treating effectively those who manifest symptoms of anxiety or depression will reduce the human cost of cancer.” n

Disclosure: The authors reported no potential conflicts of interest.

References 1. Howell D, Keller-Olaman S, Oliver T, et al: A pan-Canadian practice guideline: Screening, assessment and care of psychosocial distress (depression, anxiety) in adults with cancer. Canadian Partnership Against Cancer (Cancer Journey Action Group) and the Canadian Association of Psychosocial Oncology, 2010. Available at www.capo.ca. 2. Andersen BL, DeRubeis RJ, Berman BS, et al: Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: An American Society of Clinical Oncology Guideline Adaptation. J Clin Oncol. April 14, 2014 (early release online).

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Online Extra

Postmastectomy Radiotherapy Benefits Women With Breast Cancer That Has Spread to One to Three Lymph Nodes Among the articles most read on ASCOPost.com, January–April 2014

n women with breast cancer who had between one and three positive lymph nodes, radiotherapy reduced the recurrence rate by 32% and

the breast cancer death rate by 20%. Giving radiotherapy to these women led to nearly 12 fewer recurrences of breast cancer per 100 women after 10

Erbitux® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WArNiNG: SEriOuS iNFuSiON rEACtiONS and CArDiOPuLMONArY ArrESt infusion reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European union (Eu)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-Fu) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing information.] iNDiCAtiONS AND uSAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFr-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.] Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONtrAiNDiCAtiONS None WArNiNGS AND PrECAutiONS infusion reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] use of Erbitux in Combination With radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

years, and eight fewer deaths per 100 women after 20 years. These findings, which were presented at the 2014 European Breast

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor receptor (EGFr) Expression and response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADvErSE rEACtiONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). table 1:

incidence of Selected Adverse reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus radiation radiation therapy Alone (n=208) (n=212) body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc c Alkaline Phosphatase, high 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

Cancer Conference in Glasgow and published in The Lancet,1 confirmed the benefit of radiotherapy after mascontinued on page 52

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Online Extra Postmastectomy Radiotherapy continued from page 51

tectomy in women with four or more positive nodes. Until now, there has been uncertainty over whether women with early breast cancer that has spread to just one, two, or three lymph nodes under the arm gain any benefit from radiotherapy after surgery, said

Paul McGale, PhD, of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) at the Clinical Trial Service Unit, Oxford. However, the findings showed that radiotherapy improves their chances of remaining disease-free and reduces their risk of dying from breast cancer. “Another result from our study is that the proportional benefits of radio-

therapy were similar in women regardless of whether or not they had also received chemotherapy or hormonal therapy. This is important because most women today receive these therapies. Our results suggest that women being treated today are likely also to benefit from radiotherapy if they have any positive lymph nodes,” Dr. McGale

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux (cetuximab) provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). table 2:

incidence of Selected Adverse reactions (≥10%) in Patients with recurrent Locoregional Disease or Metastatic SCCHN Eu-Approved Cetuximab Platinum-based plus Platinum-based therapy with therapy with 5-Fu 5-Fu Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona infections and infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). table 3:

said at a news briefing. The benefit occurred regardless of whether the women were in trials where chemotherapy or hormonal therapy was given to all women. Sixty-five percent of women with one, two, or three positive nodes received chemotherapy, and a further 21% with hormone-sensitive tumors received hormonal therapy.

table 3: (Continued)

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater b c than that seen in the FOLFIRI arm. Adverse reactions were graded using the NCI CTC, V 2.0. Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). table 4:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFr-expressing, Metastatic Colorectal Cancer treated with Erbitux Monotherapya Erbitux plus bSC bSC alone (n=118) (n=124) Grades Grades Grades body System Grades 3 and 4 1–4 3 and 4 Preferred Term 1–4b % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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Online Extra Absolute Benefits Remain to Be Seen Carolyn Taylor, FRCR, a clinical oncologist in the EBCTCG, noted, “We will have to wait for results from new trials to observe directly the long-term effects of modern radiotherapy in women who are given modern chemotherapy and hormonal therapy. However, it is

likely that the percentage reductions in disease recurrence and breast cancer mortality from today’s radiotherapy will be at least as big as the benefits seen here.” Dr. McGale concluded, “Since the time when the women in these trials were randomized, there have been advances in radiotherapy and also in breast screening, surgery, lymph node staging, and systemic

therapy. So the absolute benefits from postmastectomy radiotherapy today may be smaller than those we have reported here. But the proportional benefits from radiotherapy are likely to be at least as big.” To investigate this and follow up on their findings, Dr. McGale, Dr. Taylor, and their colleagues are inviting investigators of more recent trials comparing different

radiotherapy regimens to contribute data to the EBCTCG. n Reference 1. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality. Lancet. March 19, 2014 (early release online).

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The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DruG iNtErACtiONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. uSE iN SPECiFiC POPuLAtiONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

3810101_0207501_UpTheAnti_ROB_v3_M.indd 3

Geriatric use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OvErDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLiNiCAL tOxiCOLOGY Carcinogenesis, Mutagenesis, impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PAtiENt COuNSELiNG iNFOrMAtiON Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Rev August 2013 693US13PBS02201

Meta-Analysis Shows Survival Benefit of Preoperative Chemotherapy in NSCLC

Among the articles most read on ASCOPost.com, January–April 2014

n a systematic review and individual patient meta-analysis reported in The Lancet,1 the NSCLC Meta-analysis Collaborative Group found that neoadjuvant therapy for non–small cell lung cancer (NSCLC) was associated with a significant 13% reduction in risk of death. Significant benefits in recurrence-free survival and time to distant recurrence were also observed.1 Preoperative chemotherapy was associated with a 13% improvement in overall survival. Preoperative chemotherapy was associated with a 15% improvement in recurrence-free survival and a 31% im8/22/13 3:54 PM provement in time to distant recurrence. The investigators concluded, “Findings, which are based on 92% of all patients who were randomised, and mainly stage IB–IIIA, show preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC. The findings suggest this is a valid treatment option for most of these patients. Toxic effects could not be assessed.” For full disclosures of the study authors, visit www.thelancet.com. n Reference 1. NSCLC Meta-analysis Collaborative Group: Preoperative chemotherapy for non-small cell lung cancer. Lancet. February 25, 2014 (early release online).

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The ASCO Post | MAY 15, 2014

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JCO Spotlight Supportive Care

ASCO Releases Adapted Guideline on Screening, Assessment, and Management of Fatigue in Adult Survivors of Cancer By Matthew Stenger

majority of cancer patients experience some level of fatigue during the course of their treatment, and approximately 30% contend with persistent fatigue for years after treatment. Fatigue is among the most common and distressing long-term effects of cancer treatment and significantly affects patient quality of life. ASCO has adapted a pan-Canadian guideline on screening, assessment, and care of cancer-related fatigue in adults with cancer,1 the National Comprehensive Cancer Network (NCCN) Guideline for Cancer-Related Fatigue,2 and the NCCN Guidelines for Survivorship3 for use in the screening, assessment, and management of fatigue in adult survivors of cancer. The adapted guideline, reported in

les, and Paul Jacobsen, PhD, of H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, were the cochairs of the ASCO Expert Panel. The primary guideline question was: “What are the screening, assessment, and treatment approaches to the management of adult cancer survivors who are experiencing symptoms of fatigue after completion of primary treatment?” A summary of the adapted guideline recommendations follows.

Screening All health-care providers should routinely screen patients for the presence of fatigue from diagnosis onward, including after completion of primary treatment. All patients should be screened for fatigue as clinically indicated and at

Given the multiple factors contributing to post-treatment fatigue, interventions should be tailored to each patient’s specific needs. In particular, a number of nonpharmacologic treatment approaches have demonstrated efficacy in cancer survivors. —Julienne E. Bower, MD, PhD

the Journal of Clinical Oncology,4 applies to cancer survivors diagnosed at age ≥ 18 years who have completed primary cancer treatment with curative intent and are in clinical remission off therapy as well as to patients who are diseasefree and have gone on to maintenance or prophylactic therapy. The guideline targets health-care professionals including medical, surgical, and radiation oncologists, psychosocial and rehabilitation professionals, primary care providers, nurses, and others involved in care for survivors, as well as patients, family members, and caregivers of patients who have survived cancer. The pan-Canadian and NCCN guidelines underwent methodologic review by ASCO guideline staff members and content review by an ASCO ad hoc panel, including multidisciplinary representation with guidance from an advisory group. Julienne E. Bower, PhD, of the University of California, Los Ange-

least annually. Screening should be performed and documented using a quantitative or semiquantitative assessment. The adapted guideline includes a list of instruments that can be used.

Comprehensive, Focused Assessment Assessments should be a shared responsibility of a clinical team. History and Physical: A focused fatigue history should be performed, disease status evaluated, and treatable contributing factors assessed. The clinical

Paul z, PhD

team must decide together when referral should be made to an appropriately trained professional (eg, cardiologist, endocrinologist, mental health professional, internist). Laboratory Evaluation: Laboratory evaluation should be considered based on presence of other symptoms and onset and severity of fatigue.

Treatment and Care Options Education and Counseling: All patients should be offered specific education about fatigue after treatment (eg, information about the difference between normal and cancer-related fatigue, persistence of fatigue after treatment, and causes and contributing factors). Patients should be offered advice on general strategies to help manage fatigue. Patients treated for fatigue should be observed and re-evaluated on a regular basis to determine whether treatment is effective. Contributing Factors: All medical and treatable contributing factors should be addressed, including pain, depression, anxiety, emotional distress, sleep disturbance, nutritional deficit, activity level, anemia, medication adverse effects, and comorbidities. Physical Activity: Initiating/maintaining adequate levels of physical activity can reduce cancer-related fatigue after cancer treatment. All patients should be encouraged to engage in a moderate level of physical activity after treatment—eg, 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per

Fatigue in Adult Cancer Survivors ■■ All health-care providers should routinely screen patients for the presence of fatigue from diagnosis onward, including after completion of primary treatment, at least annually and as clinically indicated. ■■ Elements of care include education and counseling, resolution of contributing factors, physical activity programs, psychosocial interventions, mind-body interventions, and pharmacologic interventions.

week with an additional two to three strength training (eg, weight lifting) sessions per week, unless contraindicated. Walking programs are generally safe for most cancer survivors. The American College of Sports Medicine recommends that cancer survivors can begin this type of program after consulting with their physician but without any formal exercise testing (such as a stress test). Survivors at higher risk of injury (eg, those with neuropathy, cardiomyopathy, or other long-term effects of therapy) and patients with severe fatigue interfering with function should be referred to a physical therapist or exercise specialist. Breast cancer survivors with lymphedema should also consider meeting with an exercise specialist before starting upper-body strength training. Psychosocial Interventions: Cognitive behavioral therapy/behavioral therapy and psychoeducational therapy/educational therapy can reduce cancerrelated fatigue in survivors. Survivors should be referred to psychosocial service providers who specialize in cancer and are trained in empirically based interventions. Psychosocial resources for fatigue may also be available through the National Cancer Institute and other organizations. Mind-Body Interventions: There is some evidence that mindfulnessbased approaches, yoga, and acupuncture may reduce fatigue in cancer survivors. Additional research, particularly in the post-treatment population, is needed for biofield therapies (touch therapy), massage, music therapy, relaxation, reiki, and qigong. Survivors should be referred to practitioners who specialize in cancer and who use protocols that have been validated in cancer survivors. Pharmacologic Interventions: There is evidence that psychostimulants (eg, methylphenidate) and other wakefulness agents (eg, modafinil) can be effective in managing fatigue in patients with advanced disease or those receiving active treatment. There is limited evidence of effectiveness in reducing fatigue in patients who are diseasefree after active treatment. Small pilot studies have evaluated the impact of such supplements as ginseng and vitamin D on cancer-related fatigue,

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Perspective

Personalized Cancer Fatigue Care: ASCO Clinical Practice Guideline Adaptation By Eduardo Bruera, MD

he majority of cancer survivors report different levels of cancerrelated fatigue that can last for many years after completion of therapy. The American Society of Clinical Oncology has made a valuable contribution to care of adult cancer survivors by providing a simple and effective clinical practice guideline adaptation.1 The guideline, which is an adaptation of Pan-Canadian2 and National Comprehensive Cancer Network3,4 guidelines, is published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post.

quently associated with physical and emotional symptoms, deconditioning, and, occasionally, laboratory abnormalities. The ASCO guideline has wisely chosen to recommend that laboratory evaluation be conducted on a personalized basis rather than using routine measurement of a large number of hormones, proinflammatory

The guideline raises our awareness of the facts that the specific pathophysiology and clinical causes of fatigue among cancer survivors are still poorly understood and that more research is greatly needed.

Detection and Evaluation Universal screening using simple numerical scales is a very useful approach. The Pan-Canadian guideline adapted by ASCO has been effective in incorporating the screening for fatigue in cancer survivors with the screening for other possible physical and emotional symptoms in these patients, such as pain, anxiety, depression, and sensation of well-being, by recommending the use of multidimensional tools such as the numerical scale Edmonton Symptom Assessment System. This tool is completely free and can be completed in just a couple of minutes by patients attending their oncologist’s or primary doctor’s clinic. For patients in whom fatigue is identified, the guideline proposes a more thorough assessment looking for contributing factors. In almost all patients, cancer-related fatigue is a multidimensional syndrome freDr. Bruera is Professor and Chair, Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston.

but as yet, there is no consistent evidence of the effectiveness of these or other supplements. n The panel stated: “Fatigue is prevalent in cancer survivors and often causes significant disruption in functioning and quality of life. Regular screening, assessment, and education and appropriate treatment of fatigue are important in managing this distressing

Counseling, particularly cognitive behavioral therapy and other integrative interventions, can also be quite effective in selected patient groups. The guideline wisely recommends caution before starting patients on pharmacologic interventions. These patients may need treatment for prolonged periods of time, and drugs that have been found to be effective in

—Eduardo Bruera, MD

markers, and other laboratory tests that are expensive and have generally limited diagnostic accuracy.

Key Interventions With regard to management, the guideline also proposes a personalized approach. As it is in the case of fatigue associated with advanced cancer, it is important to correct all identified treatable contributing factors including polypharmacy, hypogonadism, hypothyroidism, deconditioning, and, very particularly, undiagnosed mood changes and sleep disturbances. Increased physical activity and exercise are among the most useful interventions in this patient population. Most patients do not need referral to a specialist to be able to enroll in a program of increased physical activity. symptom. Given the multiple factors contributing to post-treatment fatigue, interventions should be tailored to each patient’s specific needs. In particular, a number of nonpharmacologic treatment approaches have demonstrated efficacy in cancer survivors.” n References 1. Howell D, Keller-Olaman S, Oliver

patients with fatigue associated with advanced cancer, such as methylphenidate or corticosteroids, have potentially severe side effects when used for long periods.

More Research Needed Unfortunately, the majority of our currently available interventions for fatigue in cancer survivors have a mild to moderate effect size. The current practice guideline is extremely useful in promoting an approach that emphasizes limited invasive investigations, encourages a healthy life-style, and cautions against potentially risky pharmacologic interventions. The guideline also raises our awareness of the facts that the specific pathophysiology and clinical causes of fatigue among cancer survivors are TK, et al: A pan-Canadian practice guideline and algorithm: screening, assessment and supportive care of adults with cancer-related fatigue. Curr Oncol 20:e233e246, 2013. 2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue (version 1.2013). Available at www.nccn.org. 3. National Comprehensive Cancer

still poorly understood and that more research is greatly needed. Specifically, future research should be focused on identifying subgroups of patients in whom fatigue is associated with specific pathophysiologic abnormalities rather than gathering all comers under the label of “cancer-related fatigue in survivors.” It is quite possible that some of the previously described interventions that are only mildly to moderately effective in the overall population of patients with cancer-related fatigue may be extremely effective in specific subgroups. In this regard, personalized therapy for fatigue will hopefully soon become part of future clinical guidelines. n

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

References 1. Bower JE, Bak K, Berger A, et al: Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation. J Clin Oncol. April 21, 2014 (early release online). 2. Howell D, Keller-Olaman S, Oliver TK, et al: A pan-Canadian practice guideline and algorithm: Screening, assessment and supportive care of adults with cancer-related fatigue. Curr Oncol 20:e233-e246, 2013. 3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue (version 1.2013). Available at www.nccn.org. 4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Survivorship (version 1.2013). Available at www.nccn.org.

Network: NCCN Clinical Practice Guidelines in Oncology: Survivorship (version 1.2013). Available at www.nccn.org. 4. Bower JE, Bak K, Berger A, et al: Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation. J Clin Oncol. April 14, 2014 (early release online).

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Conjunctival Conjunctival Conjunctival or corneal or corneal orirritation, corneal irritation, irritation, dry eye, dryor dry eye, eye eye, orpain eye or occurred eye painpain occurred occurred in 13%in 13% in 13% Compromised Compromised Compromised WoundWound Healing WoundHealing and Healing Gastrointestinal and andGastrointestinal Gastrointestinal Perforation: Perforation: Perforation: Since Iclusig Since Since Iclusig Iclusig of patients. of patients. of patients. VisualVisual blurring Visual blurring occurred blurring occurred occurred in 6%inof6% the in 6% ofpatients. the of the patients. patients. Other Other ocular Other ocular toxicities ocular toxicities toxicities may compromise may may compromise compromise wound wound healing, woundhealing, interrupt healing,interrupt interrupt Iclusig for Iclusig Iclusig at least for for1atatweek least leastprior 11week week to prior prior to to include include cataracts, include cataracts, cataracts, glaucoma, glaucoma, glaucoma, iritis, iritis, iridocyclitis, iritis, iridocyclitis, iridocyclitis, and ulcerative andand ulcerative ulcerative keratitis. keratitis. keratitis. Conduct Conduct Conduct major surgery. major major surgery. Serious surgery.Serious gastrointestinal Seriousgastrointestinal gastrointestinal perforation perforation perforation (fistula) occurred (fi(fistula) stula)occurred occurred in one patient inin one one patient patient comprehensive comprehensive comprehensive eye exams eye eye exams atexams baseline at baseline at and baseline periodically andand periodically periodically duringduring treatment. during treatment. treatment. 38 days38post-cholecystectomy. 38 days days post-cholecystectomy. post-cholecystectomy. Hemorrhage: Hemorrhage: Hemorrhage: Serious Serious bleeding Serious bleeding events, bleeding events, including events, including including fatalities, fatalities, fatalities, occurred occurred occurred in 5% in (22/449) 5% in 5% (22/449) (22/449) Embryo-Fetal Embryo-Fetal Embryo-Fetal Toxicity: Toxicity: Toxicity: Iclusig can Iclusig Iclusig cause can can fetal cause cause harm. fetal fetal If harm. Iclusig harm.Ifis IfIclusig Iclusig used during isisused used during during of patients of patients of treated patients treated with treated Iclusig. withwith Iclusig. Hemorrhagic Iclusig. Hemorrhagic Hemorrhagic eventsevents occurred events occurred occurred in 24%inof24% inpatients. 24% of patients. of patients. pregnancy, pregnancy, pregnancy, or if theorpatient orif the if the becomes patient patientbecomes becomes pregnantpregnant while pregnant taking while while Iclusig, taking taking the Iclusig, Iclusig, patient the the should patient patientshould should The incidence The The incidence incidence of serious of serious ofbleeding serious bleeding events bleeding events was events higher waswas higher in higher patients in patients in with patients accelerated with with accelerated accelerated be apprised bebe apprised apprised of the potential ofofthethepotential potential hazard to hazard hazard the fetus. totothe the Advise fetus. fetus.women Advise Adviseto women women avoid to pregnancy toavoid avoid pregnancy pregnancy phasephase CML phase CML (AP-CML), CML (AP-CML), (AP-CML), BP-CML, BP-CML, BP-CML, and Ph+ andand ALL. Ph+Ph+ Most ALL.ALL. hemorrhagic Most Most hemorrhagic hemorrhagic events,events, but events, notbutbut notnot while taking while while Iclusig. taking takingIclusig. Iclusig. all occurred all occurred all occurred in patients in patients inwith patients grade withwith grade 4 thrombocytopenia. grade 4 thrombocytopenia. 4 thrombocytopenia. Interrupt Interrupt Iclusig Interrupt Iclusig forIclusig serious forfor serious serious Most common Most Most common common non-hematologic non-hematologic non-hematologic adverseadverse reactions: adversereactions: reactions: (≥20%) were (≥20%) (≥20%) hypertension, were werehypertension, hypertension, or severe or severe orhemorrhage severe hemorrhage hemorrhage and evaluate. and and evaluate. evaluate. rash, abdominal rash, rash, abdominal abdominal pain, fatigue, pain, pain,fatigue, headache, fatigue,headache, headache, dry skin,dry dry constipation, skin, skin,constipation, constipation, arthralgia, arthralgia, arthralgia, FluidFluid Retention: Fluid Retention: Retention: Serious Serious flSerious uid retention fluidflretention uid retention eventsevents occurred events occurred occurred in 3% in (13/449) 3% in 3% (13/449) of (13/449) of of nausea,nausea, and nausea, pyrexia. and andpyrexia. Hematologic pyrexia.Hematologic Hematologic adverseadverse reactions adversereactions reactions includedincluded thrombocytopenia, includedthrombocytopenia, thrombocytopenia, patients patients treated patients treated with treated Iclusig. withwith Iclusig. One Iclusig. instance OneOne instance of instance brain of edema brain of brain edema was edema fatal. waswas Infatal. total, fatal. In total, In total, anemia,anemia, neutropenia, anemia,neutropenia, neutropenia, lymphopenia, lymphopenia, lymphopenia, and leukopenia. and andleukopenia. leukopenia. fluid flretention uidflretention uid retention occurred occurred occurred in 23% in 23% ofinthe 23% ofpatients. the of the patients. patients. The most TheThe common most most common common fluid retention fluid fluid retention retention PleasePlease see Please thesee Brief seethe the Summary Brief BriefSummary Summary of the full ofofthe thefull full events events were events were peripheral were peripheral peripheral edema edema (16%), edema (16%), pleural (16%), pleural effusion pleural effusion (7%), effusion (7%), and(7%), pericardial andand pericardial pericardial Prescribing Prescribing Prescribing Information Information Information on the on following on the the following following pages, pages, pages, effusion effusion (3%). effusion (3%). Monitor (3%). Monitor patients Monitor patients for patients fluid forretention flfor uidfluid retention retention and manage andand manage patients manage patients as patients clinically as as clinically clinically including including including the Boxed the the Boxed Warning, Boxed Warning, Warning, for additional for for additional additional indicated. indicated. indicated. Interrupt, Interrupt, Interrupt, reduce, reduce, orreduce, discontinue or discontinue or discontinue IclusigIclusig asIclusig clinically as clinically as clinically indicated. indicated. indicated. important important important safety safety information. safetyinformation. information. Cardiac Cardiac Arrhythmias: Cardiac Arrhythmias: Arrhythmias: Symptomatic Symptomatic Symptomatic bradyarrhythmias bradyarrhythmias bradyarrhythmias that led that tothat led a requirement led to atorequirement a requirement for pacemaker for pacemaker for pacemaker implantation implantation implantation occurred occurred occurred in 1%in(3/449) 1% in 1% (3/449) of(3/449) Iclusig-treated of Iclusig-treated of Iclusig-treated patients. patients. patients. Note: UnlessNote: otherwise Note: Unless Unless indicated, otherwise otherwise data indicated, presented indicated, data data presented presented are from Iclusig are are from [package from Iclusig Iclusig insert]. [package [package Cambridge, insert]. insert]. MA: Cambridge, Cambridge, MA:MA: Advise Advise patients Advise patients to patients report to report to signs report signs andsigns symptoms andand symptoms symptoms suggestive suggestive suggestive of slowofheart slow of slow rate heart heart raterate Iclusig is a registered Iclusig Iclusig trademark is isa registered a registered of ARIAD trademark trademark Pharmaceuticals, ofofARIAD ARIADPharmaceuticals, Pharmaceuticals, Inc. Inc. Inc. ARIAD Pharmaceuticals, ARIAD ARIAD Pharmaceuticals, Pharmaceuticals, Inc.; JanuaryInc.; 2014. Inc.; January January 2014. 2014. © 2014 ARIAD Pharmaceuticals, ©©2014 2014ARIAD ARIADPharmaceuticals, Pharmaceuticals, Inc. All rights reserved. Inc. Inc.All Allrights rightsreserved. reserved. (fainting, (fainting, (fainting, dizziness, dizziness, dizziness, or chest or chest pain). or chest pain). Supraventricular pain). Supraventricular Supraventricular tachyarrhythmias tachyarrhythmias tachyarrhythmias occurred occurred occurred in in in Reference: Reference: PB/0314/0070/US PB/0314/0070/US PB/0314/0070/US 1. Data Reference: on file. 1. Data 1. Data on fion le.file.

BRIEF SUMMARY BRIEF SUMMARY Iclusig® (ponatinib) Iclusig® (ponatinib) Rx only Rx only Please consult Please full Prescribing consult fullInformation, Prescribing Information, including Boxed including Warning, Boxed Warning, available at Iclusig.com. available at Iclusig.com.

Venous Thromboembolism Venous Thromboembolism

Venous thromboembolic Venous thromboembolic events occurred events in 5% occurred (23/449)in of5%Iclusig-treated (23/449) of Iclusig-treated patients, patients, including deepincluding venous thrombosis deep venous(8 thrombosis patients), pulmonary (8 patients), embolism pulmonary (6 patients), embolism (6 patients), superficial thrombophlebitis superficial thrombophlebitis (3 patients), and (3 patients), retinal vein and thrombosis retinal vein(2thrombosis patients). Consider (2 patients). Consider dose modification doseormodification discontinuation or discontinuation of Iclusig in patients of Iclusig who in develop patientsserious who develop venousserious venous thromboembolism thromboembolism [see Dosage and [seeAdministration Dosage and Administration (2.3)]. (2.3)]. 5.2

Heart Failure 5.2 Heart Failure

Fatal and serious Fatalheart and failure seriousorheart left ventricular failure or left dysfunction ventricularoccurred dysfunction in 5% occurred of Iclusig-treated in 5% of Iclusig-treated patients (N=22). patients Eight (N=22). percent Eight of patients percent (N=35) of patients experienced (N=35)any experienced grade of heart any grade failureoforheart left failure or lef ventricular dysfunction. ventricularMonitor dysfunction. patients Monitor for signs patients or symptoms for signs consistent or symptoms with consistent heart failure withand heart failure a See full prescribing See fullinformation prescribingfor information complete for boxed complete warning. boxed warning. treat as clinically treatindicated, as clinically including indicated, interruption includingofinterruption Iclusig. Consider of Iclusig. discontinuation Consider discontinuation of Iclusig of Iclusig • Vascular Occlusion: • VascularArterial Occlusion: and venous Arterialthrombosis and venousand thrombosis occlusions andhave occlusions occurred have in occurred in in patients who in develop patientsserious who develop heart failure serious[see heart Dosage failureand [seeAdministration Dosage and Administration (2.3)]. (2.3)]. at least 27% at of least Iclusig 27% treated of Iclusig patients, treated including patients, fatal including myocardial fatalinfarction, myocardialstroke, infarction, stroke, 5. 5.3 theHepatotoxicity 5.3 Hepatotoxicity stenosis of large stenosis arterial of large vessels arterial of thevessels brain, severe of the brain, peripheral severe vascular peripheral disease, vascular and disease, the and need for urgent need revascularization for urgent revascularization procedures. Patients procedures. withPatients and without with cardiovascular and without cardiovascular Iclusig can cause Iclusig hepatotoxicity, can cause hepatotoxicity, including liverincluding failure and liver death. failure Fulminant and death. hepatic Fulminant failurehepatic failure risk factors, risk including factors, patients including lesspatients than 50 years less than old,50 experienced years old, experienced these events.these Monitor events. Monitorleading to death leading occurred to death in anoccurred Iclusig-treated in an Iclusig-treated patient within patient one week within of starting one week Iclusig. of starting Two Iclusig. Two for evidence for of thromboembolism evidence of thromboembolism and vascularand occlusion. vascular Interrupt occlusion. or stop Interrupt Iclusig or stop Iclusig additional fataladditional cases of fatal acutecases liver failure of acute also liver occurred. failure also Theoccurred. fatal cases The occurred fatal cases in patients occurred in patients immediately immediately for vascular occlusion. for vascular (5.1). occlusion. (5.1). with blast phase with(BP) blast CML phase or Ph+ (BP)ALL. CMLSevere or Ph+hepatotoxicity ALL. Severe hepatotoxicity occurred in alloccurred disease cohorts. in all disease cohorts. • Heart Failure, • Heart including Failure, fatalities, including occurred fatalities, in 8% occurred of Iclusig-treated in 8% of Iclusig-treated patients. Monitor patients. Monitor The incidenceThe of aspartate incidenceaminotransferase of aspartate aminotransferase (AST) or alanine (AST) aminotransferase or alanine aminotransferase (ALT) elevation(ALT) elevatio 5. cardiac function. cardiac Interrupt function. or stop Interrupt Iclusig orfor stop new Iclusig or worsening for new orheart worsening failure heart (5.2). failure (5.2). was 56% (all grades) was 56% and (all8% grades) (gradeand 3 or8% 4).(grade Iclusig3treatment or 4). Iclusig maytreatment result in elevation may resultininALT, elevation in ALT, AST, or both. ALT AST, or or AST both. elevation ALT or AST was elevation not reversed was by not the reversed date of by last the follow-up date of last in 5% follow-up of patients. in 5% of patien • Hepatotoxicity, • Hepatotoxicity, liver failure and liverdeath failure have andoccurred death have in Iclusig-treated occurred in Iclusig-treated patients. Monitor patients. Monitor WARNING: VASCULAR WARNING:OCCLUSION, VASCULAR HEART OCCLUSION, FAILURE, HEART andFAILURE, HEPATOTOXICITY and HEPATOTOXICITY

hepatic function. hepatic Interrupt function. Iclusig Interrupt if hepatotoxicity Iclusig if hepatotoxicity is suspected is(2.3, suspected 5.3). (2.3, 5.3).

INDICATIONS 1 INDICATIONS AND USAGE AND USAGE

Monitor liver function Monitor tests liver function at baseline, teststhen at baseline, at least monthly then at least or as monthly clinicallyorindicated. as clinically Interrupt, indicated. Interrup reduce or discontinue reduce orIclusig discontinue as clinically Iclusigindicated as clinically [seeindicated Dosage and [seeAdministration Dosage and Administration (2.3)]. (2.3)].

5.4

Hypertension 5.4 Hypertension

Iclusig is a kinase Iclusig inhibitor is a kinase indicated inhibitor for the: indicated for the:

Treatment-emergent Treatment-emergent hypertension occurred hypertension in 67% occurred of patients in 67% (300/449). of patients Eight (300/449). patients Eight (2%) patients (2%) 5. treatedinwith clinical Iclusig trialsinexperienced clinical trialstreatment-emergent experienced treatment-emergent symptomatic hypertension symptomatic hypertensio • Treatment of• adult Treatment patients of adult with T315I-positive patients with T315I-positive chronic myeloid chronic leukemia myeloid (chronic leukemia phase, (chronic phase, treated with Iclusig as a serious adverse as a serious reaction, adverse including reaction, hypertensive including crisis. hypertensive Patientscrisis. may require Patientsurgent may require urgent accelerated phase, accelerated or blastphase, phase)ororblast T315I-positive phase) or T315I-positive Philadelphia chromosome Philadelphia positive chromosome acutepositive acute clinical intervention clinicalfor intervention hypertension for associated hypertension with associated confusion, with headache, confusion, chest headache, pain, or chest pain, or lymphoblasticlymphoblastic leukemia (Ph+leukemia ALL). (Ph+ ALL). shortness of breath shortness [see of Adverse breathReactions [see Adverse (6)].Reactions In patients(6)]. withInbaseline patients systolic with baseline BP<140 systolic mm Hg BP<140 mm H • Treatment of•adult Treatment patients of with adultchronic patientsphase, with chronic accelerated phase, phase, accelerated or blastphase, phase or chronic blast phase myeloidchronic myeloidand baseline diastolic and baseline BP<90 diastolic mm Hg, BP<90 78% (220/282) mm Hg, 78% experienced (220/282)treatment-emergent experienced treatment-emergent leukemia or Ph+ leukemia ALL fororwhom Ph+ ALL no other for whom tyrosine no other kinase tyrosine inhibitor kinase (TKI) inhibitor therapy is (TKI) indicated. therapy(1) is indicated. hypertension; (1) hypertension; 49% (139/282)49% developed (139/282) Stage developed 1 hypertension Stage 1(defined hypertension as systolic (defined BP≥140 as systolic mm Hg BP≥140 mm H or or diastolic mm Hg) BP≥90 whilemm 29%Hg) developed while 29% Stage developed 2 hypertension Stage 2 (defined hypertension as systolic (defined as systolic These indications These areindications based uponareresponse based upon rate.response There arerate. no trials Thereverifying are no trials an improvement verifying an inimprovement in diastolic BP≥90 BP≥160 mm Hg BP≥160 or diastolic mm Hg BP≥100 or diastolic mm Hg). BP≥100 In 131 mm patients Hg). Inwith 131 Stage patients 1 hypertension with Stage 1 at hypertension at 5. disease-relateddisease-related symptoms or increased symptomssurvival or increased with Iclusig. survival with Iclusig. baseline, 61%baseline, (80/131) 61% developed (80/131) Stage developed 2 hypertension. Stage 2 hypertension. Monitor and manage Monitorblood and manage pressureblood pressure CONTRAINDICATIONS 4 CONTRAINDICATIONS elevations during elevations Iclusig during use andIclusig treat use hypertension and treat to hypertension normalize blood to normalize pressure. blood Interrupt, pressure. doseInterrupt, do

None 5

reduce, or stopreduce, Iclusigorif stop hypertension Iclusig if is hypertension not medically is not controlled. medically controlled.

None 5.5

WARNINGS 5 AND WARNINGS PRECAUTIONS AND PRECAUTIONS

Pancreatitis 5.5 Pancreatitis

Clinical pancreatitis Clinicaloccurred pancreatitis in 6% occurred (28/449)in of 6%patients (28/449) (5% of grade patients 3) treated (5% grade with3)Iclusig. treated with Iclusig. Pancreatitis resulted Pancreatitis in discontinuation resulted in discontinuation or treatment interruption or treatmentininterruption 6% of patients in 6% (25/449). of patients (25/449). Arterial and venous Arterialthrombosis and venousand thrombosis occlusions, andincluding occlusions, fatalincluding myocardial fatal infarction, myocardial stroke, infarction, stroke, Twenty-two ofTwenty-two the 28 cases of of thepancreatitis 28 cases ofresolved pancreatitis withinresolved 2 weekswithin with 2dose weeks interruption with doseorinterruption or6 stenosis of large stenosis arterial of vessels large arterial of the vessels brain, severe of the peripheral brain, severe vascular peripheral disease, vascular and the disease, need and the need reduction. Thereduction. incidenceThe of treatment-emergent incidence of treatment-emergent lipase elevation lipase was elevation 41%. was 41%. for urgent revascularization for urgent revascularization procedures have procedures occurredhave in atoccurred least 27%in of at Iclusig-treated least 27% of Iclusig-treated patients patients Check serum lipase Check every serum2lipase weeksevery for the 2 weeks first 2 months for the first and2then months monthly and thereafter then monthly or as thereafter or as from the phasefrom 1 and thephase phase21trials. and phase Iclusig2 can trials. cause Iclusig fatal can and cause life-threatening fatal and life-threatening vascular vascular clinically Consider indicated. additional Consider serum additional lipase monitoring serum lipase in patients monitoring with in apatients history with of a history of occlusion within occlusion 2 weekswithin of starting 2 weeks treatment. of starting Iclusig treatment. can also Iclusig causecan recurrent also cause or multi-site recurrent or multi-site clinically indicated. pancreatitis orpancreatitis alcohol abuse. or alcohol Dose interruption abuse. Doseorinterruption reduction may or reduction be required. mayInbecases required. whereIn cases where vascular occlusion. vascular occlusion. lipase elevations lipase areelevations accompanied are accompanied by abdominal by symptoms, abdominal interrupt symptoms, treatment interrupt withtreatment Iclusig with Iclusig In the dose-escalation In the dose-escalation (phase 1) clinical (phase trial,1)48% clinical (31/65) trial, of48% patients (31/65) with of CML patients or Ph+ withALL CML or Ph+ ALL and evaluate patients and evaluate for pancreatitis patients for[see pancreatitis Dosage and [seeAdministration Dosage and Administration (2.3)]. Do not consider (2.3)]. Do not consider developed vascular developed occlusive vascular events. occlusive The median events.time Thetomedian onset of time thetofirst onset vascular of the occlusion first vascular occlusion restarting Iclusig restarting until patients Iclusig have until patients completehave resolution complete of symptoms resolution and of symptoms lipase levels andare lipase lesslevels are les event was 5 months. event was Iclusig 5 months. can cause Iclusig fatal can and cause life-threatening fatal and life-threatening vascular occlusion vascular in patients occlusion in patients than 1.5 x ULN. than 1.5 x ULN. treated at dosetreated levels at asdose low as levels 15 mg as low per day. as 15 mg per day. 5.6 Neuropathy 5.6 Neuropathy Patients with and Patients without withcardiovascular and without cardiovascular risk factors, including risk factors, patients including age 50 patients years or age younger, 50 years or younger, Peripheral andPeripheral cranial neuropathy and cranialhave neuropathy occurredhave in Iclusig-treated occurred in Iclusig-treated patients. Overall, patients. 13% Overall, 13% experienced these experienced events. Vascular these events. occlusion Vascular adverse occlusion eventsadverse were more events frequent were more with increasing frequent with increasing (59/449) of Iclusig-treated patients experienced patientsaexperienced peripheral neuropathy a peripheralevent neuropathy of any grade event of any grade age and in patients age and with in prior patients history withofprior ischemia, historyhypertension, of ischemia, hypertension, diabetes, or hyperlipidemia diabetes, or hyperlipidemia (59/449) of Iclusig-treated (2%, grade 3/4). (2%, In grade clinical3/4). trials, In clinical the mosttrials, common the most peripheral common neuropathies peripheral reported neuropathies werereported were (see Table 4). (see Table 4). peripheral neuropathy peripheral(4%, neuropathy 18/449),(4%, paresthesia 18/449),(4%, paresthesia 17/449), (4%, hypoesthesia 17/449), hypoesthesia (2%, 11/449), (2%, 11/449), and hyperesthesia and hyperesthesia (1%, 5/449). Cranial (1%, 5/449). neuropathy Cranial developed neuropathy in 1% developed (6/449) in of 1% Iclusig-treated (6/449) of Iclusig-treated Table 4: Vascular TableOcclusion 4: Vascular Incidence Occlusion in Iclusig-Treated Incidence in Iclusig-Treated Patients Patients patients (<1%patients grade 3/4). (<1% grade 3/4). in Phase 2 Trial in Phase According 2 Trial to According Risk Categories to Risk Categories Of the patientsOfwho the developed patients who neuropathy, developed31% neuropathy, (20/65) developed 31% (20/65) neuropathy developedduring neuropathy the during the Prior history of ischemia, Prior history of ischemia, No history of ischemia, No history of ischemia, treatment. month Monitor of treatment. patients Monitor for symptoms patients for of neuropathy, symptoms ofsuch neuropathy, as hypoesthesia, such as hypoesthesia, hypertension, diabetes, hypertension, diabetes, hypertension, diabetes, hypertension, diabetes, first month of first hyperesthesia,hyperesthesia, paresthesia, discomfort, paresthesia,a discomfort, burning sensation, a burning neuropathic sensation,pain neuropathic or weakness. pain or weakness. or hyperlipidemia or hyperlipidemia or hyperlipidemia or hyperlipidemia Consider interrupting ConsiderIclusig interrupting and evaluate Iclusig ifand neuropathy evaluate is if neuropathy suspected. is suspected. Age: 49 or younger Age: 49 or younger 18% (6/33) 18% (6/33) 12% (13/112) 12% (13/112)

5.1

Vascular 5.1Occlusion Vascular Occlusion

Age: 50 to 74 years Age: 50 to 74 years

33% (50/152)

18% (20/114)

Age: 75 and olderAge: 75 and older

56% (14/25)

46% (6/13)

All age groups

33% (70/210)

16% (39/239)

5.7

Ocular5.7 Toxicity Ocular Toxicity

Serious ocularSerious toxicities ocular leading toxicities to blindness leadingortoblurred blindness vision or blurred have occurred vision have in Iclusig-treated occurred in Iclusig-treated patients. Retinal patients. toxicities Retinal including toxicities macular including edema, macular retinaledema, vein occlusion, retinal vein andocclusion, retinal and retinal Total Total 24% (109/449) 24% (109/449) hemorrhage occurred hemorrhage in 3%occurred of Iclusig-treated in 3% of Iclusig-treated patients. Conjunctival patients.orConjunctival corneal irritation, or corneal dry eye, irritation, dry eye or eye pain occurred or eye pain in 13% occurred of patients. in 13%Visual of patients. blurringVisual occurred blurring in 6% occurred of patients. in 6%Other of patients. ocular Other ocul toxicities include toxicities cataracts, include glaucoma, cataracts, iritis, glaucoma, iridocyclitis, iritis,and iridocyclitis, ulcerativeand keratitis. ulcerative Conduct keratitis. Conduct Arterial Occlusion Arterial andOcclusion Thrombosis and Thrombosis comprehensivecomprehensive eye exams at baseline eye exams andatperiodically baseline and during periodically treatment during [seetreatment Adverse Reactions [see Adverse (6)]. Reactions (6)] Arterial occlusion Arterial andocclusion thrombosis andoccurred thrombosis in atoccurred least 20%in (91/449) at least 20% of Iclusig-treated (91/449) of Iclusig-treated patients patients 5.8 Hemorrhage with some patients with some experiencing patients events experiencing of moreevents than one of more type.than Patients one type. have Patients required have required 5.8 Hemorrhage revascularization revascularization procedures (cerebrovascular, procedures (cerebrovascular, coronary, and coronary, peripheraland arterial) peripheral due toarterial) vascular due to vascular Serious bleeding Serious events, bleeding including events, fatalities, including occurred fatalities, in 5% occurred (22/449)in of 5%patients (22/449) treated of patients with treated with occlusion fromocclusion Iclusig. from Iclusig. Iclusig. Hemorrhage Iclusig.occurred Hemorrhage in 24% occurred of patients. in 24%The of incidence patients. The of serious incidence bleeding of serious events bleeding events was higher in was patients higher with in accelerated patients withphases accelerated (AP) CML, phases BP-CML, (AP) CML, and BP-CML, Ph+ ALL.and Cerebral Ph+ ALL. Cerebral Cardiac vascular Cardiac occlusion, vascular including occlusion, fatalincluding and life-threatening fatal and life-threatening myocardial infarction myocardial andinfarction and hemorrhage gastrointestinal and gastrointestinal hemorrhage were hemorrhage the mostwere commonly the most reported commonly serious reported serious coronary artery coronary occlusion artery has occlusion occurred in has12% occurred (55/449) in 12% of Iclusig-treated (55/449) of Iclusig-treated patients. Patients patients. Patients hemorrhage and bleeding events. bleeding Most hemorrhagic events. Mostevents, hemorrhagic but notevents, all, occurred but notinall,patients occurred with in grade patients 4 with grade 4 have developed have heart developed failure concurrent heart failure or concurrent subsequentortosubsequent the myocardial to the ischemic myocardial event. ischemic event. thrombocytopenia thrombocytopenia [see Warnings[see and Warnings Precautions and(5.11)]. Precautions Interrupt (5.11)]. Iclusig Interrupt for serious Iclusig or for severe serious or severe Cerebrovascular Cerebrovascular occlusion, including occlusion, fatalincluding stroke, has fatal occurred stroke, in has6% occurred (27/449)inof6% Iclusig-treated (27/449) of Iclusig-treated hemorrhage and hemorrhage evaluate [see and evaluate Dosage and [seeAdministration Dosage and Administration (2.3)]. (2.3)]. patients. Iclusig patients. can cause Iclusig stenosis can cause over multiple stenosis segments over multiple in major segments arterial in major vesselsarterial that supply vessels that supply 5.9 Fluid Retention 5.9 Fluid Retention the brain (e.g.,the carotid, brain vertebral, (e.g., carotid, middle vertebral, cerebral middle artery). cerebral artery). All age groups

Fluid retentionFluid events retention judged events as serious judged occurred as serious in 3%occurred (13/449)inof3% patients (13/449) treated of patients with Iclusig. treated with Iclusig. Peripheral arterial Peripheral occlusive arterial events, occlusive including events, fatalincluding mesenteric fatal artery mesenteric occlusion artery andocclusion lifeand lifeOne instance of One brain instance edemaofwas brainfatal. edema Serious was fluid fatal.retention Serious fluid events retention in moreevents than 1inpatient more than 1 patient threatening peripheral threatening arterial peripheral disease, arterial have disease, occurredhave in 8% occurred (36/449)in of 8%Iclusig-treated (36/449) of Iclusig-treated patients. patients. included: effusion pericardial (6/449, effusion 1%), pleural (6/449,effusion 1%), pleural (5/449, effusion 1%), and (5/449, ascites 1%), (2/449, and ascites <1%).(2/449, <1% Patients have Patients developed have digital developed or distaldigital extremity or distal necrosis extremity and have necrosis required and have amputations. required amputations. included: pericardial

In total, fluid occurred retention in 23% occurred of the patients. in 23% ofThe the most patients. common The most fluid common retention fluid events retention events Clinicians should Clinicians consider should whether consider the benefits whetherofthe Iclusig benefits treatment of Iclusig are treatment expected to areexceed expected to exceed In total, fluid retention were edema peripheral (16%), edema pleural (16%), effusionpleural (7%),effusion and pericardial (7%), and effusion pericardial (3%). effusion (3%). the risks of therapy. the risks In patients of therapy. suspected In patients of developing suspected of arterial developing thrombotic arterial events, thrombotic interrupt events, or interrupt orwere peripheral stop Iclusig. Astop benefit-risk Iclusig. Aconsideration benefit-risk consideration should guide ashould decision guide to restart a decision Iclusig to restart therapy.Iclusig [see therapy. [seeMonitor patients Monitor for fluid patients retention for fluid and manage retentionpatients and manage as clinically patients indicated. as clinically Interrupt, indicated. reduce, Interrupt, or reduce, Dosage and Administration Dosage and Administration (2.3)]. (2.3)]. discontinue Iclusig discontinue as clinically Iclusig indicated as clinically [see indicated Dosage and [seeAdministration Dosage and Administration (2.3)]. (2.3)].

.10 Cardiac5.10 Arrhythmias Cardiac Arrhythmias

ft and g

.11

on .12

nts.

pt,

).13 on

.14

ose

Table 5: Adverse Table Reactions 5: Adverse Occurring Reactions in >10% Occurring of Patients, in >10% Any ofGroup Patients, Any Group CP-CML CP-CML AP-CML AP-CML BP-CML BP-CML Ph+ ALL Ph+ ALL (N=270) (N=270) (N=85) (N=85) (N=62) (N=62) (N=32) (N=32) Any CTCAE Any Any CTCAE CTCAE Any Any CTCAE CTCAE Any Any CTCAE CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade (%) 3 / 4 (%) (%) 3 3/ 4/ 4 (%) (%) 3 3/ 4/ 4 (%) (%) 3 3/ 4/ 4 (%) 3 / 4 (%) (%) (%) (%) (%) (%) (%) (%) Supraventricular Supraventricular tachyarrhythmias tachyarrhythmias occurred in 5% occurred (25/449)in of5%Iclusig-treated (25/449) of Iclusig-treated patients. patients. Cardiac or Vascular Cardiac disorders or Vascular disorders Atrial fibrillation Atrial wasfibrillation the most was common the most supraventricular common supraventricular tachyarrhythmia tachyarrhythmia and occurred and in occurred in Hypertension (a)Hypertension (a) 68 39 6871 3936 7165 3626 6553 2631 53 31 20 patients. The 20 other patients. supraventricular The other supraventricular tachyarrhythmias tachyarrhythmias were atrial flutter were(4atrial patients), flutter (4 patients), Arterial ischemia Arterial (b)* ischemia (b)* 20 11 2019 119 1910 95 103 50 3 0 supraventricular supraventricular tachycardia (4tachycardia patients), and (4 patients), atrial tachycardia and atrial(1tachycardia patient). For(113patient). patients, For 13 patients,Cardiac Failure Cardiac (c)* Failure (c)* 7 4 76 44 615 48 156 83 6 3 the event led to thehospitalization. event led to hospitalization. Advise patients Advise to report patients signstoand report symptoms signs and of rapid symptoms heart of rapid heart Gastrointestinal Gastrointestinal disorders disorders rate (palpitations, rate dizziness). (palpitations, Interrupt dizziness). Iclusig Interrupt and evaluate. Iclusig and evaluate. Abdominal painAbdominal (d) pain (d) 49 10 4940 108 4034 86 3444 66 44 6 Constipation Constipation 37 2 3724 22 2426 20 2647 03 47 3 Myelosuppression 5.11 Myelosuppression Nausea Nausea 23 1 2327 10 2732 02 3222 20 22 0 Severe (gradeSevere 3 or 4) (grade myelosuppression 3 or 4) myelosuppression occurred in 48% occurred (215/449) in 48% of patients (215/449) treated of patients with treated with Diarrhea Diarrhea 16 1 1626 10 2618 03 1813 33 13 3 Iclusig. The incidence Iclusig. The of these incidence events of was thesegreater eventsinwas patients greater with in AP-CML, patients with BP-CML, AP-CML, BP-CML, Vomiting Vomiting 13 2 1324 20 2423 02 2322 20 22 0 and Ph+ ALL than and Ph+ in patients ALL than with in chronic patientsphase with chronic (CP) CML. phase Obtain (CP)complete CML. Obtain blood complete counts blood counts Oral mucositis (e) Oral mucositis (e) 10 1 10 15 1 1 15 23 1 0 23 9 0 3 9 3 every 2 weeksevery for the 2 weeks first 3 months for the first and3then months monthly and or then as monthly clinicallyorindicated, as clinically andindicated, adjust theand adjust the GI hemorrhage GI (f) hemorrhage (f) 2 <1 28 <11 811 15 119 56 9 6 dose as recommended dose as recommended [see Dosage and [seeAdministration Dosage and Administration (2.2)]. (2.2)]. Blood and lymphatic Blood and system lymphatic disorders system disorders Tumor 5.12 Lysis Syndrome Tumor Lysis Syndrome Febrile neutropenia Febrile neutropenia 1 <1 14 <14 411 411 1125 1125 25 25 Infections and infestations Infections and infestations Two patients (<1%) Two patients treated(<1%) with Iclusig treateddeveloped with Iclusig serious developed tumorserious lysis syndrome. tumor lysis Both syndrome. cases Both cases Sepsis Sepsis 1 1 15 15 58 58 822 822 22 22 occurred in patients occurred with in advanced patients with CML. advanced Hyperuricemia CML. Hyperuricemia occurred in 7% occurred (30/449)in of 7%patients; (30/449) of patients; Pneumonia Pneumonia 3 2 311 29 1113 911 139 113 9 3 the majority had thechronic majorityphase had chronic CML (19phase patients). CML Due (19 patients). to the potential Due tofor thetumor potential lysisfor tumor lysis Urinary tract infection Urinary tract infection 7 1 712 11 120 10 09 00 9 0 syndrome in patients syndrome with in advanced patients with disease advanced (AP-CML, disease BP-CML, (AP-CML, or Ph+ BP-CML, ALL), ensure or Ph+ adequate ALL), ensure adequate Upper respiratory Upper tractrespiratory infection tract infection 11 1 118 10 811 02 110 20 0 0 hydration and hydration treat highand urictreat acid high levelsuric prior acid to levels initiating prior therapy to initiating with Iclusig. therapy with Iclusig. NasopharyngitisNasopharyngitis 9 0 912 00 123 00 33 00 3 0 Compromised 5.13 Compromised Wound Healing Wound and Gastrointestinal Healing and Gastrointestinal Perforation Perforation Cellulitis Cellulitis 2 1 24 12 411 23 110 30 0 0 system Nervous disorders system disorders No formal studies No formal of the studies effect ofofIclusig the effect on wound of Iclusig healing on wound have been healing conducted. have been Based conducted. on Based Nervous on Headache Headache 39 3 3928 30 2831 03 3125 30 25 0 the mechanism theofmechanism action [see of Clinical actionPharmacology [see Clinical Pharmacology (12.1)], Iclusig (12.1)], could compromise Iclusig couldwound compromise wound Peripheral (g)*neuropathy (g)* 16 2 1611 21 118 10 86 00 6 0 healing. Serious healing. gastrointestinal Serious gastrointestinal perforation (fistula) perforation occurred (fistula) in one occurred patient in38one days patient post-38 days post- Peripheral neuropathy Dizziness Dizziness 11 0 115 00 55 00 53 00 3 0 cholecystectomy. cholecystectomy. Respiratory, thoracic, Respiratory, and mediastinal thoracic, anddisorders mediastinal disorders Interrupt Iclusig Interrupt for at least Iclusig 1 week for at prior leastto1 major week prior surgery. to major The decision surgery. when The decision to resume when Iclusig to resume Iclusig Pleural effusionPleural effusion 3 1 311 12 1113 20 1319 03 19 3 after surgery should after surgery be based should on clinical be based judgment on clinical of adequate judgmentwound of adequate healing.wound healing. Cough Cough 12 0 1217 00 1718 00 186 00 6 0 Embryo-Fetal 5.14 Embryo-Fetal Toxicity Toxicity Dyspnea Dyspnea 11 2 1115 22 1521 27 216 70 6 0 Skin and subcutaneous Skin and tissue subcutaneous disorderstissue disorders Iclusig can cause Iclusig fetal can harm cause when fetaladministered harm when to administered a pregnant to woman a pregnant basedwoman on its mechanism based on its mechanism Rash and related Rash conditions and related conditions 54 5 5448 58 4839 85 3934 56 34 6 of action and findings of actioninand animals. findings Ponatinib in animals. caused Ponatinib embryo-fetal caused toxicity embryo-fetal in ratstoxicity at exposures in rats at exposures Dry skin 39 2 3927 21 2724 12 2425 20 25 0 lower than human lowerexposures than human at the exposures recommended at the recommended human dose. Ifhuman this drug dose. is used If thisduring drug is used during Dry skin Musculoskeletal and connectiveand tissue connective disorders tissue disorders pregnancy, or pregnancy, if the patient orbecomes if the patient pregnant becomes whilepregnant taking this while drug, taking the this patient drug, should the patient be should Musculoskeletal be Arthralgia 26 2 2631 21 3119 10 1913 00 13 0 apprised of theapprised potentialofhazard the potential to the hazard fetus. Advise to the women fetus. Advise to avoid women pregnancy to avoid while pregnancy taking while takingArthralgia Myalgia Myalgia 22 1 2220 10 2016 00 166 00 6 0 Iclusig [see Use Iclusig in Specific [see Use Populations in Specific(8.1)]. Populations (8.1)]. Pain in extremity Pain in extremity 17 2 1717 20 1713 00 139 00 9 0 ADVERSE 6 REACTIONS ADVERSE REACTIONS Back pain Back pain 15 1 1511 12 1116 22 1613 20 13 0 Muscle spasmsMuscle spasms 12 0 125 00 55 00 513 00 13 0 Because clinical Because trials are clinical conducted trials are under conducted widely varying under widely conditions, varying adverse conditions, reaction adverse ratesreaction rates Bone pain 12 <1 1212 <11 1211 13 119 33 9 3 observed in the observed clinical trials in theofclinical a drugtrials cannot of abedrug directly cannot compared be directly withcompared rates in the withclinical rates in the clinicalBone pain General disorders General and disorders administration and administration site conditionssite conditions trials of another trials drug of and another maydrug not reflect and may thenot rates reflect observed the rates in clinical observed practice. in clinical practice. Fatigue or asthenia Fatigue or asthenia 39 3 3936 36 3635 65 3531 53 31 3 The following The adverse following reactions adverse are discussed reactions are in greater discussed detail in greater in otherdetail sections in other of thesections of the Pyrexia Pyrexia 23 1 2331 15 3132 53 3225 30 25 0 prescribing information: prescribing information: Edema, peripheral Edema, peripheral 13 <1 1319 <10 1913 00 1322 00 22 0 • Vascular Occlusion • Vascular [seeOcclusion Warnings[see and Warnings Precautions and(5.1)] Precautions (5.1)] Pain Pain 8 <1 87 <10 716 03 166 33 6 3 Chills Chills 7 0 7 11 0 0 11 13 0 2 13 9 2 0 9 0 • Heart Failure• [see HeartDosage Failureand [seeAdministration Dosage and Administration (2.3) and Warnings (2.3) and and Warnings Precautions and(5.2)] Precautions (5.2)] Metabolism andMetabolism nutrition disorders and nutrition disorders • Hepatotoxicity • Hepatotoxicity [see Dosage and [seeAdministration Dosage and Administration (2.3) and Warnings (2.3) and and Warnings Precautions and(5.3)] Precautions (5.3)] Decreased appetite Decreased appetite 8 <1 812 <11 128 10 831 00 31 0 Investigations Investigations • Hypertension• Hypertension [see Warnings[see and Warnings Precautions and(5.4)] Precautions (5.4)] Weight decreased Weight decreased 6 <1 67 <10 75 00 513 00 13 0 • Pancreatitis•[see Pancreatitis Dosage and [seeAdministration Dosage and Administration (2.3) and Warnings (2.3) and and Warnings Precautions and(5.5)] Precautions (5.5)] Psychiatric disorders Psychiatric disorders 0 Insomnia Insomnia 7 0 712 00 128 00 89 00 9 • Neuropathy •[see Neuropathy Warnings[see and Warnings Precautions and(5.6)] Precautions (5.6)]

Symptomatic bradyarrhythmias Symptomatic bradyarrhythmias that led to a requirement that led to afor requirement pacemakerfor implantation pacemakeroccurred implantation occurred in 1% (3/449) inof1% Iclusig-treated (3/449) of Iclusig-treated patients. The cardiac patients.rhythms The cardiac (1 case rhythms each) (1 identified case each) identified were completewere heartcomplete block, sick heart sinus block, syndrome, sick sinus andsyndrome, atrial fibrillation and atrial withfibrillation bradycardia withand bradycardia and System Organ System Class Organ Class pauses. Advisepauses. patients Advise to report patients signstoand report symptoms signs and suggestive symptoms of suggestive slow heart rate of slow (fainting, heart rate (fainting, dizziness, or chest dizziness, pain).orInterrupt chest pain). Iclusig Interrupt and evaluate. Iclusig and evaluate.

• Ocular Toxicity • Ocular [see Warnings Toxicity [see and Warnings Precautions and(5.7)] Precautions (5.7)] • Hemorrhage•[see Hemorrhage Warnings[see and Warnings Precautions and(5.8)] Precautions (5.8)] • Fluid Retention • Fluid [seeRetention Warnings[see and Warnings Precautions and(5.9)] Precautions (5.9)] • Cardiac Arrhythmias • Cardiac[see Arrhythmias Warnings[see and Warnings Precautions and(5.10)] Precautions (5.10)]

Adverse drug reactions,Adverse reported drug using reactions, MedDRA reported and graded usingusing MedDRA NCI-CTC-AE and graded v 4.0 using (NCINCI-CTC-AE Common Terminology v 4.0 (NCI Criteria CommonforTerminology Adverse Events) Criteria forfor assessment Adverse Events) of toxicity. for assessment of toxicity. Treatment-emergent, all Treatment-emergent, causality events all causality events (a) derived from blood (a) pressure derived(BP) frommeasurement blood pressure recorded (BP) measurement monthly while recorded on trial monthly while on trial (b) includes cardiovascular, (b) includes cerebrovascular, cardiovascular, and peripheral cerebrovascular, vascular and ischemia peripheral vascular ischemia (c) includes cardiac failure, (c) includes cardiaccardiac failure congestive, failure, cardiac cardiogenic failure congestive, shock, cardiopulmonary cardiogenic shock, failure, cardiopulmonary ejection fractionfailure, decreased, ejection pulmonary fraction decreased, edema, rightpulmonary ventricularedema, failureright ventricular failure (d) includes abdominal(d) pain, includes abdominal abdominal pain upper, pain, abdominal abdominalpain painupper, lower, abdominal abdominal pain discomfort lower, abdominal discomfort (e) includes aphthous stomatitis, (e) includeslipaphthous blister, mouth stomatitis, ulceration, lip blister, oral mouth mucosal ulceration, eruption, oral oral mucosal pain, oropharyngeal eruption, oral pain, pain, pharyngeal oropharyngeal ulceration, pain, pharyngeal stomatitis, tongue ulceration, ulceration stomatitis, tongue ulceration (f) includes gastric hemorrhage, (f) includesgastric gastriculcer hemorrhage, hemorrhage, gastric hemorrhagic ulcer hemorrhage, gastritis,hemorrhagic gastrointestinal gastritis, hemorrhage, gastrointestinal hematemesis, hemorrhage, hematochezia, hematemesis, hemorrhoidal hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, hemorrhage, intra-abdominal melena, rectal hemorrhage, hemorrhage, melena, and rectal upper hemorrhage, gastrointestinal and upper hemorrhage gastrointestinal hemorrhage (g) includes burning sensation, (g) includes skinburning burningsensation, sensation,skin hyperesthesia, burning sensation, hypoesthesia, hyperesthesia, neuralgia, hypoesthesia, neuropathy neuralgia, peripheral,neuropathy paresthesia, peripheral, peripheralparesthesia, sensorimotor peripheral sensorimotor neuropathy, peripheralneuropathy, motor neuropathy, peripheral peripheral motor neuropathy, sensory neuropathy, peripheralpolyneuropathy sensory neuropathy, polyneuropathy *represents an additional *represents 13 months anofadditional follow-up13 months of follow-up

• Myelosuppression • Myelosuppression [see Dosage and [seeAdministration Dosage and Administration (2.2) and Warnings (2.2) and and Warnings Precautions and(5.11)] Precautions (5.11)]

The adverse reactions The adverse described reactions in this described sectioninwere this identified section were in a identified single-arm, in aopen-label, single-arm, open-label, international, multicenter international,trial multicenter in 449 patients trial in with 449 CML patients or Ph+ withALL CMLwhose or Ph+ disease ALL whose was disease was considered to considered be resistanttoorbeintolerant resistanttoorprior intolerant tyrosine to prior kinase tyrosine inhibitor kinase (TKI) inhibitor therapy including (TKI) therapy including Table 6: Serious Table Adverse 6: Serious Reactions Adverse (SAR) Reactions (SAR) those with thethose BCR-ABL with T315I the BCR-ABL mutation. T315I All patients mutation.received All patients a starting received dosea of starting 45 mgdose Iclusig of 45 mg Iclusig once daily. At once the time daily. of At analysis, the timetheofmedian analysis,duration the median of treatment durationwith of treatment Iclusig was with 337 Iclusig was 337 CardiovascularCardiovascular disorders disorders event*ischemic event* days in patients days with in CP-CML, patients with 362 CP-CML, days in patients 362 days with in AP-CML, patients with 89 days AP-CML, in patients 89 days with in patients withArterial ischemicArterial BP-CML, and BP-CML, 81 days inand patients 81 days with in Ph+ patients ALL.with ThePh+ median ALL.dose The intensity median dose was intensity 37 mg orwas 83%37 mg or 83%Cardiovascular Cardiovascular of the expected of 45 themg expected dose. The 45 mg events dose. of The arterial events ischemia, of arterial cardiac ischemia, failure,cardiac and peripheral failure, and peripheral CerebrovascularCerebrovascular Peripheral vascular neuropathy reported neuropathy in Tables reported 5 andin 6Tables include 5 and data6from include an additional data from 13 an months additional of follow-up 13 months of follow-upPeripheral vascular Hemorrhage Hemorrhage (median duration (median of treatment durationCP-CML: of treatment 672 CP-CML: days, AP-CML: 672 days, 590 AP-CML: days, BP-CML: 590 days, 89 days, BP-CML: 89 days, CNS hemorrhage CNS hemorrhage Ph+ ALL: 81 days). Ph+ ALL: 81 days). GastrointestinalGastrointestinal hemorrhage hemorrhage

Adverse reactions Adverse reported reactions in more reported than 10% in more of allthan patients 10% of treated all patients with Iclusig treatedinwith this trial Iclusig arein this trialCardiac are failure*Cardiac failure* Effusions(a) Effusions(a) presented in Table presented 5. Overall, in Table the5.most Overall, common the most non-hematologic common non-hematologic adverse reactions adverse (≥ 20%) reactions (≥ 20%) Atrial fibrillationAtrial fibrillation were hypertension, were hypertension, rash, abdominal rash, pain, abdominal fatigue, headache, pain, fatigue, dryheadache, skin, constipation, dry skin, arthralgia, constipation, arthralgia, Venous thromboembolism Venous thromboembolism nausea, and pyrexia. nausea, and pyrexia. Hypertension Hypertension

e, lar

%).

Gastrointestinal Gastrointestinal disorders disorders The rates of treatment-emergent The rates of treatment-emergent adverse eventsadverse resulting events in discontinuation resulting in discontinuation were 13% in were 13% in Pancreatitis Pancreatitis CP-CML, 11%CP-CML, in AP-CML, 11%15% in AP-CML, in BP-CML, 15%and in BP-CML, 9% in Ph+and ALL. 9%The in Ph+ mostALL. common The most adverse common adverse Abdominal painAbdominal pain events that ledevents to treatment that leddiscontinuation to treatment discontinuation were thrombocytopenia were thrombocytopenia (4%) and infections (4%) and (1%). infectionsBlood (1%). and lymphatic Blood and system lymphatic disorders system disorders

Febrile neutropenia Febrile neutropenia Dose modifications Dose modifications (dose delays or(dose dosedelays reductions) or dose due reductions) to adversedue reactions to adverse occurred reactions in 74% occurred in 74% Thrombocytopenia of the patients.ofThe the most patients. common The most adverse common reactions adverse (≥5%) reactions that led(≥5%) to dose that modifications led to dose modifications Thrombocytopenia Anemia Anemia include thrombocytopenia include thrombocytopenia (30%), neutropenia (30%),(13%), neutropenia lipase increased (13%), lipase (12%), increased rash (11%), (12%), rash (11%),Infections Infections abdominal (11%), pancreatitis pain (11%),(6%), pancreatitis and ALT,(6%), AST,and or GGT ALT,increased AST, or GGT (6%). increased (6%). Pneumonia Pneumonia , or abdominal pain Sepsis General Pyrexia

Sepsis General Pyrexia

(a) includes pericardial effusion, (a) includes pleural pericardial effusion,effusion, and ascites pleural effusion, and ascites * represents an additional* represents 13 months an of follow-up additional 13 months of follow-up

N (%)

53 (11.8%) 28 (6.2%) 18 (4.0%) 16 (3.6%) 22 (4.9%) 10 (2.2%) 10 (2.2%) 22 (4.9%) 13 (2.9%) 11 (2.4%) 10 (2.2%) 8 (1.8%)

23 (5.1%) 17 (3.8%)

13 (2.9%) 13 (2.9%) 12 (2.7%)

24 (5.3%) 11 (2.4%)

14 (3.1%)

Laboratory Abnormalities

USE IN SPECIFIC POPULATIONS

Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7).

8.1

Pregnancy Pregnancy Category D Risk Summary

Table 7: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22

Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. 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. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 8: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase.

8.3

It is unknown whether ponatinib 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 ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother. 8.4 8.5

8.6

In a drug interaction study in healthy volunteers, coadministration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)]. 7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS

Drugs That Are Strong Inhibitors of CYP3A Enzymes

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Forty-six percent of patients ≥ 65 years had vascular occlusion events. Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Based on in vitro studies, ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)]. 7.1

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

*Graded using NCI-CTC-AE v 4.0

Nursing Mothers

8.7

Renal Impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and noncardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (1-855-552-7423) medinfo@ariad.com PB/0314/0074/US

ASCOPost.com | MAY 15, 2014

PAGE 61

JCO Spotlight Thoracic Oncology

Ceritinib Highly Active in Patients With ALK-Rearranged Advanced NSCLC By Matthew Stenger

on–small cell lung cancer (NSCLC) harboring ALK rearrangement is sensitive to the ALK inhibitor crizotinib (Xalkori), but resistance ultimately occurs. In a phase I study reported in The New England Journal of Medicine, Alice T. Shaw, MD, PhD, of Dana-Farber/ Harvard Cancer Center, Boston, and colleagues found that the more-potent ALK inhibitor ceritinib was capable of producing responses in advanced ALKrearranged NSCLC, including in patients with prior crizotinib treatment and irrespective of the presence of ALK resistance mutations.1 Ceritinib is an oral ATP-competitive inhibitor of ALK tyrosine kinase that has been found to be 20 times more potent than crizotinib against ALK in enzymatic assays. Ceritinib also inhibits the IGF1 receptor, against which it is manyfold less potent than against ALK, and unlike crizotinib it does not inhibit MET kinase activity. Ceritinib has shown marked antitumor activity against both crizotinibsensitive and crizotinib-resistant tumors in xenograft models of ALK-rearranged NSCLC.

Study Details In the dose-escalation phase of the study, 59 patients with tumors harboring ALK alterations received ceritinib at doses of 50 to 750 mg once daily in 21-day cycles. In an expansion phase, 71 patients were treated at the maximum tolerated dose of 750 mg/d. Among the total of 130 patients, 122 had advanced NSCLC and had previously received cytotoxic chemotherapy (of the other 8 patients, 4 had breast cancer and 1 patient each had alveolar rhabdomyosarcoma, rectal adenocarcinoma, anaplastic large-cell lymphoma, and inflammatory myofibroblastic tumor). In patients with NSCLC, the presence of ALK rearrangement was required in ≥ 15% of tumor cells as detected by fluorescence in situ hybridization (FISH) assay with the use of break-apart probes. Of the 122 patients with advanced NSCLC, 83 (68%) had received crizotinib. In the dose-escalation phase, dose-limiting toxicities included diarrhea, vomiting, nausea, dehydration, elevated alanine transaminase (ALT), and hypophosphatemia. All dose-limiting toxicities resolved on discontinuation of treatment.

Response Rates Among 114 patients with NSCLC who received ceritinib ≥ 400 mg/d, 66 (58%, 95% confidence interval [CI] =

48%–67%) had an objective response, including confirmed complete response in 1 (1%) and confirmed partial response in 65 (57%); 22% had stable disease, 11% had progressive disease, and response was not known in the 10% who withdrew early from the study. Among the 78 patients receiving 750 mg daily, response rate was 59% (95% CI = 47%–70%). The response rate was 56% (95% CI = 45%–67%) among the 80 patients receiving ≥ 400 mg/d who had previously received crizotinib and 56% (95% CI = 41%–70%) among those receiving 750 mg/d. Among the 34 patients receiving ≥ 400 mg/d who had not received prior crizotinib, the response rate was 62% (95% CI = 44%–78%). The investigators noted that “some responses were rapid and dramatic.” Responses were also observed in untreated central nervous system (CNS) lesions in

Ceritinib in Advanced Lung Cancer ■■ In a dose-escalation phase, the maximum tolerated ceritinib dose was 750 mg/d, the highest tested dose. ■■ Ceritinib at ≥ 400 mg/d produced response in the majority of patients with advanced ALK-rearranged NSCLC irrespective of prior treatment with the ALK inhibitor crizotinib. ■■ Responses were observed in patients with disease progression on prior crizotinib irrespective of the presence of resistance mutations.

months) CNS metastases at baseline. Overall survival data were immature at the time of data cutoff, with data censored for 72% of patients. Overall survival at 12 months was 65%, and median overall survival had not been reached.

Response by Molecular Status A total of 19 patients with NSCLC who had disease progression during crizotinib treatment had prestudy biop-

Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. —Alice T. Shaw, MD, PhD, and colleagues

patients who had received prior crizotinib treatment, with similar tumor responses observed in those who had not received crizotinib.

Response Duration and Survival Among the 66 responding patients who had received ceritinib ≥ 400 mg/d, 64% had a response lasting ≥ 6 months. Median duration of response was 8.2 months; however, data for 47% of the patients with response were censored at the time of data cutoff. Among 114 patients receiving ≥ 400 mg/d, median follow-up was 9.5 months and median progression-free survival was 7.0 months, with data for 38% of patients being censored. Median progressionfree survival was 6.9 months in the 80 patients who had previously received crizotinib; in the 34 who had not received prior crizotinib, median progression-free survival was 10.4 months, with data censored for 53% and a median follow-up of 9.5 months. Progression-free survival was similar among the 64 patients with (6.9 months) and 50 patients without (7.0

sies showing ALK rearrangement, including 12 with no additional alteration other than the original rearrangement, 5 with secondary resistance mutations in the tyrosine kinase domain, and 2 with ALK amplification. Tumor regression was observed in all patients regardless of molecular status, with confirmed response observed in 6 of the 7 patients with ALK gene amplification or secondary resistance mutation and in 7 of 12 patients with the original ALK alteration. The investigators noted, “These findings suggest that the activity of ceritinib in patients whose tumors had progressed during crizotinib treatment may be independent of the underlying mechanism of acquired resistance.”

Toxicities The most common adverse events of any grade were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and increased ALT (35%). The most common grade 3 or 4 adverse events considered related to study drug were increased ALT (21%), increased aspartate transami-

nase (11%), diarrhea (7%), and increased lipase levels (7%), with all being reversible on discontinuation of treatment. Four cases of interstitial lung disease were considered possibly related to ceritinib, with all resolving on discontinuation of ceritinib and use of standard treatments. One case of asymptomatic grade 3 prolongation of corrected QT interval was considered possibly related to ceritinib. Dose reduction was required in 51% of patients (median duration of interruption = 7.3 days), and treatment was discontinued in 6% of patients due to adverse events. In patients receiving ceritinib at 750 mg/d, dose reduction was required in 62% of patients, with most reductions occurring in treatment cycle 3 or later. There were no treatment-related deaths. The investigators concluded: “Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK…. Among patients with ALK-rearranged NSCLC for whom crizotinib is no longer effective, more potent inhibition of the target by a structurally distinct ALK kinase inhibitor such as ceritinib can induce substantial and durable responses in the majority of cases. Confirmatory trials of the clinical activity of ceritinib in NSCLC are needed, involving patients who have received prior crizotinib treatment and those who have not.” n Disclosure: The study was funded by National Cancer Institute and V Foundation Translational Research grants, Be a Piece of the Solution, Evan Spirito Memorial Foundation, and by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.

Editors’ note: Ceritinib was recently approved by FDA for late-stage lung cancer (see page 62). Reference 1. Shaw AT, Kim D-W, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.

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FDA Update

FDA Approves Ceritinib for Late-Stage Lung Cancer

he U.S. Food and Drug Administration (FDA) has granted accelerated approval to ceritinib (Zykadia) for patients with a metastatic anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) who were previously treated with crizotinib (Xalkori). Ceritinib is an ALK tyrosine kinase inhibitor that works by blocking proteins that promote the development of cancerous cells. Ceritinib is the fourth drug with breakthrough therapy designation to receive FDA approval. It is being approved 4 months ahead of the product’s prescription drug user fee goal date of August 24, 2014, when the agency was scheduled to complete review of the drug application. The FDA granted ceritinib breakthrough therapy designation, priority review, and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time of the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively.

Safety and Efficacy Ceritinib’s safety and efficacy established in a clinical trial of 163

participants with metastatic ALKpositive NSCLC who had shown disease progression or were intolerant to crizotinib. All participants received ceritinib at a dose of 750 mg once daily. The primary endpoint supporting approval was objective response rate according to RECIST version 1.0, as evaluated by both investigator and blinded independent central review committee (BIRC). Duration of response was also assessed. The trial results demonstrated durable responses of large magnitude with an overall response rate of 44% (95 confidence interval [CI] = 36– 52) and duration of response of 7.1 months based on BIRC-determined tumor assessments. The analysis by investigator assessment showed similar results, with an overall response rate of 55% (95% CI = 47–62) and duration of response of 7.4 months. Common side effects of ceritinib include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities such as increased liver enzymes, pancreatic enzymes, and increased glucose levels were also observed. n

FDA Approves Siltuximab for Rare Castleman’s Disease

he U.S. Food and Drug Administration (FDA) has approved siltuximab (Sylvant injection) for the treatment of patients with multicentric Castleman’s disease who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)negative. Multicentric Castleman’s disease is a rare disorder similar to lymphoma that causes an abnormal overgrowth of immune cells in lymph nodes and related tissues in the body. The disease usually affects adults, who often suffer from fever, night sweats, weight loss, and weakness or fatigue. Siltuximab is the first FDA-approved drug to treat multcentric Castleman’s disease.

Durable Tumor Response With Siltuximab The approval was based on an international, multicenter, randomized (2:1), phase II study comparing every-3-week intravenous infusions of siltuximab and best supportive care to placebo and best supportive care. The trial enrolled 79 patients and randomly allocated 53 patients to the siltuximab arm plus best supportive care and 26 patients to the placebo arm plus best supportive care. Siltuximab was admin-

istered every 3 weeks as an intravenous infusion at a dose of 11 mg/kg. The primary endpoint was durable tumor and symptomatic response, defined as a tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response rates were 34% (18/53) vs 0% (0/26) for the siltuximab and placebo groups, respectively (95% confidence interval [CI] = 11.1–54.8, P = .0012). Additional supportive prespecified endpoints included tumor response, time to treatment failure, and an increase in hemoglobin of at least 1.5 g/dL at week 13 in patients who were anemic at study entry. Tumor response rates were 38% vs 4% for the siltuximab and placebo groups, respectively (P < .05). The median time to treatment failure, with a median follow-up of 422 days, was not reached in the siltuximab arm and was 134 days in the placebo arm (hazard ratio [HR] = 0.418, 95% CI = 0.21–0.82, P < .05). An increase in the level of hemoglobin described above was observed in 19 patients on the siltuximab arm and no patients on the placebo arm (95% CI = 28.3–85.1, P < .05). The common adverse reactions during treatment included pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. n

FDA Approves First HPV Test for Primary Cervical Cancer Screening

he U.S. Food and Drug Administration (FDA) approved the first human papillomavirus (HPV) DNA test that can be used as a primary cervical cancer screening test for women aged 25 years and older. The test also can provide information about the patient’s risk for developing cervical cancer in the future. Using a sample of cervical cells, the cobas HPV Test detects DNA from 14 high-risk HPV types. The test specifically identifies HPV 16 and HPV 18, while concurrently detecting 12 other types of high-risk HPV. Based on results of the cobas HPV Test, women who test positive for HPV 16 or HPV 18 should have a colposcopy;

women testing positive for one or more of the 12 other high-risk HPV types should have a Pap test to determine the need for a colposcopy. Health-care professionals should use the cobas HPV Test results together with other information, such as the patient screening history and risk factors, and current professional guidelines.

New Option for Screening The FDA first approved the cobas HPV Test in 2011 for use in conjunction with or as a follow-up to a Pap test. Today’s approval expands the use of the test to include use as either a co-test or as a primary cervical cancer screening test, however; it does

not change current medical practice guidelines for cervical cancer screening. These guidelines are developed, reviewed, and modified by groups other than the FDA. “Today’s approval offers women and physicians a new option for cervical cancer screening,” said Alberto Gutierrez, PhD, Director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health. “Roche Diagnostics conducted a well-designed study that provided the FDA with a reasonable assurance of the safety and effectiveness when used as a primary screening tool for cervical cancer.” Data supporting the use of the

cobas HPV Test as a primary screening test for cervical cancer included a study of more than 40,000 women 25 years and older undergoing routine cervical exams. Women who had a positive Pap test or whose cervical cells screened positive for HPV, as well as a subset of women whose Pap and HPV tests were both negative, underwent a colposcopy and cervical tissue biopsy. All biopsy results were compared to the Pap and cobas HPV Test results. Data from this study, which included 3 years of follow-up on women who went to colposcopy, showed that the cobas HPV Test is safe and effective for the new indication for use. n

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FDA Update

FDA Proposes to Extend Its Tobacco Authority to Additional Tobacco Products, Including E-Cigarettes

n April 24, 2014, as part of its implementation of the Family Smoking Prevention and Tobacco Control Act signed by the President in 2009, the U.S. Food and Drug Administration (FDA) proposed a new rule that would extend the agency’s tobacco authority to cover additional tobacco products. Products that would be deemed to be subject to FDA regulation are those that meet the statutory definition of a tobacco product, including currently unregulated marketed products, such as electronic cigarettes (e-cigarettes), cigars, pipe tobacco, nicotine gels, waterpipe (or hookah) tobacco, and dissolvables not already under the FDA’s authority. The FDA currently regulates cigarettes, cigarette tobacco, roll-yourown tobacco, and smokeless tobacco.

is one of the most critical public health challenges before the FDA,” said Mitch Zeller, Director of the FDA’s Center for Tobacco Products. “The proposed rule would give the FDA additional tools to

protect the public health in today’s rapidly evolving tobacco marketplace, including the review of new tobacco products and their health-related claims.” The FDA proposes different compli-

ance dates for various provisions so that all regulated entities, including small businesses, will have adequate time to comply with the requirements of the proposed rule. n

Proposed Requirements Consistent with currently regulated tobacco products, under the proposed rule, makers of newly deemed tobacco products would, among other requirements: • Register with the FDA and report product and ingredient listings; • Only market new tobacco products after FDA review; • Only make direct and implied claims of reduced risk if the FDA confirms that scientific evidence supports the claim and that marketing the product will benefit public health as a whole; and • Not distribute free samples. • In addition, under the proposed rule, the following provisions would apply to newly “deemed” tobacco products: • Minimum age and identification restrictions to prevent sales to underage youth; • Requirements to include health warnings; and • Prohibition of vending machine sales, unless in a facility that never admits youth.

Critical Public Health Challenge “Tobacco remains the leading cause of death and disease in this country. This is an important moment for consumer protection and a significant proposal that if finalized as written would bring FDA oversight to many new tobacco products,” said FDA Commissioner Margaret A. Hamburg, MD. “Science-based product regulation is a powerful form of consumer protection that can help reduce the public health burden of tobacco use on the American public, including youth.” “Tobacco-related disease and death

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FDA Update

FDA Approves Mercaptopurine Oral Suspension for Acute Lymphoblastic Leukemia

n April 28, 2014, the U.S. Food and Drug Administration approved a 20 mg/mL oral suspension of mercaptopurine (Purixan) indicated for the treatment of patients with acute

lymphoblastic leukemia (ALL) as part of a combination regimen. Successive clinical trials have demonstrated that mercaptopurine contributes to successful maintenance therapy and improved

survival of patients with ALL. This approval was based on a clinical pharmacology study that assessed the bioequivalence of mercaptopurine tablets with that of mercaptopu-

rine oral suspension in a healthy adult population.

New Formulation The drug was originally approved in

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FDA Update

1953 and has been commercially available as a 50-mg tablet. However, body surface area dosing and dose adjustments are not easily accomplished with the 50-mg tablet, and tablets are not an ideal dosage form of medication for children less than 6 years old. Ad hoc local formulations compounded in pharmacies are commonly used, and 50-mg tablets are often split to

provide children with the desired dose. Compared to tablets, a suspension offers the advantage of more accurately delivering the desired dose to children with

a wide range of weights using a consistent administration schedule and also allows more flexibility in adjusting the dose. A commercially produced suspension is more likely to provide a more consistent dose of mercaptopurine than ad hoc compounded formulations. The starting dose of mercaptopurine in multiagent combination chemo-

therapy maintenance regimens is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose. After initiating mercaptopurine, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count and platelet count to ensure sufficient drug exposure and to adjust for excessive hematologic toxicity. n

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FDA Update

Supplemental New Drug Application Submitted for Ibrutinib in CLL

harmacyclics, Inc, and Janssen Biotech, Inc, have announced the submission of a supplemental New Drug Application to the U.S. Food and Drug Administration (FDA), based on data from the randomized, multicenter, open-label phase III

RESONATE study, a head-to-head comparison of single-agent ibrutinib (Imbruvica) vs ofatumumab (Arzerra) in 391 patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma who had received at least one prior therapy.

At a planned interim analysis in January 2014, the results of the RESONATE study demonstrated a statistically significant improvement in progression-free survival, the primary endpoint of the study, in patients treated with ibrutinib. Further, patients in

the ibrutinib arm also showed a statistically significant improvement in overall survival, a key secondary end-

point of the trial. The safety profile of ibrutinib was acceptable and showed a favorable risk benefit profile. Data from this study will be discussed in a presentation at the 2014 ASCO Annual Meeting in Chicago, May 30 to June 3, 2014. The FDA granted an accelerated approval for ibrutinib as a single agent for the treatment of patients with mantle cell lymphoma or CLL, who have received at least one prior therapy. n

Volasertib Granted Orphan Drug Designation for Acute Myeloid Leukemia

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he U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to volasertib for acute myeloid leukemia. Volasertib is currently being evaluated in a phase III clinical trial for the treatment of patients aged 65 or older, with previously untreated AML, who are ineligible for intensive remission induction therapy. The agent has not been approved by the FDA regulatory authorities, and its safety and efficacy have not been established. The recommended standard of care for AML is currently intensive chemotherapy, but many patients due to age and comorbidities cannot tolerate this therapeutic approach. For them, options are limited and their prognosis is typically poor. Volasertib is currently being investigated in this specific patient population. Volasertib is an investigational compound that inhibits enzymes called Polo-like kinase (Plk). Inhibition of Plk1, the best characterized kinase of the Plk family, can result in prolonged cell cycle arrest, ultimately leading to apoptosis. Publication of the phase I/ II trial data that was used in support of the Breakthrough Therapy Designation is expected later this year. n

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Inside the Black Box Cancer Chemotherapy Use During Pregnancy

A review of pregnancy outcome data by the National Toxicology Program INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures. In this installment, National Toxicology Program scientists Kembra L. Howdeshell, PhD, and Michael D. Shelby, PhD, discuss a recently completed monograph that reviews the published data on pregnancy outcomes in women who received chemotherapy for cancer during pregnancy. Dr. Howdeshell and Dr. Shelby (retired) are Health Scientists with the Office of Health Assessment and Translation, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health.

n May 2013, the National Toxicology Program completed a Monograph on Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy.1 The Monograph is intended as a resource for clinicians and their pregnant patients and provides a comprehensive literature review of the human data, including all available data on follow-up evaluations in gestationally exposed offspring. The Monograph does not provide medical advice or guidance.

Interagency Program What are the National Toxicology Program and Office of Health Assessment and Translations? Dr. Howdeshell: The National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology. The NTP reports to the FDA, the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health. The Office of Health Assessment and Translation (OHAT), which is located within the NTP, serves as an environmental health resource to the public and to regulatory and health agencies. The purpose of OHAT is to conduct technical literature–based assessments focused on understanding the potential for adverse effects on human health by agents, substances, or mixtures at various human exposure levels. OHAT assessments are published as NTP Monographs.

Assessment Origins What initiated the NTP’s interest in chemotherapy use during pregnancy? Dr. Howdeshell: As you know, many chemotherapy agents used to treat cancer are mutagens or carcinogens. Most chemotherapy agents for the treatment of cancer also induce birth defects in animal studies, and some of these agents have been associated with birth defects in humans. This topic was selected for evaluation by the NTP because of the paucity of comprehensive reviews on pregnancy outcomes follow-

these agents in laboratory animals and any reports examining their transport via the placenta or breast milk.

Available Literature What was the extent of the literature on cancer chemotherapy use during pregnancy? Dr. Shelby: We identified 431 publications that reported pregnancy outcomes associated with chemotherapy for cancer during pregnancy. The published literature included reports from the 1950s through May 15, 2012. We made a concerted effort to avoid duplicate reporting of cases (eg, an infant reported in a case report and subsequently included in a case series was only counted once). We did not include the pregnancy outcomes of women who became pregnant after completing chemotherapy.

Kembra L. Howdeshell, PhD

Overall Conclusions What were the overall conclusions of the Monograph? Dr. Howdeshell: The NTP Monograph focused on the following five health outcomes: major congenital malformations, spontaneous fetal loss, pregnancy complications, newborn weight and height, and growth and

Overall, the National Toxicology Program evaluation found that chemotherapy for treatment of cancer appeared to be associated with a higher rate of major malformations following exposure during the first trimester compared to exposure in the second and/or third trimester only. —Kembra L. Howdeshell, PhD

ing cancer chemotherapy use during pregnancy in humans, including the integration of the developmental animal toxicology literature with observational studies in humans, and growing public interest in the developmental effects of chemotherapy on offspring exposed to cancer chemotherapy during gestation. The NTP Monograph includes data on 56 agents administered to 1,256 women during 1,261 pregnancies for which pregnancy outcomes were reported. The NTP Monograph also includes a review of the developmental toxicity of

FDA Clinical Reviewers

development of gestationally exposed children. Overall, the NTP evaluation found that chemotherapy for treatment of cancer appeared to be associated with a higher rate of major malformations following exposure during the first trimester compared to exposure in the second and/or third trimester only, and the rate of major malformations following exposure in the second and/ or third trimester only was similar to the prevalence of major malformations reported in the general U.S. population by the CDC.

Michael D. Shelby, PhD

Other findings included a higher rate of stillbirth following exposure in the second and/or third trimester compared to the general population and a higher incidence of abnormally low levels of amniotic fluid, which was primarily attributable to trastuzumab (Herceptin). In addition, chemotherapy for treatment of cancer did not appear to increase spontaneous preterm birth and did not appear to impair normal growth and development of offspring during early life. Finally, the data were characterized as insufficient for an effect of chemotherapy on impaired fetal growth and myelosuppression. These pooled data were evaluated using descriptive—not inferential— statistics because of the limitations in using a largely case report–derived literature for quantitative analysis. Data were analyzed as apparent rates of occurrence, which were based on the published literature. The apparent rates of occurrence were compared to published population studies. While they were not statistically analyzed, the general population studies provided points of reference for interpreting the apparent rates of occurrence. continued on page 71

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Inside the Black Box Chemotherapy During Pregnancy

GUEST EDITOR

continued from page 67

Illustrative Outcomes

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Can you provide an example of an NTP recommendation for consideration of use of chemotherapy for treatment of cancer during pregnancy? Dr. Howdeshell: First, I want to emphasize that the Monograph does not provide medical advice or guidance. The objective of the Monograph was to summarize the pregnancy outcomes reported in women receiving cancer chemotherapy during pregnancy. However, we did observe that some effects were specific to certain agents following exposure during certain periods of pregnancy. For example, exposure to imatinib (Gleevec), a tyrosine kinase inhibitor, in the first trimester (ie, during the period of organogenesis) appeared to be associated with a combination of malformations, including exomphalos (umbilical hernia), skeletal malformations, and/or urogenital malformations (ie, kidney agenesis). Some of the same effects have been observed in developmental toxicity studies of imatinib in laboratory animals. Another example was the high incidence of abnormally low levels of amniotic fluid that was reported with exposure to trastuzumab in the second and/or third trimester(s). This condition appeared to be reversible if administration of the agent was discontinued until birth.

Evaluation Limitations What were the challenges in interpreting this literature? Dr. Shelby: There were several limitations to the NTP’s interpretation of the published reports on pregnancy outcomes associated with cancer chemotherapy use during pregnancy, mostly stemming from the necessity of relying on case reports or case series, which limits the ability to reach conclusions with confidence. Some of these limitations included lack of a reference group for comparison (ie, few studies compared the data to nontreated pregnant cancer patients), a small number of cases reported for specific combination chemotherapy regimens, and a lack of data on the condition of the fetus from induced abortions, spontaneous miscarriages, or stillbirths. Some larger case series lacked individual data on treatment and pregnancy outcomes and could not be added to our pooled analysis. There was also

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. a lack of long-term follow-up examination of the offspring (ie, most reports examined the infant at ≤ 2 years of age), and the quality of the assessments among reports with long-term follow-up evaluation was variable. Finally, a high rate of premature birth among these pregnancies complicated the interpretation of whether adverse effects observed in offspring were due to gestational exposure to cancer chemotherapy or to prematurity.

Expert Panel What was the composition of the expert panel that peer-reviewed the Monograph? Dr. Howdeshell: The NTP convened a nine-member ad hoc expert panel to review the draft Monograph in a public meeting on October 1–2, 2012. The expert panel membership included oncologists, high-risk obstetrician/gynecologists, a developmental geneticist, an epidemiologist, and a developmental toxicologist. Two members of the panel had extensive experience in working with this patient population through their work on retrospective surveys and prospective studies of cancer diagnosed during pregnancy. In addition, the NTP received feedback from our federal agency partners, including comments from Dr. Paul Howard, the FDA liaison to the NTP. The NTP also employed technical experts in the field of high-risk obstetrics/gynecology and clinical oncology to review early drafts of the Monograph.

Available for Download How does one access the Monograph? Dr. Howdeshell: The final edited version of the NTP Monograph continued on page 72

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Online Extra Non-Small Cell Lung Cancer

Phase III Study Explores Addition of Nintedanib to Docetaxel in Second-Line Treatment of Non–Small Cell Lung Cancer Among the articles most read on ASCOPost.com, January–April 2014 By Matthew Stenger

n a phase III trial (LUME-Lung 1) reported in The Lancet Oncology, Reck et al assessed the addition of nintedanib to docetaxel in second-line treatment of non–small cell lung cancer (NSCLC).1 The combination significantly improved progression-free survival in all patients and improved overall survival in patients with adenocarcinoma. Nintedanib is an angiokinase inhibitor targeting pathways mediated by VEGFR 1-3, FGFR 1-3, and PDGFR α and β; it also reportedly inhibits receptor kinases of RET, FLT3, and the Src family.

Study Details This placebo-controlled, doubleblind trial included 1,314 patients from 211 centers in 27 countries with stage IIIB/IV recurrent NSCLC that had progressed after first-line chemotherapy. Patients were randomly assigned between December 2008 and February 2011 to receive docetaxel at 75 mg/ m2 on day 1 plus either nintedanib at 200 mg orally twice daily (n = 655) or matching placebo (n = 659) on days 2 to 21 every 3 weeks. The primary endpoint was progression-free survival on independent central review analyzed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival analyzed by intention to treat after 1,121 events had occurred in a prespecified order: first in patients with adenocarcinoma who had disease progression within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients.

Chemotherapy During Pregnancy continued from page 71

is available as a downloadable file on the NTP/OHAT website (http://ntp.niehs. nih.gov/go/36495). In addition to the Monograph itself, the website includes an appendices file, which contains detailed tables of all the cases included in the Monograph, organized by chemotherapy agent. n Disclosure: Drs. Howdeshell and Shelby reported no potential conflicts of interest.

The combination and docetaxel groups were generally balanced for age (median, 60 years in both, 31% and 33% ≥ 65 years), sex (73% male in both), race (81% and 80% white), Eastern Cooperative Oncology Group performance status (1 in 71% in both), smoking history (25% and 24% never smokers), clinical stage (eg, stage IV in 61% and 62%), metastases at screening (90% and 92%), histology (squamous cell in 42% in both, adenocarcinoma in 49% and 51%), baseline sum of longest tumor diameters (median, 81 and 76 mm), time since first diagnosis (median, 8.8 and 8.6 months), previous surgery (22% in both), previous

ard ratio [HR] = 0.79, P = .0019). The effect of nintedanib was consistent in prespecified subgroup analyses for sex, age, ethnic origin, smoking status, performance status, brain metastases, previous bevacizumab, time since start of first-line treatment, and best response to first-line treatment. Treatments after progression were balanced between both groups, with 48% of patients with squamous cell carcinoma and 56% of those with adenocarcinoma receiving subsequent treatment. After median follow-up of 31.7 months, median overall survival was significantly longer in combination patients (n = 206) vs docetaxel patients (n

Nintedanib/Docetaxel in Non-Small Cell Lung Cancer ■■ The addition of nintedanib to docetaxel improved progression-free survival in second-line treatment of NSCLC. ■■ The combination significantly improved overall survival in patients with adenocarcinoma who progressed within 9 months of starting first-line therapy and in all patients with adenocarcinoma.

radiotherapy (29% in both), previous first-line therapy (platinum-based in 97% and 98%), first-line bevacizumab (4.1% and 3.5%), and best response to first-line therapy (eg, complete or partial response in 35% and 30%, progressive disease in 20% and 21%).

Progression-Free and Overall Survival After median follow-up of 7.1 months, median progression-free survival was significantly longer in the docetaxel/nintedanib group on independent review (3.4 vs 2.7 months, hazReference 1. National Toxicology Program: NTP Monograph on Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy. May 13, 2013. NIH Publication No. 13-5956. U.S. Department of Health and Human Services, U.S. Health Service, National Institutes of Health, Research Triangle Park, North Carolina. Available at ntp.niehs.nih.gov/go/36495. Accessed on April 28, 2014.

= 199) with adenocarcinoma who progressed within 9 months after start of first-line treatment (10.9 vs 7.9 months, HR = 0.75, P = .0073) and in all combination patients (n = 322) vs docetaxel patients (n=336) with adenocarcinoma (12.6 vs 10.3 months, HR = 0.83, P = .0359), but not in the total study population (10.1 vs 9.1 months, HR = 0.94, P = .2720).

Toxicities Grade 3 or higher adverse events that were more common in the nintedanib/docetaxel group were diarrhea

(6.6% vs 2.6%), increased ALT (7.8% vs 0.9%), and increased AST (3.4% vs 0.5%). Increases in liver enzymes were reversible. Adverse events led to dose reductions for nintedanib or placebo in 19% of the nintedanib/docetaxel group and 6% of the docetaxel group, mostly due to gastrointestinal adverse events and increased liver enzymes in the combination group, and for docetaxel in 16% and 12%, mostly due to hematologic adverse events. Adverse events led to discontinuation of study treatment in 23% of combination patients and 22% of docetaxel patients. Adverse events led to death considered possibly unrelated to disease progression in 5.4% of the combination group and in 3.8% of the docetaxel group, including sepsis in five patients vs one patient, pneumonia in two vs seven, respiratory failure in four vs zero, and pulmonary embolism in zero vs three. The investigators concluded, “Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinumbased therapy, especially for patients with adenocarcinoma.” n

Disclosure: The study was funded by Boehringer Ingelheim. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib vs docetaxel plus placebo in patients with previously treated non-small cell lung cancer (LUMELung 1): A phase III, double-blind, randomized controlled trial. Lancet Oncol 15:143-155, 2014.

The ASCO Post

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

ASCOPost.com | MAY 15, 2014

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Issues in Oncology Clinical Trials

Demanding More From Clinical Trials By Ronald Piana “The function of the formal controlled clinical trial is to separate the relative handful of discoveries that prove to be true advances in therapy from a legion of false leads and unverifiable clinical impressions, and to delineate in a scientific way the extent of and the limitations that attend the effectiveness of drugs.” —William Thomas Beaver, MD

ver the 4-plus decades following the 1971 National Cancer Act, our clinical trial system has improved the lives of countless cancer patients; however, the process has too often been sluggish and costly, resulting in small, incremental improvements in overall survival. In 2010, the Institute of Medicine (IOM) released a report, A National Cancer Clinical Trials System for the 21st Century, which addressed serious concerns that the U.S. clinical trial system is falling far short of its potential to conduct the timely, innovative large-scale trials needed to improve the quality of patient care. Leaders in the oncology community agree that it is time to raise the bar of cancer clinical research by defining clinically meaningful outcomes.

ASCO Takes a Leadership Role The ability to identify the molecular drivers of carcinogenesis has grown exponentially and, therefore, it is vital to have a trial system nimble and aggressive enough to reap the clinical benefits of that knowledge. In 2012, ASCO President Sandra M. Swain, MD, appointed Lee M. Ellis, MD, as chair of the ASCO Cancer Research Committee. The primary goal of the committee’s efforts during this year was to develop goals for future clinical trials that would produce more clinically meaningful results for our patients. The Committee’s efforts were recently published in a Special Article in the Journal of Clinical Oncology ( JCO), “Raising the Bar for

Clinical Trials by Defining Clinically Meaningful Outcomes.”1 (See page 120 for more on this important paper.) Dr. Swain told The ASCO Post, “Far too often, clinical trials result in a statistical endpoint that’s significant but one that doesn’t translate into a meaningful benefit for patients. I fully supported Dr. Ellis, the ASCO Cancer Research Committee, and other members of the working groups, as I felt that it was essential to tackle this issue head on as oncologists and advocates for our patients. We conduct large expensive clinical trials, now we need to emphasize clear

of course, a statistician. This process began at the initial Committee meeting but evolved into a series of conference calls led by the chairs of each working group,” explained Dr. Ellis, Committee Chair and lead author of the JCO paper. “I pushed for a hazard ratio threshold, recognizing, however, that hazard ratios are dependent on several factors including patient profile and the number of events. Statisticians are reluctant to make hard-and-fast rules when dealing with multiple variables, but I felt it was vital to set a threshold. In the Netherlands, for instance, they’ve been con-

Our increasing knowledge of genomics should help us develop smaller and smarter clinical trials that achieve meaningful clinical outcomes. The challenge is in translating what we’ve learned from genomic analyses into a clinical reality. —Lee M. Ellis, MD

clinical benefits for patients. I think the JCO paper is the beginning of an important dialogue to that end.” The goals and strategies of the ASCO Cancer Research Committee were delineated in the JCO article, in which four disease-specific (pancreatic, breast, lung, and colon cancer) working groups were convened to consider the design of future clinical trials that would produce results that are clinically meaningful to patients. “Each of the four groups had a chair and co-chair. Along with experts in the four cancers, the groups comprised various stakeholders, including an industry oncologist representative, patient advocates, a U.S. Food and Drug Administration (FDA)-knowledgeable person, and,

Defining Clinically Meaningful Outcomes ■■ All four groups in the ASCO Cancer Research Committee used overall survival as their primary clinical endpoint. The groups identified a hazard ratio ≤ 0.8, corresponding to an improvement in median overall survival within the range of 2.5 months to 6 months as the minimum improvement over standard care by which to define a clinically meaningful outcome. ■■ The groups agreed that incremental survival gains should have little to no increase in toxicity as compared with prevailing therapies. Moreover, any new agent substantially more toxic than current standards should produce the greatest increments in overall survival to be considered a clinically meaningful outcome.

templating setting a hazard ratio threshold of 0.07 as a minimum determinate for clinically meaningful outcomes,” said Dr. Ellis, adding, “Europe, for the most part, has employed tougher drug approval standards than the United States.”

Higher Bar for Outcomes Dr. Ellis commented that pancreatic cancer served as a backdrop for the Committee’s determination to raise the “clinically meaningful” bar. “Once we reached consensus over a higher bar for outcomes, we discussed some recent examples of clinical trials that did not make major advances. The poster child example was erlotinib [Tarceva] in pancreatic cancer, which was presented in a Plenary Session at ASCO’s Annual Meeting in 2005 and published in JCO. However, gemcitabine plus erlotinib didn’t become standard of care, which shows that just because you have a P value doesn’t mean it’s going to be embraced by the oncology community. This illustration, in which an FDA-approved agent conferred an 11-day improvement in overall survival, became the underpinning for the Committee’s work.” Dr. Ellis noted that the four diseasespecific committees worked indepen-

dently, meeting via regular conference calls to keep everyone in the loop. “There were a lot of strong opinions, and although we didn’t always reach consensus, we did arrive at a reasonable compromise. Since the point of raising the clinical bar is to achieve better outcomes for our patients, I made sure we included patient advocates in all the discussions,” said Dr. Ellis. After the four committees developed their basic recommendations, they were posted on the ASCO website for feedback from the community. “We read the feedback, which consisted of well over 100 comments, varying in nature from supportive to not shooting high enough or shooting too high. After review, we revised our recommendations based on the consensus of the comments. We presented our revised recommendations to the ASCO Board of Directors and got instructive feedback. This feedback-revision process was repeated several times until the ASCO Board finally accepted it. We then submitted it to JCO, and after peer review, it was published as an ASCO Special Article,” said Dr. Ellis.

Re-envisioning Goals Dr. Ellis said the Committee recognized that the groups’ descriptions of clinically meaningful outcomes are highly nuanced and affected by numerous factors, which will likely change as standard of care evolves in cancer treatment. He pointed out that although overall survival was selected as the primary endpoint, it did not lessen the value of progression-free survival and other surrogate endpoints in certain clinical scenarios. “The value of progression-free survival is especially true in disease that produces symptoms related to progression, such as bone metastases, where a significant continuation of progressionfree survival could help physicians palliate those symptoms and improve patients’ quality of life,” said Dr. Ellis. “As pointed out in the IOM’s 2010 report, we need to improve the speed, efficiency, and conduct in our clinical trial network,” he added. “Given the challenge in accruing patients, smaller and smarter trials are needed to lower the costs and turnaround time from concept to completion.” Asked whether the Committee’s work furthered those goals, Dr. Ellis continued on page 74

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Issues in Oncology Clinically Meaningful Outcomes continued from page 73

responded, “Our recommendations do not change the policy of the National Cancer Institute or any other funding organizations, but our work does fit in with the IOM report’s ultimate goals. The days of the 3,000- to 5,000-patient clinical trial evaluating an agent that ultimately leads to marginal improvement is over. Our increasing knowledge of genomics should help us develop smaller and smarter clinical trials that achieve meaningful clinical outcomes. The challenge is in translating what we’ve learned from genomic analyses into a clinical reality.”

Thus, it is important to temper expectations with reality. Another risk is lack of knowledge, noted Dr. Dilts. As acknowledged in the JCO article, validated biomarkers to guide trials are not always available. He suggested that our growing bank of specimens and improved technology to analyze specimens could ameliorate that risk. Moving forward, Dr. Dilts maintained, every new clinical trial should

Raising the Bar With Innovation In a JCO editorial, “Time Has Come to Raise the Bar in Oncology Clinical Trials,”2 David M. Dilts, PhD, commented that it is time for oncology trials to become less incremental and more innovative, striving for more, faster. He also stressed that all radical innovations come with risks. For one thing, expectations of patients and regulatory agencies may outstrip the technical capabilities of achieving aspirational trial goals.

David M. Dilts, PhD

include “-omics” to help target the right patients and adaptive trial design to help select the treatment arms, thereby reducing total accrual needs. According to Dr. Dilts, several strategies are needed to re-envision and raise the bar for clinical trials. For example, just as there is a need to build a rapid-learning system in oncology, it’s important that such a system is linked to the design of

meaningful clinical trials. Another strategy is learning from institutions that have been set up to drive significant innovations. “The Department of Advanced Research Projects Agency (DARPA), is an organization that focuses on big changes, blending the best of basic and applied research to jump from one innovation curve to another. DARPA makes obsolete current practice and replaces it with something that is an order-of-magnitude better,” Dr. Dilts told The ASCO Post. “DARPA doesn’t just fund ‘dream teams’; it funds competitions from academia and industry. It focuses on problem-solving regardless of who comes up with the solution. Can you imagine what the state of cancer would be if the government funded that kind of research?” he continued. “Here’s a thought-experiment: A key limiting factor in oncology trials is side effects, so what basic, clinical, and practice teams need to be brought together to achieve the goal of zero side effects regardless of the treatment? That is a DARPA type of goal.”

Important First Step Dr. Swain noted that the published outcomes of the ASCO Cancer Research Committee represent an impor-

tant first step that will potentially inspire future investigators to raise the bar in an effort to significantly advance the state of cancer care. Dr. Ellis and his colleagues have laid out an ambitious challenge for clinical investigators, one that will need a concerted effort by government, industry, and patient advocates. An opportunity exists to set the future direction of the entire system, but clinical trialists must be willing to take necessary risks. “I think that it is past time for some major restructuring of what is considered ‘good research’ in oncology. Raising the bar is an excellent first step, but if we stop there, we are doing a major disservice to oncology patients of 2025,” said Dr. Dilts. n

Disclosure: For full disclosures of the authors, visit jco.ascopubs.org.

References 1. Ellis LM, Bernstein DS, Voest EE, et al: American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. March 17, 2014 (early release online). 2. Dilts DM: Time has come to raise the bar in oncology clinical trials. J Clin Oncol. March 31, 2014 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post John C. Byrd, MD, on AG-221 in AML and MDS see page 16

Edith Perez, MD, on Neratinib in HER2-Positive Breast Cancer see page 20

Alice T. Shaw, MD, PhD, on Ceritinib in NSCLC see page 61

Ronald A. DePinho, MD, on Reducing Cancer Mortality see page 115

Steven Gore, MD, on Myelodysplastic Syndromes see page 118

William T. Curry, Jr, MD, on Glioblastoma see page 130

Eliezer Robinson, MD, on Quality of Life in Cancer Survivors see page 149

Thomas J. Lynch, Jr, MD, on Schwartz Center RoundsR Program see page 161

Eduardo Cazap, MD, PhD, FASCO, on Clinical Research in South America see page 168

Visit The ASCO Post online at ASCOPost.com

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ASCOPost.com | MAY 15, 2014

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JCO Spotlight Genitourinary Oncology

Continued Survival Benefits Seen With Radical Prostatectomy vs Watchful Waiting in Long-Term Follow-up of the SPCG-4 Trial By Matthew Stenger

he long-term benefits of radical prostatectomy vs watchful waiting in men with localized prostate cancer has remained a debated issue. As reported in The New England Journal of Medicine by Anna Bill-Axelson, MD, of Uppsala University Hospital, and colleagues, additional long-term follow-up in the Scandinavian Prostate Cancer Group-4 trial (SPCG-4) continues to show significant benefits of radical prostatectomy vs watchful

undergone radical prostatectomy (23 with node-positive disease did not undergo radical prostatectomy) and 294 men in the watchful waiting group had not received curative treatment. Totals of 200 men in the radical prostatectomy group and 247 in the watchful waiting group had died (18-year cumulative incidence = 56.1% vs 68.9%) and totals of 63 and 99 had died from prostate cancer (18-year cumulative incidence = 17.7% vs 28.7%).

Extended follow-up 23 years after the initiation of the study corroborated a substantial reduction in the rate of death after radical prostatectomy. —Anna Bill-Axelson, MD, and colleagues

waiting in early prostate cancer, including reduced risk of all-cause mortality, prostate cancer–specific mortality, and distant metastases and reduced need for androgen-deprivation therapy.1 Survival benefits have increased over time.

Study Details In SPCG-4, 695 men with early prostate cancer were randomly assigned between 1989 and 1999 (ie, before the prostate-specific antigen [PSA] era) to radical prostatectomy or watchful waiting. The primary endpoints were death from any cause, death from prostate cancer, and risk of metastases; secondary endpoints included initiation of androgen-deprivation therapy. Patients in both groups had a mean age of 65 years, only 12% had nonpalpable T1c tumors at baseline, and mean PSA level was approximately 13 ng/mL.

Cumulative Mortality By December 31, 2012, after a median follow-up of 13.4 years (range, 3 weeks to 23.2 years), a total of 294 men in the radical prostatectomy group had

Survival and Other Benefits Patients in the radical prostatectomy group had significantly reduced risk of death from any cause (absolute 12.7% reduction, relative risk [RR] = 0.71, P < .001), death from prostate cancer (absolute 11.0% reduction, RR = 0.56, P = .001), and distant metastases (absolute 12.2% reduction, RR = 0.57, P < .001). Patients in the radical prostatectomy group less frequently required androgen-deprivation therapy (absolute reduction 25.0%, RR = 0.49, P < .001). These patients also less frequently required other palliative treatments, including radiation therapy (14.1% vs

18.1%), chemotherapy (3.7% vs 4.9%), and laminectomy due to metastases (1.2% vs 2.6%).

Effect of Age and Tumor Risk In subgroup analyses, reductions in any-cause mortality for prostatectomy were significant in patients under 65 years old (RR = 0.50, P < .001) and in patients with low-risk (RR = 0.57, P = .002) and intermediate-risk disease (HR = 0.71, P = .02). Reductions in risk for prostate cancer–specific mortality were significant in patients aged < 65 years (RR = 0.45, P = .002) and patients with intermediate-risk disease (RR = 0.38, P < .001). Reduced risk of distant metastasis was significant both in patients aged < 65 years (RR = 0.49, P < .001) and in those aged ≥ 65 years (RR = 0.68, P = .04) as well as in patients with low-risk (RR = 0.40, P = .006) and intermediate-risk disease (HR = 0.49, P < .001). Patients in the prostatectomy group were significantly less likely to receive androgen-deprivation therapy in both age categories (RR = 0.39 for < 65 years and 0.60 for ≥ 65 years, both P < .001) and in all three risk categories (HR = 0.45 for each, P = .001 for low, P < .001 for intermediate and high).

Increased Benefits Over Time Between 10 and 18 years of followup, the number needed to treat to prevent one death from any cause decreased from 20 to 8 in the whole cohort and from 8 to 4 in patients aged < 65 years. One patient died after surgery in the prostatectomy group. For prostate can-

Benefits of Prostatectomy in Prostate Cancer ■■ Radical prostatectomy was associated with significantly reduced risk of anycause mortality, prostate cancer–specific mortality, distant metastasis, and need for androgen-deprivation therapy, with mortality benefits increasing over time. ■■ Benefits were most marked in patients aged < 65 years and in those with intermediate-risk disease. ■■ No palliative treatment has been needed by 40% of the watchful waiting group.

cer–specific mortality, the difference favoring the prostatectomy group continued to increase from 9.6 deaths per 1,000 person-years during 5 to 10 years of follow-up to 24.5 deaths per 1,000 personyears during 15 to 20 years of follow-up. The difference between groups in use of palliative treatment also increased with time. At 18 years, approximately 40% of men in the prostatectomy group and 60% in the watchful waiting group had disease progression with or without confirmed metastases and received androgen-deprivation therapy or other palliative treatments. The pattern for use of palliative treatments was similar in the < 65 and ≥ 65 year age groups. The investigators concluded: Extended follow-up 23 years after the initiation of the study corroborated a substantial reduction in the rate of death after radical prostatectomy. The number needed to treat to prevent one death has continued to decrease. The hypothesisgenerating subgroup analyses and the large proportion of long-term survivors in the watchful waiting group who never required palliative treatment provide support for active surveillance as an alternative in adequately selected groups. However, the overall long-term disease burden is also a reminder that factors other than survival should be considered when counseling men with localized prostate cancer; the risk of metastases and ensuing palliative treatments also affect quality of life. n Disclosure: The study was supported by the Swedish Cancer Society, National Institutes of Health, Karolinska Institutet, Prostate Cancer Foundation, and Percy Falk Foundation. For full disclosures of the study authors, visit www.nejm. org.

Reference 1. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

See related commentary by Derek Raghavan, MD, PhD, on page 82.

More on Prostate Cancer In This Issue Blood biomarker may identify patients with prostate cancer unlikely to repsond to enzulutamide, see page 14. Presentation by Emmanuel Antonarakis, MD (left), with comments from Daniel Petrylak, MD (right).

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Opinion

Beyond the Cystoscope: Thinkers and Technicians By Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

have spent my career working with urologists. Over a long period of time, I have concluded that they are fine and interesting people who work hard, live well, support interesting hobbies, generally take good care of their families, and are very enjoyable company at parties. The recent discussion of prostatespecific antigen (PSA) and prostate screening, with a host of encyclicals and guidelines decrying the utility of these tools, accompanied by the development of a series of novel treatment agents, has led to discussions of whether the domain of urology is really necessary for cancer management, beyond the role of initial diagnosis.

Pioneers of Uro-oncology I have had the good fortune to work with some very fine uro-oncology surgical thinkers and technicians of the modern era, including Don Skinner, Paul Lange, Elwin Fraley, John Rogers, the late Bruce Pearson, and the late John Stein, among others. Each of them had the gift of looking beyond the cystoscope, or the tools of laparotomy and laparoscopy, and thinking about the biology and management of the range of urologic malignancies, and the interplay of those broader issues with their own technical craft. Skinner, Stein, and their colleagues thought carefully about the evolution of invasive bladder cancer and its association with gene mutation, and developed a superb technical approach to local control, augmented by strategic thinking about prediction, prognostication, and management of occult metastases.1,2 Similarly Lange, Fraley and their teams advocated multidisciplinary management of genitourinary cancer, predicated on outstanding surgical skill, rational use of molecular predictors, and thoughtful interplay with basic scientists focused on extensions of basic biology of testis,3 bladder,4 and prostate cancer.5 Rogers and Pearson, both technically Dr. Raghavan is President, Levine Cancer Institute, Charlotte, North Carolina. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

excellent, worked with me 30 years ago to develop the early paradigms of neoadjuvant therapy for bladder cancer,6,7 interspersed with their support of extensive preclinical modeling,8 and then tested those paradigms in a series of randomized trials.9,10 What has united these fine fellows is the quest for understanding, and their preparedness to test hypotheses carefully, integrating strong basic science with carefully constructed and executed clinical trials. In addition, they had the ability to undertake complex postchemotherapy surgery (for example, extensive retroperitoneal lymph node dissection after chemotherapy for advanced germ cell tumors), with sure hands and the ability to avoid apologies for being unable to resect the residual masses. This made Skinner, Stein, and Rogers absolutely invaluable in the curative treatment of

Bill-Axelson and colleagues13 from Scandinavia have shown quite clearly the importance of surgery in achieving cure of prostate cancer, and the potential dangers of loosely structured watchful waiting. This is a well-designed and meaningful study. Over a 10-year period from 1989, this team randomly assigned 695 men younger than 75 years of age with clinical stage T1-T2 prostate cancer to radical prostatectomy or watchful waiting. Of importance, all patients were required to have a PSA level less than 50 ng/ mL and a negative bone scan, and the PSA cutoff may have had important implications for the outcome of the study. PSA values greater than 20 ng/ mL can easily reflect nodal or more distant involvement, and this could have influenced some of the outcomes of the trial.

The study showed a significantly higher overall death rate, prostate cancer–specific death rate, and rate of distant metastases in the watchful waiting group. However, many patients in this group did not develop metastases or die of cancer. As is often the case in prostate cancer, there are few absolute truths. —Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

testis cancer. We surely know how important that contribution is.11

Meaningful Study Prostate cancer is more puzzling, and the issues of PSA and screening, while appropriately under attack, remain conundrums for further investigation.12 That said, it is clear that aggressive prostate cancers do require treatment. Recently there has been an increasing trend toward watchful waiting—or even the more aggressive “active surveillance”—for newly diagnosed stage I-II prostate cancer. In an important, planned update of their randomized trial,

The study showed a significantly higher overall death rate, prostate cancer–specific death rate, rate of distant metastases, and rate of use of androgen-deprivation therapy in the watchful waiting group. However, also of importance, many patients in this surveillance group did not develop metastases or die of cancer. As is often the case in prostate cancer, there are few absolute truths. Another important caveat is that the study population may differ somewhat from that found in the United States, and watchful waiting, in a potentially less anxious and less testoriented population, could be less intense and less effective (but also much

cheaper) than in the U.S. This study certainly signals the need for caution and structured follow-up when placing patients with localized prostate cancer into observational protocols.

Closing Thoughts After 30 years in the field, I still don’t know whether radical prostatectomy, image-guided external-beam radiotherapy, or brachytherapy is the best option for the definitive treatment of localized prostate cancer, nor am I able to easily define the exact population requiring active treatment. However, I do realize that there are cases where something active needs to be done by someone with expertise. I just wish that more urologists would be prepared to test hypotheses, secure structured data, and practice evidence-based medicine like the wonderfully valuable pioneers and statesmen of uro-oncology mentioned above. n

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

References 1. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001. 2. Stadler WM, Lerner SP, Groshen S, et al: Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on P53 status. J Clin Oncol 29:3443-3449, 2011. 3. Lange PH, Vogelzang NJ, Goldman A, et al: Marker half-life analysis as a prognostic tool in testicular cancer. J Urol 128:708-711, 1982. 4. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 141:873-879, 1989. 5. Limas C, Lange P, Fraley EE, et al: A, B, H antigens in transitional cell tumors of the urinary bladder: Correlation with the clinical course. Cancer 44:2099-2107, 1979. 6. Raghavan D, Pearson B, Coorey G, et al: Intravenous cisplatinum for invasive bladder cancer: Safety and feasibility of a new approach. Med J Aust 140:276-278, 1984. 7. Raghavan D, Pearson B, Duval P, et al: Initial intravenous cis-platinum therapy: Improved management for invasive high risk bladder cancer? J Urol 133:399-402, 1985.

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Opinion

8. Russell PJ, Raghavan D, Gregory P, et al: Bladder cancer xenografts: A model of tumor cell heterogeneity. Cancer Res 46:20352040, 1986. 9. Wallace DM, Raghavan D, Kelly KA, et al: Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma

of the bladder. Br J Urol 67:608-615, 1991. 10. International Collaboration of Trialists: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 29:2171-

2177, 2011. 11. Riggs SB, Burgess EF, Gaston KE, et al: Postchemotherapy surgery for germ cell tumors—what have we learned in 35 years? Oncologist. April 9, 2014 (early release online). 12. Raghavan D: PSA: Please stop ago-

nizing (over prostate-specific antigen interpretation). Mayo Clin Proc 88:1-3, 2013. 13. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

GAZYVATM (obinutuzumab)

include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

The most common adverse reactions (incidence ≥10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders.

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive multifocal leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mgs infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)]. For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy. Table 3 Summary of Adverse Reactions Reported with ≥5% Incidence and ≥2% Greater in the GAZYVA Treated Arm Adverse Reactions (MedDRAa) System Organ Class

Injury, Poisoning and Procedural Complications

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12-24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12-24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. 5.5 Infection Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. 5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days). Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered. 5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 12% of patients in the trial. In 5% of patients, GAZYVA caused an acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution. Transfusion of blood products (i.e., platelet transfusion) may be necessary. 5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [See Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [See Warnings and Precautions (5.2)] • Infusion reactions [See Warnings and Precautions (5.3)] • Tumor lysis syndrome [See Warnings and Precautions (5.4)] • Infections [See Warnings and Precautions (5.5)] • Neutropenia [See Warnings and Precautions (5.6)] • Thrombocytopenia [See Warnings and Precautions (5.7)]

Chlorambucil GAZYVA n =116 + Chlorambucil n =240 All Grades All Grades Grades % 3-4b % Grades % 3-4b %

Infusion related reactions

Blood and lymphatic system disordersc Neutropenia

Thrombocytopenia

Anemia

Leukopenia

General disorders and administration site conditions Pyrexia

Respiratory, thoracic and mediastinal disorders Cough

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms. Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant.

Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥5% Incidence and ≥2% Greater in the GAZYVA Treated Arm

Investigations

GAZYVA + Chlorambucil n =240

Chlorambucil n =116

All Grades All Grades Grades % 3-4 % Grades % 3-4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

22 16

<1 0

14 11

<1 0

The ASCO Post | MAY 15, 2014

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FDA Update

FDA Discourages Use of Laparoscopic Power Morcellation for Removal of Uterus or Uterine Fibroids

n a safety communication notice issued recently, the U.S. Food and Drug Administration (FDA) discouraged the use of laparoscopic power morcellation for the removal of the uterus (hysterectomy) or

uterine fibroids (myomectomy) in women because, based on an analysis of currently available data, it poses a risk of spreading unsuspected cancerous tissue, notably uterine sarcomas, beyond the uterus.

Laparoscopic power morcellation is one of several available treatments for fibroids. It is a procedure that uses a medical device to divide the uterine tissue into smaller pieces or fragments so it can be

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and <1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)].

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. 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. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those <75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/min. [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6, and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA™ [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

removed through a small incision in the abdomen, such as during laparoscopy.

Undetected Uterine Sarcoma Based on an analysis of currently available data, the FDA has determined that approximately 1 in 350 women who are undergoing hysterectomy or myomectomy for fibroids have an unsuspected type of uterine cancer called uterine sarcoma. If laparoscopic power morcellation is performed in these women, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival. “The FDA’s primary concern as we consider the continued use of these devices is the safety and well-being of patients,” said William Maisel, MD, MPH, Deputy Director for Science and Chief Scientist at the FDA’s Center for Devices and Radio-

logical Health. “There is no reliable way to determine if a uterine fibroid is cancerous prior to removal. Patients should know that the FDA is discouraging the use of laparoscopic power morcellation for hysterectomy or myomectomy, and they should discuss the risks and benefits of the available treatment options with their health-care professionals.” A number of additional treatment options are available for women with symptomatic uterine fibroids, including traditional surgical hysterectomy and myomectomy, and laparoscopic hysterectomy and myomectomy without morcellation, as well as other nonsurgical options.

Next Steps The FDA will convene a public meeting of the Obstetrics and Gynecological Medical Devices Panel to discuss information related to laparoscopic power morcellation. “Input from clinical and scientific experts will help provide valuable information and perspectives to clarify the proper clinical role for these devices,” said Dr. Maisel. In the interim, the agency has instructed manufacturers of power morcellators used during laparoscopic hysterectomy and myomectomy to review their current product labeling for accurate risk information for patients and health-care professionals. n

ASCOPost.com | MAY 15, 2014

PAGE 85

JCO Spotlight Gastrointestinal Oncology

Neoadjuvant Chemotherapy Without Routine Radiotherapy Shows Promise in Patients With Locally Advanced Rectal Cancer By Matthew Stenger

n a pilot study reported in the Journal of Clinical Oncology, Deborah Schrag, MD, MPH, and colleagues from Memorial Sloan Kettering Cancer Center, New York, assessed outcomes with neoadjuvant FOLFOX (fluorouracil, leucovorin, oxaliplatin)/bevacizumab (Avastin) with selective use of chemoradiotherapy.1 They found that this strategy does not appear to compromise outcome; the strategy is being assessed in a phase III trial.

Study Details In this phase II study, 32 patients with clinical stage II to III rectal cancer at Memorial Sloan Kettering Cancer Center who were candidates for low anterior resection with total mesorectal excision received six cycles of modified FOLFOX6, with bevacizumab in cycles 1 to 4. Patients with stable or progressive disease were to have radiation before total mesorectal excision, and responders were to have immediate excision. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX for six cycles was recommended, but regimens were left to clinician discretion. The primary outcome measure was R0 resection rate. Patients had a median age of 52 years, and 17 (53%) were women. Overall, 23 (72%) were clinically node-positive; 20 had T3, N+, 9 had T3, N–, and 3 had T2, N+ rectal tumors. At the cutoff date (April 15, 2003), patients had been followed for a mean of 53 months and a median of 54 months (range, 43–73 months). All patients underwent R0 resection (100%), with 8 (25%) having pathologic complete response. Local

recurrence has not been observed in any patient. Two patients (6%) did not complete preoperative chemotherapy due to cardiovascular toxicity, with both having preoperative chemoradiotherapy or radiotherapy followed by R0 resection. The remaining 30 patients (94%) completed four cycles of FOLFOX/bevacizumab and two cycles of FOLFOX alone.

Outcomes All patients had evidence of clinical response to neoadjuvant chemotherapy at restaging and directly underwent total mesorectal excision, usually with a

OLFOX/bevacizumab. Study treatF ment was discontinued, and she received standard chemoradiotherapy, underwent R0 resection of a pathologic T3, N1 tumor, received postoperative FOLFOX, and remained free of rectal cancer at last follow-up. The other was a 69-year-old man with a cT3, N+ tumor who developed angina after two cycles of FOLFOX/ bevacizumab. The regimen was discontinued, and he was treated with neoadjuvant radiotherapy without chemotherapy and had an R0 resection with yT3, N1 disease. He subsequently developed metastatic lung disease and

For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. —Deborah Schrag, MD, MPH, and colleagues

temporary diverting ostomy. One patient received postoperative radiotherapy. Four patients (12.5%) developed metastatic disease to the lung. Three patients (9%) died, two due to metastatic rectal cancer and one due to postoperative complications. Overall, the 4-year local recurrence rate was 0%, 4-year disease-free survival was 84%, and 4-year overall survival was 91%.

Patients Not Completing FOLFOX/Bevacizumab Of the two patients who did not complete neoadjuvant chemotherapy, one was a 63-year-old woman with a cT3, N+ tumor who developed arrhythmia after one cycle of

Neoadjuvant Chemotherapy in Rectal Cancer ■■ A strategy of neoadjuvant chemotherapy without routine chemoradiation did not appear to adversely affect outcomes. ■■ This study is the basis of an ongoing randomized trial.

died from rectal cancer 57 months later.

Other Patient Outcomes The patient who received postoperative radiotherapy was an 81-year-old woman with a cT3, N1 and yT3, N2 tumor with 14 of 16 lymph nodes positive and a radial margin with residual tumor within 3 mm of the surgical specimen. She underwent postoperative radiotherapy but developed pulmonary metastasis within 1 year of surgery and died from metastatic disease without local recurrence. Of the two surviving patients with metastatic disease, one had surgical resection of an isolated lung metastasis and was alive with no evidence of disease at last follow-up and one was alive with pulmonary metastases. The patient who died from postoperative complications was a 64-year-old man with a cT3, N0 and yT1, N1 tumor who had syncope and renal failure that appeared to be due to dehydration from high-volume ileostomy output at 17 days after surgery. He died from renal failure

with no evidence of infection, thromboembolism, or other precipitating event. The investigators noted that they could not rule out a contribution of bevacizumab to cardiac complications during neoadjuvant FOLFOX/ bevacizumab in two patients and the death that appeared to be attributable to dehydration. They stated, “Given the negative results of two large-scale trials of bevacizumab in the adjuvant setting in colon cancer, we do not believe that our favorable results are attributable to bevacizumab and do not plan to incorporate it into future studies.” They concluded, “For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes.” “Although this preliminary experience is promising, it must be corroborated in the multicenter setting,” Dr. Schrag told The ASCO Post. “To accomplish just that, PROSPECT or N1048 is a randomized phase II/III clinical trial that is evaluating standard pelvic neoadjuvant chemoradiation with induction FOLFOX and selective use of chemoradiation. This trial is endorsed by all of the NCI cooperative groups and is available at many practice sites in North America. We really need to determine whether consistent or selective use of chemoradiation is optimal. PROSPECT will carefully assess outcome metrics, including quality of life and local and distant recurrence rates.” Leonard B. Saltz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article. (See his related commentary on page 86). n

Disclosure: The study was funded by Genentech. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: A pilot trial. J Clin Oncol. January 13, 2014 (early release online).

Also in This Issue Project Data Sphere: Clifford A. Hudis, MD, and Richard L. Schilsky, MD, address questions about how this “giant digital laboratory” will work, see page 95

The ASCO Post | MAY 15, 2014

PAGE 86

Perspective

Getting It Right in the End: Individualization of Care for Patients With Rectal Cancer By Leonard Saltz, MD

ata from trials conducted mostly in the 1970s and 1980s established the paradigm that optimal treatment of rectal cancer requires a combination of radiation therapy, chemotherapy, and surgery.1 Virtually all of these trials, however, demonstrated that radiotherapy added only to the local control rate—an important endpoint in its own right—while only one outlier trial, the Swedish Rectal Cancer Trial, demonstrated an overall survival benefit for radiotherapy.2 That trial utilized a shortcourse radiation schedule of 500 cGy daily for 5 consecutive days, with no chemotherapy as part of the treatment strategy in either arm.

Heretical Question About a decade ago, our group noted an interesting phenomenon. We had three patients over a short period of time who had either medical contraindications to pelvic radiotherapy or suspected extrapelvic metastases, and so were treated with FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin) chemotherapy as an initial maneuver. These three patients underwent endoscopic evaluation 2 to 3 months into therapy for the purpose of assuring that the tumors were not at risk of obstruction. In each case, either a complete or near-complete clinical response was seen. At operation, two of the three had a pathologically confirmed complete response, and the third had only rare viable tumor cells seen, for a nearcomplete pathologic response, and these patients remained recurrencefree in follow-up. This led us to ask a heretical question: Do we need to be radiating the pelvises of all patients with locally advanced rectal cancer? Our pilot data, recently reported in the Journal of Clinical Oncology3 and reviewed in this issue of The ASCO Post, suggest that a sizable proportion of patients with stage II or III rectal cancer might be able to be safely treated without the added long- and short-term toxicities, or the added expense, of pelDr. Saltz is Chief, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Professor of Medicine, Weill Medical College of Cornell University, New York.

vic radiotherapy. Our findings are hypothesis-generating, and serve as the basis for a phase III National Cancer Institute cooperative group trial, which is now open and accruing patients.

Pilot Study Our pilot study included 32 patients with rectal cancer at our institution who would otherwise have received preoperative chemotherapy plus radiotherapy. We treated them with neoadjuvant FOLFOX plus bevacizumab (Avastin). In addition, selective use of preoperative chemotherapy/radiotherapy was administered only for patients in whom tumor progression was seen after 12 weeks of chemotherapy. All patients subsequently had surgery and then 12 additional weeks of the same chemotherapy. Two patients discontinued treat-

years from the date of operation, none of the 30 patients treated with preoperative chemotherapy only had a local recurrence of tumor. Four patients developed distant metastatic disease, all in the lung. One of these patients had had a pathologic complete response in the rectum, and developed a solitary lung metastasis 18 months later, which was resected; she remains cancer-free 4 years later.

Key Changes What has changed in the past several decades to allow us to question the continued universality of the role of radiotherapy? First, the quality of surgery has changed dramatically with the understanding that total mesorectal excision is the appropriate operation for removal of a locally advanced rectal

Our pilot data suggest that a sizable proportion of patients with stage II or III rectal cancer might be able to be safely treated without the added long- and short-term toxicities, or the added expense, of pelvic radiotherapy. —Leonard Saltz, MD

ment early due to cardiac events. One went on to receive standard preoperative chemotherapy plus pelvic radiotherapy, followed by total mesorectal excision and then standard FOLFOX chemotherapy; she remained free of recurrence. The other was found to have substantial coronary artery disease, had a coronary stent placed, and received preoperative radiotherapy alone. He subsequently developed pulmonary metastases. Thirty patients completed the planned 3-month course of chemotherapy. None showed progression, and all 30 went on to have an R0 resection. One patient with 14 positive nodes was given postoperative radiotherapy. Eight of the original 32 (25%) were found to have a pathologic complete response to chemotherapy alone, with no viable tumor identifiable in the surgical specimen. With a minimum follow-up of 4

tumor.4 Older surgical techniques called for a blunt dissection of the rectum off of the pelvic sidewall, with avulsion of the rectosacral ligament. This led to a tearing of the outer surface of the mesorectum, a fatty sheath that surrounds the rectum and contains the regional lymph nodes, and greatly increased the chance for residual tumor to be left at the local site. A total mesorectal excision involves a sharp dissection of the outer surface of the mesorectum, creating a surgical plane and resulting in an intact mesorectum, and a far cleaner removal of local-regional nodes. The second major change is in the quality of chemotherapy. The use of infusional rather than bolus 5-FU and the addition of oxaliplatin have meaningfully improved the activity of chemotherapy for rectal cancer. A third factor is the vast improvement in the accuracy of presurgical

staging. With the advent of endorectal ultrasound and high-quality rectal magnetic resonance imaging, a far more accurate assessment of local invasiveness and, to a lesser extent, nodal involvement allows for more accurate delineation of locally resectable vs locally invasive tumors. The dramatic improvement in the accuracy of computed tomography imaging also allows for a far more sensitive and specific identification of synchronous small-volume stage IV disease. The final factor that supports investigation of a non–universal radiotherapy approach is the observed increased, and as yet, unexplained sensitivity of the primary tumor to garden variety FOLFOX chemotherapy. Chau et al had previously reported outstanding activity of capecitabine/ oxaliplatin when used as an initial maneuver in the treatment of locally advanced rectal cancer, with an 88% radiologic response rate, prior to planned capecitabine plus radiotherapy.5 Our group had also noted this increased sensitivity of the primary.6

Role of Bevacizumab Our trial was initiated before the results of the colon adjuvant trials with bevacizumab were known. We chose to include bevacizumab in our pilot trial with the plan that if the colon adjuvant trials were positive, we would take bevacizumab forward in our rectal strategies, whereas if they were negative, we would drop the bevacizumab going forward. Both largescale trials of bevacizumab in the adjuvant setting were subsequently found to be decidedly negative.7,8 In addition, results of a 1,400-patient randomized trial that became available after our rectal trial had started showed that bevacizumab had absolutely no impact on the objective response rate of capecitabine/oxaliplatin or FOLFOX in the metastatic setting.9 We therefore do not believe that bevacizumab had any contribution to our promising results, and we do not advocate its use in the adjuvant or neoadjuvant setting.

PROSPECT Trial Our preliminary results have led to the current Alliance phase III study known as the PROSPECT trial (Pre-

ASCOPost.com | MAY 15, 2014

PAGE 87

News

Phase III Trial Reports Focused Ultrasound Reduces Cancer Pain

phase III clinical trial has shown that noninvasive magnetic resonance-guided focused ultrasound treatment that heats the cancer within the bone, relieves pain and improves function for most patients when other treatment options are limited. The results were published recently in the Journal of

Chairman of Quality, Safety and Performance Excellence and Director of Thermal Oncology in the Department of Radiation Oncology at Thomas Jefferson University. Although radiation therapy is commonly used to treat bone-related pain and effective for most patients,

This approach offers a new way to help alleviate that pain via an outpatient noninvasive procedure. —Mark Hurwitz, MD

the National Cancer Institute ( JNCI). Magnetic resonance–guided focused ultrasound surgery (MRgFUS) is a technique that’s been safely used to treat thousands of women with uterine fibroids. However, “this is the first phase III study to use this technology in the treatment of cancer,” says the study’s principal investigator and lead author Mark Hurwitz, MD, Vice 1

operative Radiation Or Selective Preoperative Evaluation of Chemotherapy and Total mesorectal excision). This trial is randomly assigning patients to a standard arm of preoperative pelvic radiotherapy with concurrent capecitabine vs preoperative FOLFOX for 12 weeks. For patients experiencing less than an estimated 20% reduction in tumor volume on preoperative FOLFOX, preoperative radiotherapy with capecitabine is then given, while those with acceptable tumor reduction go on to total mesorectal excision without radiotherapy. Postoperative care in each arm is at the discretion of the treating physician. This trial is open to rectal cancer patients with stage II or III rectal can-

not all patients experience pain relief and over time those who do may have recurrence of pain. In cases where radiation therapy is not an option, alternative treatments are required.

Study Design A total of 147 patients from 17 centers in the United States, Canada, Israel, Italy, and Russia were enrolled in

cer and tumors above 5 cm from the anal verge. The study is widely available throughout North America, and consideration of this trial for all eligible patients is strongly encouraged. n Disclosure: Dr. Saltz reported no potential conflicts of interest.

References 1. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Nat Cancer Inst 80:21-29, 1988. 2. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997. 3. Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant chemotherapy

the study and randomized to undergo MRgFUS or a sham treatment. Patients in the treatment group received focused ultrasound precisely targeted to their bone tumors to heat the tumor tissue to between 65 and 85 degrees Celsius, resulting in its destruction. During each treatment, the patients were monitored real-time via magnetic resonance imaging to ensure the right tissue was targeted and the right temperatures were reached while ensuring heat in surrounding normal tissues and organs remained at safe levels. The control group underwent the same procedure but without the ultrasound device turned on. Finally, patients who did not respond to the placebo treatment within 2 weeks were allowed to be unblinded and offered MRgFUS. According to the study authors, patients responded well to treatment, with 64% experiencing either no pain or a significant reduction in their pain at 3 months as measured by a two point or greater decrease in the numeric rating score for pain, a clinically validated measurement tool. Many patients were able to reduce or stop use of opioid medications. Most patients experienced pain

without routine use of radiation therapy for patients with locally advanced rectal cancer: A pilot trial. J Clin Oncol 32:513518, 2014. 4. Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133:894-899, 1998. 5. Chau I, Brown G, Cunningham D, et al: Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging–defined poor-risk rectal cancer. J Clin Oncol 24:668-674, 2006. 6. Cercek A, Weiser MR, Goodman K, et al: Complete pathologic response in the primary of rectal or colon cancer treated with FOLFOX without radiation.

relief and improved functioning within several days of treatment.

Outpatient, Noninvasive Procedure “It’s clear that for many of these patients, pain has a major impact on their everyday lives,” says Dr. Hurwitz. “This approach offers a new way to help alleviate that pain via an out-patient noninvasive procedure.” The next steps in this line of research, said Dr. Hurwitz, is to refine the treatment technique to get an even greater response rate, and to apply radiation and thermal therapy together in treatment of bone metastases noting the established clinical benefits for other malignant conditions with this combination. n

Disclosure: This study was supported by InSightec Ltd, Tirat Carmel, Israel. Dr. Hurwitz has provided expert testimony on behalf of Insightec for the purpose of regulatory approval.

Reference 1. Hurwitz MD, Ghanouni P, Kanaev SV et al: Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: Phase III trial results,” J Natl Cancer Inst. April 23, 2014 (early release online).

J Clin Oncol 28 (suppl), abstract 3649, 2010. 7. Allegra CJ, Yothers G, O’Connell MJ, et al: Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol 31:359-364, 2013. 8. de Gramont A, Van Cutsem E, Schmoll H-J, et al: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): A phase 3 randomised controlled trial. Lancet Oncol 13:1225-1233, 2012. 9. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013-2019, 2008.

Visit The ASCO Post website at ASCOPost.com

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (N=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (N=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A Phase II, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are 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 a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

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

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Announcements

Researchers Cornelia Ulrich, PhD, and Bruce A. Edgar, PhD, Join Huntsman Cancer Institute

ornelia Ulrich, PhD, and Bruce A. Edgar, PhD, scholars in the fields of cancer prevention and molecular biology, respectively, will join Huntsman Cancer Institute

at the University of Utah as early as September 1, 2014. Dr. Ulrich is currently serving as a Director of the National Center for Tumor Diseases and Department Head at This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

the German Cancer Research Center in Heidelberg, Germany. She will assume a leadership role at Huntsman Cancer Institute, serving as Senior Director of Population Sciences. Her husband, Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

Bruce A. Edgar, PhD, currently a Professor and Researcher at the German Cancer Research Center-Center for Molecular Biology Heidelberg Alliance, will head a laboratory at Hunts(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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Announcements

Cornelia Ulrich, PhD

Bruce A. Edgar, PhD

• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

man Cancer Institute. Both researchers have previously held faculty positions at the Fred Hutchinson Cancer Research Center in Seattle, Washington. “Dr. Ulrich and Dr. Edgar are a ‘dynamic duo,’ bringing with them an incredible breadth of knowledge and experience from

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

the cancer research world. They are highly regarded researchers, both in the United States and in Europe, and we are indeed fortunate to have them join our ranks,” said Mary Beckerle, PhD, CEO and Director of the Huntsman Cancer Institute. Dr. Ulrich is an epidemiologist whose work is focused on how factors, such as diet, exercise, and use of nonRisk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

steroidal anti-inflammatory agents influence colorectal cancer risk, prevention, and prognosis. Dr. Edgar will join the faculty of the University of Utah as a Professor in the Department of Oncological Sciences and an Investigator in HCI’s Nuclear Control of Cell Growth and Differentiation program. n

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Announcements

Michael S. Gordon, MD, Named Medical Director for Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare

ichael S. Gordon, MD, has been named the new Medical Director for the Virginia G. Piper Cancer Center Clinical Trials program at Scottsdale Healthcare in Phoenix. Dr.

Gordon will oversee the center’s phase I clinical trials program. Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, a partnership with TGen, is a leading clinical re-

8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

search site for phase I investigations of new anticancer agents. Dr. Gordon, a Medical Oncologist, currently serves as CEO of Pinnacle Oncology Hematology, a division of Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

Arizona Center for Cancer Care, in Scottsdale, focusing on translational research and the care and management of cancer patients seeking phase I and phase II clinical trials. He is a

Michael S. Gordon, MD

Clinical Professor of Internal Medicine at the University of Arizona College of Medicine in P hoenix, and he is actively engaged in the education of medical students as Co-Director of the Oncology Block. Dr. Gordon’s principal research interests are in development of new cancer therapies with a focus on targeted and immunologic therapies as well as drugs that affect angiogenesis. Bevacizumab (Avastin), pertuzumab (Perjeta), and oprelvekin (Neumega) are among the drugs Dr. Gordon has helped validate for FDA approval. His area of disease focuses include kidney cancer, melanoma, prostate cancer, lung cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer.

Commitment to Patients and Community “The care and management of patients with cancer and associated diagnoses is rapidly evolving. The ability to provide patients with cutting-edge treatments has the potential to transform the way cancer care is delivered. The Virginia G. Piper Cancer Center at Scottsdale Healthcare has always been a leader in this regard, and its relationships with its community partners defines Scottsdale Healthcare’s commitment to our patients and our community,” said Dr. Gordon. “I look forward to working with my colleagues and to the evolution of a new dynamic as we work to accelerate the access to new cancer drugs to our patients in need. By focusing on innovation in a collaborative spirit with our community physicians, we reinforce our primary commitment to our patients and their families,” he continued. n

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PAGE 95

Technology Clinical Trials

Project Data Sphere: Megadata in the Cloud Could Speed Clinical Trials Here on Earth By Margot J. Fromer

roject Data Sphere, which launched on April 8, is a “giant digital laboratory, an enormous library containing data about tens of thousands of patients and hundreds of clinical trials, all of which will be in the public domain,” said Martin J. Murphy, Jr, DMedSc, PhD, FASCO, Chief Executive Officer of the CEO Roundtable on Cancer.

Martin J. Murphy, Jr, DMedSc, PhD, FASCO

The Roundtable is composed of executives from more than 30 domestic companies in diverse profit and nonprofit industries, as well as several National Cancer Institute (NCI)-designated can-

cer centers. It was founded in 2001. Project Data Sphere is an independent endeavor of the Roundtable and its affiliate Life Sciences Consortium, founded in 2005. Its major goal is to advance cancer research, primarily by speeding drug discovery and development via cancer clinical trials, and secondarily by contributing to the education of oncologists. The data sphere has been designed to provide a place where the cancer community can share, integrate, and analyze historical data about individual patients (whose identity has been obliterated) and comparator arm results from phase III trials conducted by industry and academic institutions.

How It Will Work “Project Data Sphere, LLC, will enable the research community to bring to light previously unrecognized insights buried within vast amounts of cancer clinical data,” said Howard I. Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan Ket-

Anything that makes a study more efficient from beginning to end should accelerate the entire drug development and approval process. —Clifford A. Hudis, MD

The utility of the data [from Project Data Sphere] will depend on their volume and diversity—the more data, the more useful. —Richard L. Schilsky, MD

tering Cancer Center. “The benefits of sharing comparator arm data could lead to a better understanding of disease

Organizations That Have Contributed Financially or in Kind to Project Data Sphere ■■ Alliance for Clinical Trials in Oncology (sponsored by the National Cancer Institute) ■■ American Century Investment ■■ Amgen ■■ Aptuit

■■ Hogan Lovells US, LLP ■■ Independence Blue Cross ■■ Johnson & Johnson ■■ The University of Texas MD Anderson Cancer Center

■■ Astellas Pharma, Inc

■■ Memorial Sloan Kettering Cancer Center

■■ AstraZeneca

■■ Merrimack Pharmaceuticals

■■ Bayer HealthCare Pharmaceuticals, Inc

■■ Millennium: The Takeda Oncology Company

■■ Blue Cross Blue Shield of North Carolina

■■ Novartis

■■ Boehringer Ingelheim USA Corporation

■■ PPD

■■ C-Change ■■ Celgene ■■ Covance ■■ Duke University Health System ■■ Eli Lilly and Company ■■ EMD Serono ■■ GlaxoSmithKline ■■ Hatteras Venture Partners ■■ Helsinn Group ■■ Highmark Health Services

■■ Pfizer, Inc ■■ Publicis Healthcare Communications Group ■■ Quest Diagnostics ■■ Quintiles Transnational ■■ RTI International ■■ Sanofi ■■ SAS Institute ■■ State Farm Insurance Companies ■■ The Livestrong Foundation ■■ Valeant Pharmaceuticals International

Howard I. Scher, MD

progression and endpoints, and maximize a patient’s contribution beyond a single trial to the benefit of others.” The data repository will be “course changing” in pharmaceutical development, said Dr. Murphy, because it builds on others’ work. He explained that aggregate historical data from many previous trials can be put together by new scientists to avoid repetition. This could be especially useful for childhood cancer, rare cancers, and genetic mutations. This approach has the potential for other benefits as well, including: • Ready-made comparisons of various treatment options • Creation of pseudo-experimental treatment and control groups to study the effect of risk factors • Use of multiple small-sample studies to develop a valid population estimate for epidemiologic work • Solution of legal and technical prob-

lems as a result of enhanced data security and anonymization strategies that have plagued such efforts in the past The vast majority of clinical trial data now belongs to private companies, academic institutions, and cooperative groups. They are thus not usable by outside researchers or the general public. But, added Dr. Murphy, those organizations have a “moral responsibility” to share data, as well as an obligation to help other patients with cancer. He believes that most people who participate in clinical trials want this too, which, in fact, is one of the reasons they agree to do so. Nancy Roach, Founder and Chair of the Board of Fight Colorectal Cancer, expressed a similar sentiment. “This is a huge win for the patient community, first because aggregation of big data is always helpful, and also because it extends the reach and benefit of every patient who has ever participated in a clinical trial.” Project Data Sphere charges no user fees, and anyone can log onto its website (projectdatasphere.org).

Will It Work? The ASCO Post asked Richard L. Schilsky, MD, ASCO Chief Medical Officer, and Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, and ASCO President, three questions about Project Data Sphere: continued on page 96

The ASCO Post | MAY 15, 2014

PAGE 96

Announcements

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Announces Faculty Appointments, Grants

oah M. Hahn, MD, has been selected as Associate Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Before joining Johns Hopkins, Dr. Hahn was the Director of the Genitourinary

Noah M. Hahn, MD

Medical Oncology Program at Indiana University. He is an experienced clinical investigator and has led the Hoosier Oncology Group since 2009. Dr. Hahn is a member of the Bladder Cancer Task Force for the NCI Genitourinary Cancer Steering Committee and is Co-Chair of the Bladder Cancer Subcommittee of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOGACRIN) Genitourinary Committee.

Project Data Sphere continued from page 95

1. Of how much practical use do you think the data platform will be? That is, will researchers actually use it as they design clinical trials? Dr. Schilsky said, “Time will tell. The utility of the data will depend on their volume and diversity—the more data, the more useful. Most of them right now come from prostate cancer trials, with a relatively small number so far loaded into the sphere. As the database grows, understanding of the natural history of the disease will increase, as will the heterogeneity of outcomes in populations with varying characteristics. Such insight will stimulate new hypotheses and facilitate design of future clinical trials.” Dr. Hudis agreed. “The ability to access large databases of well annotated, high-quality information from completed trials should allow researchers to make even better estimates of control arm per-

Dr. Hahn’s research adds to areas of strength within the Cancer Center—evaluating epigenetic and immunologic strategies in bladder cancer and conducting trials of new agents in early bladder cancer. He will provide outpatient care, attend on the oncology inpatient service, and staff outpatient fellow clinics as well as grow and expand the Bladder Cancer Multi-Disciplinary Clinic. Patrick Forde, MB, BCh, has been appointed an Instructor of Oncology at Johns Hopkins Kimmel Cancer Center. Dr. Forde recently completed his medical oncology fellowship at the Kimmel Cancer Center at Johns Hopkins. He is interested in developing a translational and clinical investigation program focused on lung cancer with a primary research interest in immunotherapy within our Upper Aerodigestive Program at the Kimmel Cancer Center at Johns Hopkins. Dr. Forde earned his MB, BCh, BAO, from the Royal College of Surgeons in Ireland and completed his Internal Medicine internship at Beaumont Hospital, in Dublin, Ireland. After residencies in internal medicine formance as they design new studies.” 2. Will it make a significant difference in the duration of trials and the speed with which FDA analyzes data? Dr. Schilsky said that’s hard to know. “I think it can help refine trial design, particularly by identifying groups of patients at high risk of disease progression. Enriching future trials with such patients could potentially shorten them.” Again, Dr. Hudis agreed. “Anything that makes a study more efficient from beginning to end should accelerate the entire drug development and approval process.” 3. What will the data sphere mean for nonresearch oncologists in the community? Dr. Schilsky said again that it’s hard to say. “If community oncologists can access the database, they could glean insights into how standard regimens perform across different groups of patients, or how different regimens perform in a particular patient group. Clearly, such

and hematology at Connolly Hospital, Dublin, Ireland, as well as Adelaide and Meath Hospital, in Dublin, Ireland, Dr. Forde completed a medical oncology fellowship at the Royal College of Physicians of Ireland. While a fellow at the Johns Hopkins Kimmel Cancer Center, he was involved in the development of a clinical trial of single-agent preoperative anti-PD-1 antibody (Nivolumab) in resectable stage II/IIIA NSCLC.

Rally Foundation Announces Grant Rally Foundation for Childhood Cancer Research, a national non-profit organization, has awarded a $50,000 Rally for Research grant to Donald Small, MD, PhD, to support child-

hood leukemia research. This grant is cofunded with The Truth 365, a nonprofit organization dedicated to raising awareness and the critical funds needed for childhood cancer research, as well as uniting the childhood cancer community. “The money from the Rally Foundation will enable us to carry out experiments to try to improve treatments for one of the most deadly pediatric leukemia, FLT3 mutant AML” said Dr. Small. “In this era of challenging funding from the NIH we are grateful to the Rally Foundation for these funds.” Dr. Small is Director, Pediatric Oncology Division of the Sidney Kimmel Comprehensive Cancer Center. n

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

Donald Small, MD, PhD

inferences would not be as reliable as head-to-head comparisons of different treatments, but they still might prove useful. To do this, however, community oncologists would need assistance from data analysis experts.” Dr. Hudis took a slightly different approach: “Apart from offering greater speed and efficiency for the entire drug development system, it allows study participants to know that they are contributing to scientific progress in ways that stretch beyond the study question. Eventually, these kinds of data may be useful for quality measures and comparative effectiveness research as well. All this is directly relevant to all oncologists.”

Stocking the Sphere and Paying the Bills In making the switch from privately held data to the public sphere, numerous organizations are already participating (see sidebar on page 95). Other life sciences organizations, health advocacy groups, medi-

cal data standards organizations, researchers, universities, and technology providers will be brought into the fold. Dr. Murphy said, “Funding for Project Data Sphere is being borne entirely by members of the CEO Roundtable, who have made significant financial and pro bono contributions.” The law firm of Hogan Lovells gave free legal advice, and SAS is providing the analytic tools and security systems. Project management support is being given by Celgene and Sanofi US. “We also are grateful for the counsel, commentary, and encouragement we have received over the years from many cancer centers and other organizations, including Memorial Sloan Kettering Cancer Center, Duke University, the Institute of Medicine, NCI, the U.S. Food and Drug Administration, and the White House Office of Science and Technology,” said Dr. Murphy. n Disclosure: Drs. Murphy, Schilsky, and Hudis reported no potential conflicts of interest.

Amgen is exploring the expanded potential of biomarker analysis in metastatic colorectal cancer (mCRC)

When is your RAS analysis complete?

Expanding the potential of biomarker analysis means helping physicians not only determine what options are appropriate for patients but, equally as important, understanding what options are not appropriate for patients. Amgen is investigating extended RAS testing to further biomarker analysis in mCRC.

Learn more at www.amgenoncology.com

77929-R1-V1

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The ASCO Post | MAY 15, 2014

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Expert’s Corner Value in Cancer Care continued from page 1

Over the past 2 decades, ASCO has been active in promoting high-quality, evidence-based cancer care through its clinical practice guidelines and its National Initiative on Cancer Care Quality, which formed the basis of ASCO’s Quality Oncology Practice Initiative (QOPI®). Now, the Society is focused on assuring high value in cancer care through its Value in Cancer Care Initiative. The undertaking represents a mandate of the ASCO Board of Directors and is being implemented through the Value in Cancer Care Task Force. In addition to the central goal of assuring broad access to the best cancer care possible for a given clinical situation, the initiative has three additional goals: 1. To provide oncologists with the skills and tools needed to evaluate the relative value of interventions and use them when discussing treatment options with their patients 2. To provide patients access to information to help them in selecting high-value treatment that meets their specific needs 3. To develop a framework for defining and assessing the relative value of cancer care options In a wide-ranging interview with The ASCO Post, Lowell E. Schnipper, MD, Chair of ASCO’s Value in Cancer Care Task Force and Chief of Hematology/ Oncology at Beth Israel Deaconess Medical Center in Boston, talked about potential methods for reducing cancer care costs and the task force’s development of a framework for evaluating cancer treatment options based on their clinical benefit and toxicity, as well as their cost.

mous need for innovative new therapies in the context of many advanced forms of cancer and the extraordinary vulnerability that many patients feel when meaningful fractions of the cost of some of the treatments we recommend are passed along to the individual through health insurance copays. We know that medical issues contribute in a substantial way to personal bankruptcy, which often occurs not just because somebody who is sick is out of work, but also as a result of high medical cost-sharing. Patients are picking up larger and larger fractions of the cost of expensive medications, and that is an issue we have to confront. Many patients are feeling great finan-

End-of-Life Care Was end-of-life care discussed as being another big driver in the high cost of cancer care? Yes, not as directly related to the cost of drugs, but in the context of cancerdirected therapy that will not do any

The concept underlying value in oncology really relates to what the optimal treatment for a given clinical scenario is at the lowest cost. —Lowell E. Schnipper, MD

Please define what value in cancer care means. The concept underlying value in oncology really relates to what the optimal treatment for a given clinical scenario is at the lowest cost. The idea is if there are multiple possible equivalent or near-equivalent choices in a treatment decision, oncologists should have tools that enable them to factor in the cost of those treatments, after considering the clinical parameters of clinical benefit and side effects.

cial stress on top of the stress of their life-threatening illness, so that was one theme that resonated with the meeting participants. From the drug manufacturers’ perspective, they recognize their obligation to produce drugs that are innovative if they can, and acknowledge that innovation costs are enormous. Nobody would dispute the fact that research and development costs are very large, especially as a promising agent moves through the clinical trial process before it ever gets to the FDA for a decision. Members of the pharmaceutical industry emphasize the high rate of failure for experimental drugs; for every winner, there are many losers for which there is no return on that investment. Superimposed on this are many regulatory hurdles to overcome, which delay the evaluation process, and this too contributes to increased costs. They also argue that while an effective drug may be expensive, its costs are offset by its benefit to society through fewer hospitalizations and greater worker productivity. What they are saying is that while a drug may look expensive because it has a big price tag, a high-value drug has many other downstream benefits to society.

Summit Discussions

Keeping Drug Costs Down

What were some of the major concerns presented at the recent summit on high-value cancer care? The issues that we talked about on the patient side had to do with the enor-

Were potential solutions raised for maintaining drug innovation while keeping costs down? The pharmaceutical industry understands that better science will enable us

Defining Value

to pick smarter drugs for people with cancer. By that I mean if we can identify biologic markers in a patient’s specific tumor type that can predict drug targets with a high degree of reliability, development costs will be lower for a given successful drug. And that lower cost should enable manufacturers to lower the pricing bar. I don’t know if this will occur, but it’s a conceptual possibility.

good and might produce toxicity. The assumption is that properly done endof-life care can—to a much larger extent than is the case now—be more home-based, with fewer emergency room visits, fewer hospitalizations, and certainly less in the way of active cancer-directed therapy in the last several weeks or months of life. Were we to succeed in delivering more home-based end-of-life care—and we have been talking about this for a long time—it would be a way of enhancing the value of cancer care in that particular time frame. If we eliminated intensive medical interventions in the final days of patients’ lives and treated them in a more respectful, humane way that avoids to the extent possible hospital admission, intrusive procedures, and chemotherapy that is not likely to result in a prolonged benefit, it would improve the quality of health care we deliver.

Summit Upshot What were the conclusions of the summit? We all agreed that we need to lower the cost of developing drugs, and that means we need to look at streamlining the clinical trial process and discovering efficiencies that are currently escaping us. We are also hoping to figure out the real-world effectiveness of drugs on specific patients with cancer. For example, the ASCO CancerLinQ™ initiative will help us understand how valuable treatments are in the general cancer patient population as opposed to the highly controlled clinical study popula-

tion. And that may give us a better sense of when to use some of these agents, which, again, are quite costly, and when not to.

Next Steps What are the next steps in addressing the issues of value in cancer care? We are still in the conceptual stage and not yet in the planning stage of a follow-up meeting, but as a series of next steps, we’ve been contemplating taking on one or two of these major issues in great depth. This initial meeting was more of a general discussion of our concerns. There is so much substance to some of these topics that subsequent meetings are required to fully examine them and develop possible solutions. For example, incentivizing drug innovation and developing a cost structure for drugs that reflect the value that those drugs deliver. Those two concepts may seem irreconcilable, but the question is whether there are novel ways of thinking about the universe of patent law and intellectual property that might lead us to a solution. When an innovator develops a novel cancer treatment as opposed to a similar treatment that is an analog of an agent already available, the distinction might well be acknowledged sufficiently by way of enhancing the possible reward for this breakthrough agent. Were that to be the case, the developer would reap a substantial return on an investment. The logical corollary is that a less innovative and less impactful agent should not command the same level of reward in the medical marketplace.

Value Framework ASCO is developing a framework for determining the relative value of cancer treatments. Please explain that framework. The framework is still in its early stages of development and is not yet ready to be rolled out. The Value in Cancer Care Task Force formed a steering

Nancy E. Davidson, MD

avidson, group chaired by Nancy E. D MD [Director, University of Pittsburgh Cancer Institute], charged with developing a framework, or methodology,

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Expert’s Corner

for assessing the relative value of treatment options according to their clinical benefit, toxicity, and cost. The framework will serve as a decision-making tool for physicians and patients, to help them determine the most appropriate evidence-based, highquality treatment regimen for a given patient considering the patient’s clinical status, preferences, and personal and family needs. Once we feel that the framework represents a reasonable approach to care by the oncology community, we will share the information with other stakeholders. These include our patients, the payer community, and representatives from the biotech and pharmaceutical

industries. We are using a thoughtful, deliberative process that will draw from many perspectives and reflect the realities of current oncology practice.

Membership Response What reaction have you gotten from ASCO members on the steps ASCO is proposing to improve value in cancer care and reduce health-care costs? We have shared the concepts I’m discussing with members of our Clinical Practice Committee and state affiliate leaders, and they all feel that this is an important challenge to undertake. Everybody recognizes the issues involved in America’s soaring health-care costs, so there is a sense that ASCO’s initiative

represents a responsible and appropriate undertaking.

Perception Concerns How can ASCO help dispel the perception that examining treatment options based on both value and outcome is not health-care rationing? ASCO is not going to recommend rationing cancer care in any way, shape, or form. The final clinical decisionmaking path is between the doctor and the patient. As a group, we have a consensus that we are not “getting into the space” between the doctor and the patient. We are not going to exclaim, as individuals or as a Society, “You should do this, or you can’t do that.”

We are trying to be an honest broker in helping oncologists and patients make their best-informed treatment decisions based on effectiveness and cost. If we can define a way to assess value that makes sense, perhaps it will help the oncologist and his or her patient make their best choice of a therapy or regimen for a given cancer indication. n

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

Reference 1. Marlotto AB, Yabroff KR, Shao Y, et al: Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 103:117-128, 2011.

Announcements

Centers for Disease Control and Prevention Awards Grants of More Than $1.25 Million to College of American Pathologists

he College of American Pathologists (CAP) has been awarded two grants from the Centers for Disease Control and Prevention (CDC). The funding, totaling more than $1.25 million, will be used to improve the adoption of evidence-based laboratory testing guidelines and to standardize reporting of biomarker test results to cancer registries. The grant dollars will be used over a 5-year period. “Patients and physicians rely on accurate and consistent test results to guide treatment decisions,” said Charles Roussel, CAP’s Chief Executive Officer. “Our goal is to help improve patient care through the delivery of standardized laboratory testing and reporting. The CDC funding will enable us to achieve this goal on behalf of patients, pathologists, and

laboratory and health care professionals nationwide.”

Adoption of Guidelines Leads to Improved Patient Care The College of American Pathologists develops evidence-based guidelines and consensus recommendations to standardize laboratory practices among the nation’s medical laboratories. To date, the College has released six evidence-based guidelines, including those related to biomarker testing for breast and lung cancer, as well as validation of immunohistochemical assays and whole slide imaging. “By implementing guidelines into clinical practice, hospitals and patients can be assured that the laboratory is following consistent procedures based on scientific evidence

and expert consensus opinion,” said Raouf Nakhleh, MD, FCAP, a Pathologist at the Mayo Clinic in Jacksonville, Florida, and lead on CAP’s CDC project to improve the impact of laboratory practice guidelines. “With the CDC grant, we hope to increase awareness for and adoption of the published guidelines, as well as guidelines in development.”

Streamlined Cancer Biomarker Reporting Furthers Understanding Through the CDC grant, CAP, along with other health care organizations, is developing a standardized approach to streamline how cancer biomarker data is collected and recorded. Collection of this data enables public health professionals to

better understand cancer trends and identify needs across the nation. “Tumor biomarkers are used to help detect, diagnose, and determine optimal treatment strategies for many types of cancer,” said Patrick L. Fitzgibbons, MD, FCAP, a Pathologist at St. Jude Medical Center in Fullerton, California, and CAP member who is involved in the CAP’s CDC project on cancer biomarker data reporting. “The CDC grant will enable us to develop and maintain standards and best practices for reporting cancer biomarker test results to cancer registries. Our long-term goal is to standardize the reporting of cancer biomarker data and eliminate the need for manual abstraction of biomarker data, reducing errors and costs and, ultimately, improving patient care.” n

Read About ASCO’s Recently Issued Clinical Guidelines Harold Burstein, MD, on the ASCO Peripheral Neuropathy Guideline see page 45

Jimmie Holland, MD, on the ASCO Guideline for Anxiety/ Distress Screening see page 50

Visit The ASCO Post online at ASCOPost.com

Eduardo Bruera, MD, on the ASCO Fatigue Management Guideline see page 55

THE BATTLE AGAINST MELANOMA STARTS INSIDE THE BODY… WHERE IMMUNITY BEGINS. Evolve your understanding of the complex interplay between melanoma and the immune system

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American Society of Clinical Oncology Honors Researchers, Patient Advocates, and Leaders of the Global Oncology Community

eaders in cancer care will be recognized as part of the American Society of Clinical Oncology Special Awards Program at the 2014 ASCO Annual Meeting. The Special Awards recognize the dedication and significant contributions of researchers, patient advocates, and leaders of the global oncology community to enhancing cancer care and improving the lives of people living with cancer. “The recipients of this year’s awards are striving to connect science and society, leading a global approach to the treatment and quality of life for people living with cancer,” said Sandra M. Swain, MD, FACP, Immediate Past President of ASCO and Chair of the Special Awards Selection Committee. “It is our honor to bestow these awards upon them.” The 2014 Special Awards Honorees are:

David A. Karnofsky Memorial Award and Lecture H.M. (Bob) Pinedo, MD, PhD Dr. Pinedo is Professor Emeritus of the VU University Medical Center (VUmc) and a consultant to the Board of the VUmc Cancer Center Amsterdam, Netherlands. He has served as a founder of the Center for Translational Molecular Medicine in Eindhoven, Netherlands (2006), and as President of the European Society of Medical Oncology (1987–1989).

Science of Oncology Award and Lecture Harald zur Hausen, MD Dr. zur Hausen is a virologist and cancer researcher who discovered the important role that human papillomavirus (HPV) plays in cervical cancer. His groundbreaking research in the 1970s and 1980s paved the way for the development of the HPV vaccine in 2006 and he received a Nobel Prize in Medicine in 2008 for this achievement.

ASCO-American Cancer Society Award and Lecture Graham A. Colditz, MD, DrPH Dr. Colditz is the Niess-Gain Professor of Surgery and Professor of Medicine; Chief of the Division of Public

Health Sciences, Department of Surgery; and Deputy Director, Institute for Public Health at Washington University in St. Louis.

B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology Stuart M. Lichtman, MD, FACP Dr. Lichtman is an attending physician at Memorial Hospital for Cancer and Allied Diseases, a member of Memorial Sloan Kettering Cancer Center and its 65+ Clinical Geriatric Group, and Professor of Medicine at Weill Cornell Medical College. He is also actively involved with the Cancer and Leukemia Group B and the Elderly Task Force of the Gynecologic Oncology Group, Cancer and Aging Research Group, and Editorial Board of the Journal of Geriatric Oncology.

Distinguished Achievement Award Jaime de la Garza, MD Dr. de la Garza is the Executive Secretary of the Science Advisory Council for the President of the Mexican Republic as well as a clinical research investigator at the Instituto Nacional de Cancerología in Tlalpan, Mexico.

Excellence in Teaching Award Michael H. Levy, MD, PhD Dr. Levy is Professor and Vice-Chair of the Department of Medical Oncology at the Fox Chase Cancer Center, Medical Director of Payer Relations at Fox Chase, and a Professor of Medicine at Temple University School of Medicine.

Gianni Bonadonna Breast Cancer Award and Lecture Aron Goldhirsch, MD Dr. Goldhirsch serves as Director of the Multidisciplinary Program of

Senology and Deputy Scientific Director at the European Institute of Oncology, Milan, Italy. He is also Professor of Medical Oncology at the University of Bern, Switzerland.

Cancer Consortium, and has also worked on the national level to address prescription drug shortages by proposing several reforms in the Prescription Drug User Fee Authorization.

Humanitarian Award Surendra S. Shastri, MBBS, MD, DPh, DHA

Special Recognition Award James O. Armitage, MD

Dr. Shastri has served as Professor and Head of the Department of Preventive Oncology at Tata Memorial Centre in Mumbai, India, since 1997. Dr. Shastri also heads the World Health Organization’s (WHO) Collaborating Centre for Cancer Prevention, Screening, and Early Detection and often serves on their expert panels for cancer and noncommunicable diseases.

Partners in Progress Award Michael S. Katz, MBA Mr. Katz is Vice President of the International Myeloma Foundation. He has served as Chairman of the Patient Representatives Committee at the Eastern Cooperative Oncology Group, the National Cancer Institute’s Director’s Consumer Liaison Group, and the Association of Cancer Online Resources.

Pediatric Oncology Award and Lecture Leslie L. Robison, PhD Dr. Robison is the Associate Director for Cancer Prevention and Control at St. Jude Comprehensive Cancer Center and Chair of the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital.

Public Service Award Congressman John Carney Rep. Carney serves as Delaware’s representative in the U.S. House of Representatives. He is a member of the Advisory Committee and the former Chair of the Disparities Committee of the Delaware

Dr. Armitage is the Joe Shapiro Professor of Medicine at the University of Nebraska Medical Center and Past President of the American Society of Clinical Oncology. Dr. Armitage developed and directed the bone marrow transplant programs at the University of Iowa and later at the University of Nebraska.

Fellows of the American Society of Clinical Oncology The Fellow of the American Society of Clinical Oncology (FASCO) distinction recognizes ASCO members for their extraordinary volunteer service, dedication, and commitment to ASCO: • Jonathan S. Berek, MD, MMS • Dean E. Brenner, MD • Gary I. Cohen, MD • Leon H. Dragon, MD, FACP • Lee M. Ellis, MD • Daniel F. Hayes, MD • Michael P. Kosty, MD, FACP • Neal J. Meropol, MD • Ann H. Partridge, MD, MPH • Julie M. Vose, MD, MBA • Peter P. Yu, MD • Robin T. Zon, MD, FACP All of the awards listed above and the Fellows of the American Society of Clinical Oncology will be presented at the 2014 ASCO Annual Meeting taking place in Chicago, May 30 to June 3 at McCormick Place, with the exception of the Public Service Award, which will be presented at a private event, and the Gianni Bonadonna Breast Cancer Award and Lecture, which will be presented at the 2014 Breast Cancer Symposium, taking place September 4 to 6 in San Francisco, California. For a list of the specific dates and room locations of the awards presentations, please contact Amy Thompson, amy.thompson@asco.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | MAY 15, 2014

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Conquer Cancer Foundation and Strike 3 Foundation Work Together to Conquer Pediatric Cancers

nvision a world where a diagnosis of pediatric cancer is met with the same reaction as a diagnosis of the common cold. In this idyllic world, the word “cancer” no longer carries with it the same traumatic response or stigma that it does today. This hopeful vision is what drives Craig Breslow in his work as Executive Director of the Strike 3 Foundation, a charitable organization that heightens awareness, mobilizes support, and raises funding for childhood cancer research. His wife Kelly Breslow is the Foundation’s Director of Business Operations and Development. Mr. Breslow, a Major League pitcher for the Boston Red Sox, knows all too well how scary and traumatic a cancer

diagnosis can be for a family, especially when it affects a child. His sister Lesley was diagnosed with thyroid cancer when she was 13 and he was only 11. She is now fully recovered and lives an unrestricted life as a cancer survivor, but “obviously, the impact that has on a child is lasting,” Mr. Breslow said. The Strike 3 Foundation was born out of a conversation that took place on the couch at his parents’ house in 2008. Recalling this moment, Mr. Breslow said, “I wanted to do something concrete to give back to the community. I had the support of family and friends, and within a couple of months the organization was up and running, and we were planning our first fundraiser.”

Supporting Young Cancer Researchers Since 2011, the Strike 3 Foundation has generously supported five pediatric cancer researchers through the Conquer Cancer Foundation of ASCO Young Investigator Award program (see sidebar on page 105 for full listing) and will be supporting two additional promising young investigators in 2014. According to Mr. Breslow, “We support the Conquer Cancer Foundation Young Investigator Award program

Craig and Kelly Breslow

because a number of accomplished research scientists directed us to the Foundation as a prestigious organization with a reputation for receiving the best, most insightful, and hopefully most fruitful applicants. We felt like it made sense to align ourselves with an organization when we didn’t quite have the infrastructure to evaluate grant ap-

plications with the same rigor as the Conquer Cancer Foundation does.”

From Baseball to the Nonprofit Sector Over the years, Mr. Breslow has “learned a lot” about the nonprofit sector and the field of philanthropy. “Mancontinued on page 105

ASCO Launches New Resources for Providers and Patients to Address Link Between Obesity and Cancer

s the obesity epidemic takes its toll on the nation’s health, ASCO is making strides to address this growing concern as it relates to cancer. ASCO has developed a suite of educational resources designed to help oncology providers educate their patients about the negative effects of obesity on cancer risk and cancer-related mortality, and the need to maintain a healthy weight and lifestyle during and after treatment. These resources are just one component of a multiphase obesity initiative by ASCO funded through the Conquer Cancer Foundation that aims to increase public awareness of the link between obesity and cancer, which remains low despite mounting evidence of the obesity–cancer connection. In 2007 alone, more than 50,000 new cases of cancer in women (7%)

and 34,000 new cases in men (4%) were due to obesity.1

Obesity is on its way to replacing tobacco as the number one preventable, modifiable cause of cancer. — Clifford A. Hudis, MD

“Obesity is on its way to replacing tobacco as the number one preventable, modifiable cause of cancer,” said ASCO President Clifford A. Hudis, MD. “We recognize this risk and are collaborating with other experienced organizations nationally and globally to both learn

from their efforts and contribute our own. We need to confront this growing problem and develop all the necessary tools to limit its impact.”

Online Toolkit One of these tools includes a new set of online resources, the “Obesity and Cancer Toolkit,” to help providers initiate conversations regarding weight management with their patients and to assist patients in making healthy lifestyle changes after a cancer diagnosis. The Toolkit includes a guide for providers and is available at asco.org/obesity. Resources for patients about weight management during and after cancer care and treatment are available on Cancer.Net, at cancer.net/obesity. Additionally, printed versions of the provider guide and patient booklet can be ordered

in bulk for your practice at asco.org/store. Later this year ASCO will issue a policy statement laying out a set of recommendations for addressing obesity and cancer and the role ASCO will take in advancing these recommendations. Additionally, to foster research on obesity, the Society will host a research summit of investigators from across many disciplines to address the growing needs in this area. n Reference 1. National Cancer Institute at the National Institutes of Health: Obesity and cancer risk fact sheet. Available at www.cancer. gov/cancertopics/factsheet/Risk/obesity. Accessed October 2, 2013

The ASCO Post | MAY 15, 2014

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Direct From ASCO

Visit the Conquer Cancer Foundation Donor Lounge at the ASCO Annual Meeting

he work that we do at the Conquer Cancer Foundation would not be possible without the support of generous donors who share our vision to create a world free from the fear of cancer. Conquer Cancer Foundation supporters are invited to visit the Donor Lounge during the ASCO Annual Meeting, held May 30 to June 2 in Chicago, Illinois. The lounge will be open Friday through Monday, and donors will be given exclusive, complimentary access to light refreshments and a quiet place to relax and meet with friends and colleagues. It also offers multiple computer stations for checking email and accessing the Internet. Not a donor? Not a problem! Stop by the Donor Lounge at any time to make your gift or do so online at

Help Your Patients Understand the Latest Research to be Highlighted at the 2014 ASCO Annual Meeting

irect your patients to Cancer.Net, ASCO’s patient information website, to find easyto-read summaries of studies released on May 14 in advance of this year’s Annual Meeting. In addition, encourage them to listen to a panel discussion and Q&A session about these latest advances in a recording of a teleconference for patient advocates. These materials, as well as continuing coverage from the 2014 meeting can be found at www .cancer.net/ascoannualmeeting. n © 2014. American Society of Clinical Oncology. All rights reserved.

ccf.asco.org. The Donor Lounge will be located in room S401 of McCormick Place and will be open Friday from 8:30 AM–2:30 PM and Saturday through Monday from 8:30 AM–5:00 PM.

Would you like to learn more about planning your estate? Register for Conquer Cancer Foundation’s Planned Giving session on Sunday, June 1, from 8:00 AM– 9:00 AM in Room S403a. Planning tools

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | MAY 15, 2014

PAGE 105

Direct From ASCO Strike 3 Foundation continued from page 103

aging an organization is a full-time job, one in which the commitment cannot be taken lightly. But I also think it is incredibly gratifying and not something I’d ever trade.” “Work can be as gratifying as any successful athletic achievement. There are a number of athletes and celebrities who lend their names to causes, but I would argue that being invested in the day-to-day operations makes the reward and success far more significant,” he said. A Yale University graduate with a degree in molecular biophysics and biochemistry, Mr. Breslow was on a path to becoming a physician until his career took another turn. Although it has been some time since he has been in the classroom, Mr. Breslow enjoys

learning about the cancer research projects that the Conquer Cancer Foundation and Strike 3 Foundation– supported investigators are working on and believes that reading about their progress is a way for him to stay involved. The Conquer Cancer Foundation is thankful for the generous support of the Strike 3 Foundation and is honored to be working with Mr. Breslow and his organization to eradicate childhood cancers. Learn more about the Conquer Cancer Foundation of ASCO Young Investigator Award program at www .conquercancerfoundation.org/YIA. To learn more about the Strike 3 Foundation, visit www.strike3foundation.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date

Conquer Cancer Foundation of ASCO Young Investigator Award Recipients Supported by the Strike 3 Foundation ■■ Sarah K. Tasian, MD (2011 Young Investigator Award) The Children’s Hospital of Philadelphia Predicting Biochemical and Genetic Responses to JAK Inhibitor Therapy in Patients With CRLF2-Overexpressing Acute Lymphoblastic Leukemia ■■ Kasey Leger, MD (2012 Young Investigator Award) University of Texas Southwestern Medical Center Evaluation of microRNAs as Novel Markers of Cardiotoxicity in Children Undergoing Anthracycline Therapy for Pediatric Cancer ■■ Justin Wahlstrom, MD (2012 Young Investigator Award) University of California, San Francisco Mechanisms of Chemotherapy Resistance in Childhood T-ALL ■■ Kira Bona, MD, MPH (2013 Young Investigator Award) Dana-Farber Cancer Institute Material Hardship in Families of Children With Cancer ■■ Heather Schuback, MD (2013 Young Investigator Award) Fred Hutchinson Cancer Research Center Biologic and Clinical Implications of ETV6 Genomic Variations in AML

Volume 29, Issue 15

May 20, 2011

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

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al

Best of ASCO® Boston

Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico

August 8-9, 2014 Renaissance Boston Waterfront Hotel Boston, Massachusetts

ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

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

What’s Hot in

JCO JCO.org

Approaches to Regional Nodes in Patients With Melanoma by Danielle K. DePeralta, et al

Best of ASCO® Chicago August 15-16, 2014 Hilton Chicago

Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium and Magnesium to Prevent OxaliplatinInduced Sensory Neurotoxicity (N08CB/Alliance) by Charles L. Loprinzi, et al

Chicago, Illinois Recent Clinical Advances in Lung Cancer Management by David H. Johnson, et al

Best of ASCO® Seattle August 22-23, 2014 The Westin Seattle Seattle Washington

Curable Patient With Metastatic Colorectal Cancer: Balancing Effective Therapies and Toxicities by Katherine Van Loon, et al

Estrogen Receptor and Receptor Tyrosine Kinase Signaling: Use of Combinatorial Hormone and Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2– Targeted Therapies for Breast Cancer by Daniel J. Zabransky, et al

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

For patients with

RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone. For more information, please visit www.REVLIMID.com or call 1-888-423-5436. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the following pages.

Efficacy and safety of REVLIMID were evaluated in pretreated patients with advanced disease1 • In a multicenter, single-arm, single-agent, open-label study (N=134)* • 92% (124/134) of patients had stage III-IV disease; 78% (105/134) of patients had received ≥3 prior systemic therapies; 60% (81/134) of patients were refractory to prior bortezomib; 55% (74/134) of patients were refractory to last prior therapy • Refractory disease was defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen; relapsed disease was defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen† • Patients received REVLIMID 25 mg orally, once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent *134 patients evaluated for safety; 133 patients evaluated for efficacy.1 † Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination.1

REVLIMID may help continue the fight against relapsed or refractory MCL1‡

26 ORR %

(34/133)

Overall response rate (CR + CRu + PR) (95% CI: 18.4, 33.9)

7 CR %

(9/133)

Complete response rate (CR + CRu) (95% CI: 3.1, 12.5)

median

16.6 months DOR (n=34)

Median duration of response (95% CI: 7.7, 26.7) • Median time to response was 2.2

months (range: 1.8 to 13 months)

CI=confidence interval; CR=complete response; CRu=complete response unconfirmed; DOR=duration of response; ORR=overall response rate; PR=partial response. ‡ §

Based on all evaluable patients who received ≥1 dose of REVLIMID.1 Response was determined based on review of radiographic scans by an independent review committee, according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999); ORR was defined as: CR + CRu + PR.1,2

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are 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 Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients References: 1. Revlimid [package insert]. Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244-1253.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41], consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

ADVERSE REACTIONS

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

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Announcements

Shelagh Tippet-Fagyas Named President of The Leukemia & Lymphoma Society of Canada

he Leukemia & Lymphoma Society recently announced that its Canadian affiliate, The Leukemia & Lymphoma Society of Canada, has named Shelagh Tippet-Fagyas as its new President.

Ms. Tippet-Fagyas will lead the Canadian Society in its efforts to find cures and ensure access to therapies for all patients with blood cancer in Canada. She will be working with the Board of Directors.

Most recently Ms. Tippet-Fagyas was a consultant for UrbanKinistics Consulting Group, where she provided strategy and fundraising counsel in the social service, health, and education sectors. n

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary for mantle cell lymphoma; refer to full prescribing information for complete product information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

Shelagh Tippet-Fagyas

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category Renal Function Dose in MCL (Cockcroft-Gault) Moderate Renal CLcr 30-60 mL/min 10 mg Impairment Every 24 hours Severe Renal CLcr < 30 mL/min 15 mg Impairment (not requiring dialysis) Every 48 hours End Stage CLcr < 30 mL/min 5 mg Renal Disease (requiring dialysis) Once daily. On dialysis days, administer the dose following dialysis. After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. 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 [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of Cosmos Communications K

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Awards

AACR Honors Douglas Hanahan, PhD, With AACR Lifetime Achievement in Cancer Research Award

ouglas Hanahan, PhD, Director of the Swiss Institute for Experimental Cancer Research at the Swiss Federal Institute of Technology, in Lausanne, Switzerland, was recently

honored with the 11th annual American Association for Cancer Research (AACR) Lifetime Achievement in Cancer Research. The award was presented during the AACR Annual Meet-

female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

ing held recently in San Diego. AACR presented Dr. Hanahan with the award in recognition of his careerlong history of making groundbreaking discoveries that have had an ex-

In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. 5.6 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to Cosmos Communications K

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traordinary impact on cancer research nationally and internationally. “Dr. Hanahan is a preeminent scientist and we are very pleased to reccontinued on page 112

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Awards Awards continued from page 111

ognize his stellar contributions to a number of areas in cancer research,” said Margaret Foti, MD, PhD, (h.c.), Chief Executive Officer of the AACR. “His ability to integrate ideas from many areas of cancer biology helped

establish a paradigm-shifting framework for studying cancer that has provided a foundation for cancer researchers and those looking to identify new therapeutic targets for more than a decade. We look forward to watching him build on his seminal accomplishments in the coming years,” Dr. Foti said.

Ushered in Genetic Era of Cancer Research “I am honored by this recognition, not only of my past accomplishments in cancer research, but also of my future potential to continue contributing to our mission to better understand mechanisms and apply such knowledge toward im-

withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor lysis syndrome [see Warnings and Precautions (5.9)] • Tumor flare reactions [see Warnings and Precautions (5.10)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia$ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia$ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea$ 42 (31) 8 (6) Nausea$ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting$ 16 (12) 1 (<1) Abdominal pain$ 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) (continued)

Douglas Hanahan, PhD

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of Cosmos Communications K

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Awards

proved therapies for human cancer,” said Dr. Hanahan. Dr. Hanahan is recognized as a pioneer in several fields of cancer research. He helped usher in the genetic era of cancer research whereby researchers use genetically engineered mouse models of cancer to further the understanding of cancer initia-

tion and progression. He developed one of the first transgenic mouse models of cancer and demonstrated that oncogenes could initiate multistep tumorigenesis. He also used his transgenic mice to study the immune system and made groundbreaking contributions to understanding autoimmunity. Dr. Hanahan also col-

treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the

laborated with the late Judah Folkman, MD, helping to establish the field of tumor angiogenesis. Fellow of AACR Academy, Dr. Hanahan’s research achievements have also been recognized this year with election as a Fellow of the AACR Academy. Dr. Hanahan received his bach-

rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation. Cosmos Communications K

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elor’s degree in physics from the Massachusetts Institute of Technology in Cambridge, and his doctorate in biophysics from Harvard University. Before moving to the Swiss Federal Institute of Technology, he was Professor of Biochemistry and Biophysics at the University of California, San Francisco. n

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Announcements

James P. Allison, PhD, Receives 2014 Canada Gairdner International Award

he Gairdner Foundation of Canada has named James P. Allison, PhD, for one of its 2014 Canada Gairdner International Awards. Dr. Allison is Chair and Professor of Immunology at The University of Texas MD Anderson Cancer Center in Houston.

The honor, announced recently by the Gairdner Foundation, recognizes Dr. Allison’s research in T-cell biology that led to his discovery of a unique treatment that frees the immune system to attack cancer. “Dr. Allison’s concept has opened

a new field of cancer therapy, immune checkpoint blockade, and many cancer patients are alive today because of his vision,” the Foundation noted in its announcement. Dr. Allison discovered that a molecule on T cells turns off an immune James P. Allison, PhD

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for: Celgene Corporation Summit, NJ 07901 REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_MCL_HCP_BSv18 11_2013

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attack on cancer before those white blood cells, primed to kill the tumor, can complete their work. He created an antibody to block this off switch and prolong immune response that became the first drug to increase survival of people with late-stage melanoma. The drug, ipilimumab (Yervoy), was approved by FDA for patients with metastatic or surgically unremovable melanoma in 2011.

Potential of Immunotherapy Just Being Realized “By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating all cancers that’s the most exciting and promising area of cancer research today,” said Ronald A. DePinho, MD, President of MD Anderson. “The potential of cancer immunotherapy is just beginning to be realized, and Jim is working to expand and hone this approach as Executive Director of MD Anderson’s immunotherapy platform,” Dr. DePinho said. “Recognition by the Gairdner Foundation is gratifying for any scientist,” said Dr. Allison. “It’s also a boost for the field of immunotherapy as we continue to develop new drugs and combinations that will more effectively unleash the immune system on cancer.” Dr. Allison was recruited to MD Anderson in 2012 from Memorial Sloan Kettering Cancer Center in New York City to build an immunotherapy platform—infrastructure, technology or expertise—to support translational and clinical cancer research at MD Anderson. The platform also supports MD Anderson’s Moon Shots Program, an ambitious effort to dramatically reduce cancer deaths, starting with six moon shots that target eight cancers (see page 115 for an interview with Dr. DePinho about the Moon Shots Program). Dr. Allison and seven other honorees will receive their awards and a $100,000 CDN prize to support their research in Toronto on Oct. 30. n

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Expert’s Corner

Setting a ‘Moon Shots’ Goal to Drastically Reduce Cancer Mortality Over the Next Decade A Conversation With Ronald A. DePinho, MD By Jo Cavallo

n 2012, just 1 year after taking the reins as President of The University of Texas MD Anderson Cancer Center, Ronald A. DePinho, MD, announced his plans to launch the Moon Shots Program, the most ambitious endeavor undertaken by the cancer center to dramatically accelerate the pace of reducing cancer deaths within 10 years. Inspired by President John F. Kennedy’s clarion call in 1962 for America’s space program to accomplish the goal of reaching the moon before the end of the decade, Dr. DePinho reasoned it would take that same kind of organized and focused effort to reduce cancer deaths by more than its current pace of just 1% per year. The program is initially targeting eight cancers—acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, melanoma, lung cancer, prostate cancer, triple-negative breast cancer, and ovarian cancer—in efforts overseen by six Moon Shots multidisciplinary teams of basic scientists, clinicians, pathologists, computational biologists, and epidemiologists. Supporting the Moon Shots teams are a variety of scientific and technical infrastructure platforms, including adaptive learning in genomic medicine, big data, cancer prevention and control, and the center for co-clinical trials. Fully implemented last year, the first 10 years of the Moon Shots Program is expected to cost an estimated $3 billion. The ASCO Post talked with Dr. DePinho about the goals of the Moon Shots Program, improving cancer mortality rates through reliable early-detection screenings, and using IBM’s Watson rapid-learning system to improve patient outcomes.

Program Goals Please talk about the goals of the Moon Shots Program. The overall goal of the program is to accelerate declines in cancer mortality based on current knowledge and existing technology. A subtext of that goal is to develop an optimized framework for the conversion of knowledge into new policies, new drugs, and new diagnostics that make a difference for patients. That often requires organizational attributes that are not always present in a robust way in the academic setting,

such as having large multidisciplinary teams work together in a goal-oriented manner, and well-defined collaborations across departments within and between institutions, and sometimes between academic institutions and other organizations, including government and private foundations. It’s also important to have technology platforms with professional expertise for execution as well as adequate financial resources guided by clear achievable milestones and goals. Our primary goal—the deliverable, in a sense—is to assemble these teams and platforms to plan and execute large impactful projects with the potential to accelerate declines in cancer mortality by more than the current 1% per year. Importantly, such projects would be based on knowledge in hand today and enabled by major technologic break-

trol Moon Shots platform, we brought academic scholars in prevention and melanoma together with private foundations and experts in legislative affairs to educate legislators here in Texas about the harmful effects of tanning beds. That coordinated effort across disciplines and organizations resulted in Texas becoming the fourth state in the country with a law prohibiting tanning bed access to children under age 18. With our platform, we’ve since reached out to seven other states in the past year, and some have passed similar legislation.

Choosing the Targets How did you choose the eight cancers for initial targeting in the program? We went through a think tank process over 6 months involving hundreds

The overall goal of the program is to accelerate declines in cancer mortality based on current knowledge and existing technology. —Ronald A. DePinho, MD

throughs that have come online in the past few years. The concept is to develop an ecosystem that ensures the systematic translation of knowledge into endpoints that matter for patients. For example, we’ve known for more than 10 years that early childhood sunburns and tanning bed usage during adolescence results in a significantly increased risk of melanoma in an individual’s 30s and 40s. In fact, just 11 tanning bed episodes before age 20 increases a person’s risk of melanoma by 85%. Yet there are inadequate state and federal laws prohibiting access to tanning bed usage to children under the age of 18. So while we have clear knowledge of the carcinogenic effects of ultraviolet rays on our youth, we have failed to convert such knowledge into effective legislation that would protect our children from the harmful effects of that carcinogen. For the cancer prevention and con-

of MD Anderson Cancer Center investigators. They assembled into integrated disease teams, each focused on one of a dozen or so major cancers that collectively cause approximately 90% of cancer deaths. I asked faculty this question: Is there actionable information known today that if simply applied to practice would accelerate declines in cancer mortality? Teams were empowered to assemble the needed diverse expertise, receive adequate resources, and utilize professional platforms. The projects were judged on the basis of impact and feasibility. The peer-review team of 24 leading scholars from academia and industry was led by Frank McCormick, PhD, FRS, DSc (hon) [Director of the University of California, San Francisco Cancer Center], who was President of the American Association for Cancer Research at the time. Approximately eight cancers were

selected on the basis of actionable information that if simply applied, would accelerate declines in cancer mortality within the next 10 years. Across the cancers, our investigators came up with about 50 flagship projects, of which 13 are now underway.

Frank McCormick, PhD, FRS, DSc (hon)

Do you know which cancer types you will target next? We have just announced a request for applications to build additional Moon Shot teams, and I anticipate applications from our investigators focused on glioblastoma, pancreas cancer, bladder cancer, colorectal cancer, and head and neck cancer. We are also interested in [human papillomavirus]–associated cancers. These projects in development will be provided with adequate seed support to assemble teams and expand platform capabilities to take on several major projects that if applied, would result not just in incremental science, but would actually have a clinical impact on the population level.

Measuring Success Do you have benchmarks that you hope to achieve in the next 5 to 10 years? Yes, we do. In the case of legislation, our ultimate goal is to educate federal policymakers in Washington to consider policy changes that curb and ultimately ban access to tanning beds for people aged 18 and younger. On the therapeutic front, when our planning team began, we were on the cusp of durable responses in advanced melanoma due to advances in immunotherapy. We now know that ipilimumab (Yervoy), an anti-CTLA-4 blocking antibody, results in a 23% sustained elimination of disease 10 years out. We reasoned that combinations of drugs would do even better. And, incontinued on page 116

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Expert’s Corner ‘Moon Shots’ continued from page 115

deed, the combination of ipilimumab and nivolumab, an anti–PD-1 antibody, shows impressive responses for the majority of patients. Thanks to the work of many, particularly James P. Allison, PhD [Professor and Chair of The University of Texas MD Anderson Cancer Center Department of Immunology], there is a solid likelihood that we will reach our goal of reducing mortality from advanced melanoma by at least 50% in the next 5 to 10 years. In the context of our melanoma moon shot, we are conducting novel clinical trials that combine agents and have developed an immune therapy platform to monitor immune cells as patients receive such therapy. This will help us understand responses to specific combinations and guide therapeutic options more quickly in our clinical trials.

zon over the next decade. At these early stages, however, it would be prudent to use the term “durable complete responses,” because these agents have not been in use for long, and we don’t yet know if these patients’ cancers will recur in the years ahead. These immune drugs and other targeted agents are generating a lot of optimism. For example, the prostate cancer Moon Shot team has launched two trials

I anticipate that we are going to continue to have declines in cancer mortality … mostly as a result of more intensive efforts in tobacco prevention and cessation, making a strong commitment to early detection and prognostication, and facilitating the development of immune checkpoint and targeted therapies, with guidance from in-depth profiles of a patient’s tumor. —Ronald A. DePinho, MD

Potential of New Agents With the Moon Shots Program, will it be possible to actually cure more cancers or have greater success in turning more cancers into chronic diseases? I wouldn’t have used the word “cure” in the same sentence with cancer pre2010. But I think that everybody is feeling that with more targeted agents, especially the immune-modulating drugs, we are going to have a significant impact on creating durable responses if not cures for an increasing number of patients with advanced disease. The question is, how can we fully harness the potential of those game-changing agents? We don’t yet understand why some patients respond to these immune checkpoint drugs and others don’t, and we don’t yet understand how to combine them in the most effective way possible to increase remissions and cure rates. So those are some of the questions we, and others in the field will be sorting out over the next few years. I am most excited by the signal of activity in early-stage clinical trials for these immune checkpoint inhibitors for lung cancer, bladder cancer, head and neck cancer, and colon cancer. These early results in some cases are similar to the melanoma responses, albeit, in a more limited number of patients, suggesting that for an increasing number of cancers, more durable responses are on the hori-

ly, spiral CT and current image analysis yields about a 96% false-positive rate, making it clear that another test, perhaps a blood test, would need to be joined with spiral CT to reduce the false-positive rate. We also need better risk models to know whom to screen in the first place. Our team is working on developing both solutions, and we are joining forces with other institutions in the United States, Europe, and Asia to find answers.

with curative intent for at least 30% of prostate cancer patients based on preliminary data from early-stage clinical trials. In the case of chronic lymphocytic leukemia, ibrutinib (Imbruvica), the Bruton’s tyrosine kinase inhibitor, is impressive and clearly represents a potential breakthrough therapy with sustained responses for a large fraction of patients.

Early Detection Efforts Please talk about improving cancer mortality through more accurate screening methods. Early detection of cancer is another major focus of the Moon Shots Program. In one flagship project, a large multidisciplinary team is working hard to achieve a practical strategy for the early detection of lung cancer. In lung cancer, we know that we can achieve a 20% reduction in cancer mortality by screening heavy smokers and catching the disease earlier. Dozens of our investigators have come together from different disciplines in an effort to develop an early detection strategy for lung cancer that would be effective and economically feasible. Based on a recent national trial, spiral computed tomography (CT) screening of 50- to 64-year-olds with a 30 pack-year history of smoking resulted in reductions in mortality that, if scaled, would save about 10,000 lives per year. Unfortunate-

Augmented Decision-Making You are using IBM’s Watson supercomputer in the Moon Shots Program and are initially testing it in the treatment of leukemia patients. Do you have results from the pilot program? Watson is just one of the analytics we are using to help physicians make clinical decisions and improve patient care. We have worked to reorganize our approach to even address how patients come into and flow through the system, how the bioanalytes are isolated from that patient, how the information from that patient is ingested into a big data environment, and how it interfaces with other types of information, including data from other patients and research to help drive the practice of evidencebased medicine. We used data from 10,000 patients with leukemia to teach Watson about that cancer, and now this established platform works well for leukemia. In the next phase, we will add other cancer types and pilot MD Anderson’s Oncology Expert Advisor (powered by Watson) for use at institutions in the United States and around the world. We hope to elevate the quality of oncology care by assisting physicians to make better evidence-based medical decisions for cancer patients, particularly for those patients who can’t come to our cancer

center in Houston or to one of our partner institutions in the United States or internationally.

Looking Ahead Are you optimistic that there will be substantial improvement in cancer mortality in the next 10 years? One of the greatest challenges we are facing is an aging population, and that aging trend is escalating. By 2025, there are going to be 1.2 billion people worldwide over the age of 60, and by 2030, the cancer incidence in the United States is going to rise by approximately 45%. I think that we could make a significant dent in that incidence rate if we do our best to end tobacco smoking, reduce obesity rates, and encourage sun protection. Beyond prevention, early cancer detection has the potential to be a game changer when it comes to mortality rates. I believe that with today’s technology, early detection is going to become a reality. But early detection has to be coupled with prognostication. It is thought that the majority of older individuals possess aspiring cancers, but if discovered, one would need prognostic determinants to decide which cancers might be aggressive and cause lethality vs cancers that would lay dormant for decades. I believe that the technology is at hand to enable early detection of many of the major cancers through a simple blood test. Such tests could be developed within the next 10 years and would have a significant impact on cancer mortality, but to generate them, we need a concerted effort and adequate dedicated resources. I anticipate that we are going to continue to have declines in cancer mortality—no one can say for sure by how much, but there is a clear potential for it to be more than the 1% per year we have been seeing, even in the face of increased incidence. And that will happen mostly as a result of more intensive efforts in tobacco prevention and cessation, making a strong commitment to early detection and prognostication, and facilitating the development of immune checkpoint and targeted therapies, with guidance from in-depth profiles of a patient’s tumor. This is a new era in cancer medicine. n Disclosure: Dr. DePinho reported no potential conflicts of interest.

Should You Pursue a Business Degree? Surgical oncologist Martin J. Heslin, MD, discusses the pros and cons for oncologists interested in pursuing a business degree. See page 175.

Vis B it us

NOW ENROLLING

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A Phase 3 Trial for Newly Diagnosed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It targets EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients are found to express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ACT IV is an international, randomized, double-blind, controlled phase 3 study of rindopepimut added to standard of care temozolomide in patients with newly diagnosed EGFRvIII-positive glioblastoma

Rindopepimut Every 2 weeks x2, then monthly

1:1 Randomization

Temozolomide Diagnosis/Resection Chemoradiation EGFRvIII-positive glioblastoma N=~700

Days 1-5 in 28 day cycle 6-12 cycles

Treat until tumor progression, intolerance, or withdrawal of consent

Blinded KLH Control Every 2 weeks x2, then monthly

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles

Key Inclusion Criteria

Key Exclusion Criteria

• Newly diagnosed glioblastoma

• Evidence of metastatic disease, diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• Attempted resection followed by chemoradiation with temozolomide • Provide a tumor specimen which tests positive for EGFRvIII at the protocol specified central laboratory • ECOG PS ≤ 2, and dexamethasone ≤ 2 mg/day (or equivalent) for ≥ 3 days prior to randomization

• Other treatments for glioblastoma • Unequivocal progression during chemoradiation therapy Key Trial Endpoints • Primary: Overall Survival (OS) • Secondary: Progression-free Survival (PFS)

For more information visit www.celldex.com or email info@celldex.com. See more at booth #19127. 1. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722-4729. 3. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324-333. ©2014 Celldex Therapeutics Inc.

4/14

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News Hematology

Forward Progress in Myelodysplastic Syndromes Is Largely in Genetics By Caroline Helwick

ost recent advances in the management of myelodysplastic syndrome (MDS) are in the area of genetics, according to Steven Gore, MD, of Yale University School of Medicine, New Haven. “New genomics research is leading to a better understanding of MDS heterogeneity and disease biology, and may identify new treatment targets. But there have been no new breakthrough drugs—it’s been a ho-hum year in that regard—though some combinations with azacitidine appear promising,” Dr. Gore said in a review of the topic at the 2014 Highlights of ASH in North America meeting in Miami. Dr. Gore drew from the most important studies presented in MDS at the American Society of Hematology (ASH) Annual Meeting to present his “highlights” in the field.

Genetic Landscape Further Explored A mostly Japanese team of researchers further mapped the genetic landscape of MDS, finding that among 944 MDS patients, the genes most commonly mutated were involved in splicing and DNA methylation.1 Spliceosome mutations were observed in 85% of patients, and they essentially never overlapped with other spliceosome mutations. “One is all you appear to need,” he said. The researchers combined mutational status with conventional prognostic factors to construct a prognostic model, though this work remains clinically premature. The most important finding will be the identification of genetic targets that are druggable—for example, agents targeting spliceosome mutations might be effective. “This will be required for us to take the next quan-

tum leap,” Dr. Gore said. In another study of 1,407 patients, the monosomal karyotype was associated with worse survival, independent of complex karyotype.2 The monosomal karyotype is defined as the presence of at least two autosomal monosomies or a single monosomy with at least one structural abnormality. Since patients with the monosomal karyotype had a

ylating agents significantly improved overall and AML-free survival in MDS patients classified as high risk by the International Prognostic Scoring System (IPSS) or very high risk by the revised system (IPSS-R), and have partial or total monosomy 7.4 “These abstracts confirm the adverse prognostic importance of abnormalities of chromosomes 3 and 7, and the

New genomics research is leading to a better understanding of MDS heterogeneity and disease biology, and may identify new treatment targets. There have been no new breakthrough drugs, though some combinations with azacitidine appear promising. —Steven Gore, MD

2.5-fold increased risk of death, this information might be relevant in the management of patients, he said.

Other Abnormalities A retrospective European study of MDS and acute myeloid leukemia (AML) patients with 3q abnormalities showed that azacitidine was not very effective in these subgroups, whose median overall survival was 10.6 months.3 One cytogenetic subgroup—patients with t3q21 mutations—appeared to fare much better, as their median 4-year overall survival was not yet reached. Additionally, the study showed that patients with overexpression of the tumor-suppressor gene EVI1 had a prognosis as poor as those with 3q structural abnormalities. Finally, in a study by the German Multicenter Study Group, demeth-

New Data in Myelodysplastic Syndromes ■■ The most commonly mutated genes in MDS appear to involve splicing and DNA methylation, with spliceosome mutations observed in 85% of patients. ■■ Monosomal karyotype is associated with worse survival, independent of complex karyotype. ■■ Azacitadine may not be very effective in patients with 3q abnormalities. ■■ Demethylating agents may improve survival in patients classified as high- or very high-risk, who have partial or total monosomy 7. ■■ The combination of azacitidine plus vorinostat in patients with IPSS intermediate-1 or -2 or high risk yields a response rate around 70%. ■■ Very poor outcomes are observed in patients with lower-risk MDS who progress after treatment with a hypomethylating agent.

monosomal karyotype. The monosomal karyotype retains prognostic value independent of age, risk, trisomy 8, and other features. We also learned that EVI1 overexpression is comparable in prognosis to chromosome 3 structural abnormalities, though we cannot yet test for this,” Dr. Gore said. The growing identification of mutations that appear to be associated with prognosis is not yet clinically applicable, according to Dr. Gore, who says he does not yet test for these. “I don’t think there are prospective data showing the consequence of clinical decisions based on genetic criteria, or data that show the extent to which this information adds to our clinical prognostic scoring system,” he said. “Though the genetic data are interesting, we still have validated clinical data and clinical judgment. At this point, I would not take the patient who is low risk by all conventional criteria, but who has a mutation believed to be associated with risk, and treat that patient as high risk.”

Potential Benefit for Combinations The New York Cancer Consortium phase II 6898 study combined azacitidine plus vorinostat (Zolinza) in patients with IPSS intermediate-1 or -2 or high risk, naive to these agents, and achieved response rates of 67% to 73%.5 These rates are much better than the historical results with azacitidine alone, Dr. Gore pointed out, adding that ran-

domized trials of high-risk patients are needed to confirm the benefit of combination therapy in the front-line setting. This is the aim of the S1117 study. A phase I dose-escalation/expansion study of ARRY-614 showed promise in patients with IPSS low/intermediate-1 risk.6 The compound inhibits p38 MAP kinase, a major regulator of pathways that sense stress and inflammation, and also Tie2, which has pleiotropic effects on progenitors and AML blasts. ARRY6143 reduced phoso-p38 in the bone marrow and led to durable responses in 20% of patients.

Poor Outcomes After Treatment Failure In the largest cohort of lower-risk MDS patients ever treated with hypomethylating agents, investigators confirmed very poor outcomes after disease progression.7 The study included 423 patients with IPSS low- and intermediate-1 risk treated with a hypomethylating agent at The University of Texas MD Anderson Cancer Center and Moffitt Cancer Center between 2000 and 2011. Patients received a median of six cycles for a median duration of 7 months. The best response to treatment was complete response (10%), partial response (3%), bone marrow complete response (1%), and hematologic improvement (22%). Median overall survival was 15 months, and 1- and 3-year estimated survival rates were 55% and 27%, respectively. In the multivariate analysis, the following were predictive of progression into a higher-risk category: lack of response to a hypomethylating agent (odds ratio [OR] = 1.8; P = .02), absolute neutrophil count < 1.5 × 109/L (OR = 3.2; P = .02) and IPSS intermediate/poor (OR = 6.0; P = .01). In low-risk MDS patients, after failure on hypomethylating agents, median survival was 10 months without further treatment, 28 months with conventional treatment, 39 months after stem cell transplant, and 17 months with investigational treatment. “Even low-risk patients who don’t respond to [hypomethylating agents] don’t do well,” Dr. Gore pointed out. “We have to ask, are we harming our patients by giving these drugs? Are we introducing new mutations? I don’t give azacitidine to low-risk patients, because I worry about this,” he said. “The mechanisms underlying the

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News

lack of response require investigation. By understanding the reasons (which could be genetic, pharmacologic), rational salvage treatments or regimen modifications may be possible,” Dr. Gore suggested. n Disclosure: Dr. Gore is a consultant for and has received research support from Celgene.

References 1. Nagata Y, Grossmann V, Okuno Y, et al: Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. 2013 ASH Annual Meeting. Abstract 521. Presented December 9, 2013. 2. McQuilten ZK, Sundararajan V, Wood EM, et al: Monosomal karyotype I associated with worse survival independent of complex karyotype in patients with myelodysplastic syndrome. 2013 ASH Annual Meeting. Abstract 1523. Presented December 7, 2013. 3. Wanquet A, Berthon C, Sebert M, et al: Azacitidine treatment for patients with myelodysplastic syndromes and acute myeloid leukemia harboring chromosome 3q abnormalities. 2013 ASH Annual Meeting. Abstract 1512. Presented December 7, 2013. 4. Schanz J, Braulke F, Shirneshan K, et al: Therapy with demethylating agents sig-

The ASCO Post

nificantly improves overall- and AML-free survival in patients with MDS classified as high-risk by IPSS or very high risk by IPSSR and partial or total monosomy 7—results from a German Multicenter Study. 2013 ASH Annual Meeting. Abstract 2784. Presented December 8, 2013. 5. Silverman LR, Verma A, OdchimarReissig R, et al: A phase II trial of epigenetic

modulators vorinostat I combination with azacitidine in patients with the myelodysplastic syndrome: initial results of Study 6898 of The New York Cancer Consortium. 2013 ASH Annual Meeting. Abstract 386. Presented December 9, 2013. 6. Garcia-Manero G, Sekeres MA, List AF, et al: Phase I dose-escalation/expansion study of ARRY-614 in patients with

IPSS low/Int-1 risk myelodysplastic syndromes. 2013 ASH Annual Meeting. Abstract 387. Presented December 9, 2013. 7. Jabbour E, Garcia-Manero G, Xiao L, et al: Outcome of patients with low and intermediate-1 risk myelodysplastic syndrome after hypomethylating agent failure. 2013 ASH Annual Meeting. Abstract 388. Presented December 9, 2013.

Now Enrolling

OAK

A Randomized Phase III Study of MPDL3280A (an engineered anti-PDL1 antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

MPDL3280A1

Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

Primary Endpoint:

(an engineered anti-PDL1 antibody) N=850 Randomized 1:1

Docetaxel

Secondary Endpoints: • Safety: incidence of adverse events

• Overall survival

• Overall response rate • Progression-free survival

• Duration of response

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Locally advanced or metastatic NSCLC

(stage IIIB, stage IV, or recurrent)

@ASCOPost

• History of autoimmune disease • Active hepatitis B or hepatitis C

• Representative FFPE tumor specimens

• Prior treatment with docetaxel, CD137 agonists,

• Disease progression during or following

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

platinum-containing treatment regimen • Measurable disease, defined by RECIST v1.1 • ECOG performance status of 0 or 1

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

The ASCO Post | MAY 15, 2014

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JCO Spotlight Clinical Trials

ASCO Committee Defines Clinically Meaningful Goals for Clinical Trials in Pancreas, Breast, Lung, and Colorectal Cancers By Matthew Stenger

he ASCO Cancer Research Committee recently convened four disease-specific working groups—in pancreas, breast, lung, and colon cancers—to “consider the design of future clinical trials that would produce results that are clinically meaningful to patients.” An ASCO perspective statement, reported in the Journal of Clinical Oncology by Lee M. Ellis, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues, offers their conclusions.1 The statement furnishes the criteria for clinically meaningful improvement arrived at by the working groups for phase III trials in (1) pancreatic cancer patients who are eligible for FOLFIRINOX, gemcitabine-, or gemcitabine/ nab-paclitaxel, (2) lung cancer patients with non–squamous cell or squamous cell carcinoma, (3) patients with metastatic triple-negative breast cancer with no previous treatment for metastatic disease, and (4) patients with colon cancer who have had disease progression on all prior therapies or are not candidates for standard second- or third-line options. Each working group included clinical investigators, patient advocates, biostatisticians, U.S. Food and Drug

Family Comprehensive Cancer Center at University of California San Francisco, for the colon cancer group.

‘Smaller and Smarter’ Trials The goals set forth in the perspective statement are meant to further the paradigm of designing and generating clinical trials that can demonstrate larger therapeutic gains in selected groups of patients with smaller trial populations (“smaller and smarter” trials). Furtherance of this paradigm will

tive statement, there currently are no validated biomarkers available to select patients for specific treatments. However, as the authors note, “[W]e expect that over time, such biomarkers will be identified and that the goals set forth by these working groups will be achievable.”

Primary Goal In arriving at goals for clinical trials, both survival and quality of life were considered as important to outcomes that are clinically meaningful for pa-

[W]e expect that over time, … biomarkers will be identified and that the goals set forth by these working groups will be achievable. —Lee M. Ellis, MD, and colleagues

tients. There was agreement in all working groups that quality of life is difficult to measure and interpret even when validated instruments are used, with the definition of a clinically meaningful change in global quality-of-life measures being acknowledged as a particular challenge. The working groups concluded that serial assessment of specific cancer-related symptoms using validated instruments and shorter, more cancerspecific surveys can define a clinically meaningful outcome for patients. In the absence of agreed-upon measurements of quality of life for the settings considered in the Emile Voest, MD, PhD Roy Herbst, MD, PhD Lowell E. Schnipper, MD Alan P. Venook, MD current publication, no Administration oncologists, and indus- that genomic tests used to guide cancer quality-of-life elements are included in try oncologists. Working Group Chairs treatment “will not only improve in sen- the clinical trial goals. It was also recwere Emile Voest, MD, PhD, Nether- sitivity and specificity but also decrease ognized that quality-of-life issues are lands Cancer Institute, Amsterdam, for the amount of biologic sample neces- cancer-specific and therapy-specific. the pancreas cancer group, Roy Herbst, sary and lower the cost and turnaround The relationship of progressionMD, PhD, Yale Cancer Center, New time to enable widespread use.” free survival to overall survival in parHaven, Connecticut, for the lung canDiscussion in the working groups was ticular clinical contexts was extensively cer group, Lowell E. Schnipper, MD, not limited to biomarker-driven trials, al- discussed within the working groups, Beth Israel Deaconess Medical Center, though it is acknowledged that the goals with each deciding to use overall surBoston, for the breast cancer group, established in the treatment settings vival as the primary measure of cliniand Alan P. Venook, MD, Helen Diller discussed, as well as in other treatment cally meaningful outcome. All groups settings, will require enrichment strate- acknowledged the challenges of using For more on this issue, see the interview with gies. In the settings considered by the overall survival as the primary measure, Dr. Lee Ellis and others on page 73. working groups in the current perspec- including the need for longer follow-up reflect continued improvement in the ability to identify molecular drivers of cancer and to prospectively identify patients most likely to benefit from targeted treatments. Progress in newer modalities such as immune therapies and antibody-drug conjugates, which are providing large therapeutic gains, should also facilitate this approach. Moreover, it is expected

and the potential confounding effect of crossover and other poststudy therapies in assessing overall survival. Due, in part, to such considerations, the use of progression-free survival as a clinically meaningful endpoint was considered to be appropriate, and it is included in the current perspective statement as a secondary endpoint. The magnitude of overall survival benefit that should be considered clinically meaningful was also extensively discussed, with complete consensus not being achieved in the Breast Cancer Working Group, although compromise was reached.

Targets for Meaningfulness The conclusions of the working groups are summarized below. All groups except the colon cancer group focused on patients with metastatic disease receiving first-line systemic treatment. All groups selected overall survival as the primary clinical endpoint, with all stipulating a hazard ratio (HR) ≤ 0.8 corresponding to improvement in median overall survival of 2.5 to 6 months, depending on setting, as the minimum incremental improvement over standard therapy that defines a clinically meaningful outcome. Pancreatic Cancer—FOLFIRINOX-Eligible Patients: The current baseline median overall survival was estimated at 10 to 11 months. The minimum improvement over current overall survival considered clinically meaningful is 4 to 5 months, with a target hazard ratio of 0.67 to 0.69. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 63% from the current rate of 48%, and progression-free survival is expected to improve by at least 4 to 5 months. Pancreatic Cancer—Gemcitabine- or Gemcitabine/Nab-paclitaxel-Eligible Patients: The current baseline median overall survival was estimated at 8 to 9 months. The minimum improvement over current overall survival considered clinically meaningful is 3 to 4 months, with a target hazard ratio of 0.6 to 0.75. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 50% from the current rate of 35%, and progression-free survival is expected to improve by at least 3 to 4 months.

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JCO Spotlight

Defining Clinical Trial Goals ■■ Minimum improvements in median overall survival were selected as the primary goal for demonstrating clinically meaningful outcomes in phase III clinical trials. ■■ Minimum improvements in 1-year overall and progression-free survival were selected as secondary goals for demonstrating clinically meaningful improvements.

Lung Cancer—Non–Squamous Cell Carcinoma: The current baseline median overall survival was estimated at 13 months. The minimum improvement over current overall survival considered clinically meaningful is 3.25 to 4 months, with a target hazard ratio of 0.76 to 0.8. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 61% from the current rate of 53%, and progression-free survival is expected to improve by at least 4 months. Lung Cancer—Squamous Cell Carcinoma: The current baseline median overall survival was estimated at 10 months. The minimum improve-

ment over current overall survival considered clinically meaningful is 2.5 to 3 months, with a target hazard ratio of 0.77 to 0.8. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 53% from the current rate of 44%, and progression-free survival is expected to improve by at least 3 months. Breast Cancer—Metastatic TripleNegative Disease, Previously Untreated for Metastatic Disease: The current baseline median overall survival was estimated at 18 months. The minimum improvement over current overall survival considered clinically meaningful is 4.5 to 6 months, with a target hazard

ratio of 0.75 to 0.8. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 71% from the current rate of 63%, and progression-free survival is expected to improve by at least 4 months. Colon Cancer—Disease Progression With All Prior Therapies (or Not a Candidate for Standard Second- or Third-Line Options): The current baseline median overall survival was estimated at 4 to 6 months. The minimum improvement over current overall survival considered clinically meaningful is 3 to 5 months, with a target hazard ratio of 0.67. As secondary endpoints, 1-year overall survival would be expected to improve to a minimum of 35% from the current rate of 25%, and progressionfree survival is expected to improve by at least 3 to 5 months.

Clarifying Remarks The authors stated that the conclusions reached by the working groups are not intended to set standards for regulatory approval or insurance coverage, “but

rather to encourage patients and investigators to demand more from clinical trials.” They also observed that symptoms from cancer progression and tolerability of treatment are of critical importance when considering whether a new treatment is associated with a clinically meaningful outcome for patients. The authors stated: For the most part, the working groups agreed that if a therapy is less toxic than prevailing treatments, a smaller improvement in efficacy is acceptable. Conversely, a highly toxic therapy should be accompanied by an expectation of substantially greater benefit to provide a clinically meaningful outcome to patients. n Disclosure: For full disclosures of the authors, visit jco.ascopubs.org.

Reference 1. Ellis LM, Bernstein DS, Voest EE, et al: American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. March 17, 2014 (early release online).

Issues in Oncology

Discussions About the Cost of Cancer Care Are Still Uncommon

Cost of Care

By Caroline Helwick

atients with cancer are extremely interested in discussing the cost of treatment, especially their share of the cost, but some oncologists are still hesitant to enter into these conversations, according to a study reported at the National Comprehensive Cancer Network (NCCN) 2014 Conference.1 “We have demonstrated that patients do want to know the costs of the treatment, and that these costs are not being routinely discussed in academic medicine,” said lead author Ronan J. Kelly, MD, MBA, of Johns Hopkins School of Medicine. “For the first time, we show that there are minimal conflicts and no harm to the doctor-patient relationship when costs are introduced.”

Is Cost of Care Being Discussed in the Clinic? In 2007, the ASCO Cost of Care Task Force was established to deal with the soaring costs of cancer treatment in the United States. One of the key recommendations was that the cost of chemotherapy should be introduced into the patientphysician discussion from the outset. “It is unknown if these discussions are occurring in academic institutions and

what, if any, is the impact on the doctor/ patient relationship,” said Dr. Kelly. The prospective study included patients attending Johns Hopkins for the management of advanced or metastatic

shared decision-making process when costs were introduced into the discussion. Patients were interviewed before and after their consultation to measure their satisfaction with the process, includ-

We have demonstrated that patients do want to know the costs of the treatment, and that these costs are not being routinely discussed in academic medicine. —Ronan J. Kelly, MD, MBA

lung, colorectal, or breast cancer in 2013. During the clinical encounter between physician and patient, the NCCN Guidelines and the eviti® advisor platform (a digital library of evidence-based standards for cancer care) were jointly used during the consultation to demonstrate treatment options and display the costs at the time of prescribing to providers and patients alike. Questionnaires measured the oncology providers’ attitudes to cost discussions and assessed their satisfaction with the

ing their attitudes to cost discussions and shared decision-making as it pertained to cost and outcomes.

Cost of Care an Important Issue to Patients Of 18 oncologists interviewed for the study, only 5 (28%) reported feeling comfortable when discussing costs with patients and only one (6%) regularly asked patients about their financial wellbeing. Despite this, 83% of providers

felt that the NCCN guidelines should contain cost information. Of 107 patients asked to participate in the study, 96 (90%) gave written consent. More than 80% of respondents reported that it is “quite important” or “extremely important” for them to know the amount they will be personally responsible for paying. Interestingly, in spite of their desire for information, 72% of patients noted that no health-care professional has ever discussed costs with them. The majority of patients—80%—had no negative feelings to hearing cost information. “In an era of rising copays, patients want cost-of-treatment discussion and these do not lead to negative feelings in the majority of patients,” Dr. Kelly said. “Additional training to prepare clinicians for how to discuss costs with their patients is needed.” n

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

Reference 1. Kelly RJ, Forde PM, Bagheri A, et al: Measuring the impact of chemotherapy cost discussions between patients and providers at the time of prescribing. 2014 NCCN Annual Conference. Presented March 2014.

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Palliative Care in Oncology The Role of Psychosocial Supportive Services in Palliative Care A Conversation With Deane L. Wolcott, MD By Jo Cavallo

ore than 2 decades ago, Deane L. Wolcott, MD, helped develop comprehensive patient-centered psycho-oncology care in cancer centers across the country. Today, many aspects of that patient-centered care, including psychiatric, dietary, pain management, cancer rehabilitation medicine, survivorship, and palliative care services, have been integrated into a multidisciplinary, collaborative care model in hospital cancer centers, as well as in some community oncology practices. However, more needs to be done, especially in private oncology practices, said Dr.

high-quality cancer care outlined five principles of cancer patient care from diagnosis onward, and they include care planning, palliative care, psychosocial support, prevention/management of long-term and late effects, and family/ caregiver support.1 The definition of palliative care has had a difficult history in both public and physician perceptions of that term. As a result, for many people, palliative care is synonymous with hospice end-of-life care. I believe the human aspects of cancer care, including what we historically have called psychosocial oncology or

Palliative care should be provided not instead of traditional medical oncology care, but in collaboration with all appropriate active cancer treatment, from the moment of diagnosis—or even before diagnosis— through the remainder of the patient’s disease trajectory. —Deane L. Wolcott, MD

Wolcott, to ensure that all patients with cancer get integrated, comprehensive supportive care, including palliative care, from the moment of diagnosis and throughout all phases of cancer survivorship. The ASCO Post talked with Dr. Wolcott, Director, Oncology Supportive Care Services at the Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center in Los Angeles, about the role of psychological supportive services in palliative care, the psychosocial issues patients contend with at different stages of their illness and survivorship, and the importance of screening cancer survivors for distress and providing referrals to mental health specialists if necessary.

Critical Part of Cancer Care Please talk about the role of psychological supportive care services in palliative care. The first point to make is that palliative and psychosocial care should be made available to patients from the moment of cancer diagnosis and throughout survivorship. The Institute of Medicine (IOM) report on delivering

palliative care are critical parts of cancer care delivery from the moment of diagnosis forward. The fundamental aspect of palliative care is a genuine commitment to whole-person care, including managing patients’ physical, psychological, and spiritual distress, thereby seeking to preserve patients’ quality of life. Palliative care should be provided not instead of traditional medical oncology care, but in collaboration with all appropriate active cancer treatment, from the moment of diagnosis—or even before diagnosis—through the remainder of the patient’s disease trajectory. One of the challenges we face is that palliative care services often have developed relatively independently of other supportive oncology services. For example, oncologists, nurses, psychiatrists, psychologists, social workers, and dietitians tend to work in separate departments, and their services are often not integrated into whole-patient care. But there is a sea change underway in the models of care for hospital-based palliative care programs, with greater emphasis on multidisciplinary collaborative care.

We are facing a workforce shortage—currently there are only about 200 psychiatrists and psychologists who are members of the American Psychosocial Oncology Society. Many of these professionals work in major academic cancer centers and have academic as well as clinical roles. We need adequate professional resources and sustainable models to ensure that patients with cancer treated in smaller hospital cancer centers and in community-based oncology practices have access to needed psychiatric and psychological care. We also need to rapidly increase the workforce of palliative care physicians to meet the needs of patients with cancer in all oncology care environments. This workforce shortage is becoming particularly acute as the number of cancer survivors is rapidly increasing. Community cancer service organizations, such as the American Cancer Society and CancerCare, are a critically important component of our national cancer supportive care services delivery system. We need to further develop models for collaborative supportive care among hospital programs, community oncology providers, and community-based resources. The role of psychiatry in comprehensive patient-centered cancer care is important, but it is most valuable if it is part of an integrated multidisciplinary care delivery system where patients have access to psychological expertise, social workers, dietitians, experts in pain and symptom palliative care management, and patient and family support groups.

Disease Phases and Distress Please describe the psychosocial issues patients may experience at different stages of their illness and survivorship. Thirty-five years ago, Avery D. Weisman, MD, published a study on the psychosocial phasing in cancer,2 in which he described a prediagnosis phase, early diagnosis and active treatment phase—what we now call the survivorship phase—recurrence/ relapse phase, and end-of-life phase. And throughout those different phases, there are distinctive typical patterns of distress and anxiety. Often the prediagnosis phase—for example, when someone has a lump that needs to be evaluated—causes the highest level of acute anxiety and fear.

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

Some people in this situation will have tremendous cancer anxiety and will not have cancer. And while that is often the time of greatest distress, we have very few resources available to support people during that prediagnosis phase. Once people are diagnosed with cancer, we tend to see understandable initial fear: What is my prognosis? Am I going to survive? Do I have to face the possibility of death? This initial concern is often followed by fears of having significant pain as a result of their cancer or cancer treatment. So, fear of pain, death, and dying, and then the distress brought on by the treatment itself can all cause tremendous anxiety. For people who are doing well and have completed active treatment, there are often conflicting emotions. There may be a sense of initial relief but then a feeling of anxiety over not getting the same level of care and clinical observation they received during treatment. Patients often feel a sense of abandonment, which is where I think the whole cancer survivorship emphasis is really important. The recurrence phase is another time of great distress, anxiety, and fear—and, not uncommonly, anger—because the patient has to go from being a long-term cancer-free survivor to possibly accepting a limited life expectancy. So it is a time of great distress that needs a lot of attention and care. Patients who develop rapidly procontinued on page 126

When mCRC tumors

after progression on an oxaliplatin-containing regimen, should you consider an alternative approach? ZALTRAP® (ziv-aflibercept), in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. ZALTRAP inhibits angiogenesis by trapping VEGF-A, VEGF-B, and PLGF as shown in pre-clinical studies1-3,* * The clinical significance is unknown.

Important Safety Information for ZALTRAP® (ziv-aflibercept) WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. — Bleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP/ FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade 3-4 hemorrhagic events, including GI hemorrhage, hematuria, and post-procedural hemorrhage, occurred in 3% of ZALTRAP/ FOLFIRI patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial hemorrhage and pulmonary hemorrhage/ hemoptysis including fatal events have occurred in patients receiving ZALTRAP. — Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. — Across three clinical trials (colorectal, pancreatic, and lung cancer), GI perforation (all grades/Grade 3-4) occurred in 0.8%/0.8% of ZALTRAP patients and 0.3%/0.2% for placebo patients. — Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP in patients who experience GI perforation. ZALTRAP impairs wound healing in animal models. Grade 3 compromised wound healing occurred in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI and none of the patients treated with placebo/FOLFIRI. — Discontinue ZALTRAP in patients with compromised wound healing. — Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed. — For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.

ZALTRAP.com/HCP

increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP. — There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who developed Grade 3-4 hypertension, 54% had onset during the first two cycles of treatment. — Monitor blood pressure at least every two weeks, treat with appropriate anti-hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment. Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy. Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3-4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE. Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. — Proteinuria was reported in 62% of ZALTRAP/FOLFIRI patients compared to 41% of placebo/FOLFIRI patients. Grade 3-4 proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/ FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. — Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24-hour urine collection in patients with a dipstick of ≥2+ for protein or UPCR >1. — Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours. — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg. — Discontinue ZALTRAP if nephrotic syndrome or TMA develops. A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. — Grade 3-4 neutropenia occurred in 37% of ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI patients. Grade 3-4 febrile neutropenia occurred in 4% of ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI patients. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI patients. — Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.

Incidence

of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI. — Grade 3-4 diarrhea was reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of placebo/FOLFIRI patients. Grade 3-4 dehydration was reported in 4% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. — The incidence of diarrhea is increased in patients ≥65 years of age compared to patients <65 years of age. Monitor closely. RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death. ADVERSE REACTIONS The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. The most common Grade 3-4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/ FOLFIRI and 7% of patients treated with placebo/FOLFIRI. PREGNANCY AND NURSING MOTHERS ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. It

is not known whether ZALTRAP is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Please see Brief Summary of full Prescribing Information on next page. References: 1. ZALTRAP Prescribing Information. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; October 2013. 2. Tew WP, Gordon M, Murren J, et al. Clin Cancer Res. 2010;16:358-366. 3. Riely GJ, Miller VA. Clin Cancer Res. 2007;13(15 suppl):4623s-4627s.

In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. US.AFL.14.02.002 2/14 Printed in the U.S.A. © 2014 sanofi-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

Rx Only

Brief Summary of Prescribing Information WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

INDICATIONS AND USAGE

ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus. Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and postprocedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/ FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/ FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC, proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/ FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/ FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/ FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)]

6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria. The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/ FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI (N=605) Primary System Organ Class Preferred Term (%)

ZALTRAP/FOLFIRI (N=611)

All grades

Grades 3–4

All grades

Grades 3–4

0.8%

Infections and infestations Urinary Tract Infection Blood and lymphatic system disorders Leukopenia

72%

12%

78%

16%

Neutropenia

57%

30%

67%

37%

Thrombocytopenia

35%

48%

Decreased Appetite

24%

32%

Dehydration

0.3%

22%

11%

1.5%

41%

19%

28%

0.2%

Metabolism and nutrition disorders

Nervous system disorders Headache Vascular disorders Hypertension

Respiratory, thoracic and mediastinal disorders Epistaxis

Dysphonia

25%

0.5%

Dyspnea

0.8%

12%

0.8%

Oropharyngeal Pain

0.2%

Rhinorrhea

Diarrhea

57%

69%

19%

Stomatitis

33%

50%

13%

Abdominal Pain

24%

27%

4% 1%

Gastrointestinal disorders

Abdominal Pain Upper

11%

Hemorrhoids

Rectal Hemorrhage

0.5%

0.7%

Proctalgia

0.3%

0.5%

11%

Proteinuria*

41%

62%

Serum creatinine increased

19%

0.5%

23%

Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysesthesia Syndrome Skin Hyperpigmentation Renal and urinary disorders

General disorders and administration site conditions Fatigue

39%

48%

13%

Asthenia

13%

18%

AST increased

54%

62%

ALT increased

39%

50%

Weight decreased

14%

0.8%

32%

Investigations

Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4),

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/ FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2013 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-OCT13

Revised: October 2013

The ASCO Post | MAY 15, 2014

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Palliative Care in Oncology Psychosocial Supportive Services continued from page 122

gressive disease and are approaching end-of-life, along with their families, experience a whole other series of stresses. These include such uncertainties as: Is it realistic to maintain hope? To what extent is it important to continue aggressive active treatment? And when should the process of accepting a likely limited life expectancy begin? Other factors that contribute to the levels of distress, anxiety, and depression patients may feel include the age of the patient and other illnesses the patient may have. We are also continuing to learn how many cancer patients at all phases of their illness cope very effectively, constructively engage with their families and social support systems, maintain active social role function, and often develop a greater clarity of their life priorities and values. The common and often remarkable resilience of patients with cancer is one of the most important aspects of the cancer experience.

Interrelated Symptoms How do pain and fatigue contribute to anxiety, depression, and insomnia? They are all interrelated. Anxiety, depression, fatigue, and pain are the four most common symptoms patients with cancer experience, and they can each

contribute to insomnia. You cannot diagnose major depression in someone who is in pain. If you get the pain under control, the next day the patient is usually less depressed. You need to systematically assess and manage pain, fatigue, anxiety, depression, and insomnia. Successful management of one symptom often contributes to decreased severity of the other symptoms. We ideally want to continuously minimize each of these symptoms throughout the patient’s medical course.

Distress Assessment How can oncologists assess patients for psychological distress? It is an enormous challenge. We are seeing an exploding incidence of cancer with a relatively small number of oncologists available to treat these patients. It is not reasonable to expect medical oncologists to spend significant amounts of time communicating with their patients about the psychological distress they may be experiencing. A number of distress screening instruments have been developed, including the National Comprehensive Cancer Network (NCCN) Distress Thermometer and the Edmonton Symptom Assessment Scale, which can be used in the office practice environment. I don’t think there will be a real solution to this problem until we have a national commitment to develop and implement a comprehensive supportive

oncology care delivery system, including palliative care services that are available to all physicians in all locations. Matthew J. Loscalzo, MSW [Executive Director, Department of Supportive Care Medicine, and Professor, Department of Population Sciences at City of Hope, Duarte, California], has developed SupportScreen, a Webbased touch-screen tool that patients can use to self-report both physical and psychosocial concerns via a questionnaire. SupportScreen is being used at City of Hope and other cancer centers, and we are implementing this screening tool at the Samuel Oschin Comprehensive Cancer Institute. Our early findings show that with this technology, we are identifying many more supportive care needs than we had previously. The Commission on Cancer has mandated that by 2015, hospital providers must have a plan in place to evaluate patients for distress and refer them to programs for help. Tools such as the NCCN Distress Thermometer, which measures a patient’s distress on a 0-to10 scale, can also be useful. If a patient has a score of 4 or higher, it is an indication that the person should be further evaluated and, if warranted, referred to a mental health-care specialist. How we will effectively screen all patients with cancer for psychological distress with the limited resources we currently have, however, remains a big challenge.

Closing Thoughts Do you have any final considerations about supportive care services you’d like to emphasize? I believe the important themes in oncology supportive care services must include integrated, multidisciplinary supportive care teams that fully assist the care provided by medical oncologists, that integrate traditional care with palliative care and cancer survivorship services, and that help support patient resilience during the profound stresses of cancer and its treatment. At the cancer care delivery system level, we need to develop clinically effective, high-value, sustainable business models to support truly comprehensive supportive care for all patients with cancer in all care environments, throughout all phases of their illness and survivorship, as was so eloquently outlined in the IOM report. n

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

References 1. Institute of Medicine: Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Washington, DC, National Academies Press, 2013. 2. Weisman AD: A model for psychosocial phasing in cancer. General Hospital Psychiatry 1(3):187-195, 1979.

Don’t Miss These Important Reports in This Issue of The ASCO Post Lowell E. Schnipper, MD, on Value in Cancer Care see page 1

Eduardo Bruera, MD, on Cancer Fatigue Care see page 55

Paul K. Paik, MD, on FGFR Inhibitors in Bladder and Lung Cancer see page 18

Andrew D. Zelenetz, MD, PhD, on the Elderly Lymphoma Patient see page 30

David Garcia, MD, on Challenges in Clinical Practice Guidelines see page 39 Kembra l. Howdeshell, PhD, and Michael D. Shelby, PhD, on Cancer Chemotherapy Use During Pregnancy see page 67 Lee M. Ellis, MD, on Clinical Trials see page 73

Derek Raghavan, MD, PhD, on Uro-Oncology see page 82

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MAY 15, 2014

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Integrative Oncology Maximizing the Benefits of Exercise in Patients With Cancer By Kathleen Wesa, MD, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center

any nonpharmacologic therapies increase both physical and emotional strength during cancer treatment as well as throughout survivorship. These therapies include the mind-body practices of meditation, self-hypnosis, guided imagery, and breath awareness, touch therapies including massage and reflexology, music therapy, acupuncture, better nutrition, and physical fitness. Exercise is also well recognized as a powerful tool to help cope with cancer.

Exercise Decreases Cancer Risk Many clinical trials demonstrate the benefits of physical fitness in patients with cancer, and physical activity is increasingly acknowledged as a legitimate medical therapy. Insurers in some states reimburse physical fitness programs. The many treatmentrelated side effects are decreased by exercise, and mounting clinical trial evidence indicates that ongoing enhanced physical fitness not only decreases the risk of developing cancer, but also provides a survival advantage following cancer diagnosis. More than 200 studies demonstrate decreased cancer risk with increased fitness. The evidence for an association with physical activity is convincing for colon and breast cancers, probable for endometrial cancer, possible for prostate, gastric, and ovarian cancers, and insufficient for all other cancer sites.1 More than 70 studies indicate a more than 25% reduction in risk of breast cancer for physically active vs least active women.

Survival Advantage The Nurses’ Health Study involving more than 121,000 women showed a strong association between physical activity and outcomes in colon (N = 600) and breast cancer (N = 3,000). Enhanced survival benefits were attributed to the effects on estrogen levels. In the LACE and Collaborative Women’s Longevity Study, physical activity reduced all-cause mortality. In 832 patients with stage III colorectal cancer, patients who engaged in 6 to Dr. Wesa is an integrative medicine specialist at Memorial Sloan Kettering Cancer Center, New York.

9 hours of physical fitness vs less than 1 hour per week had a 51% decreased risk of dying from colorectal cancer. Those who engaged in 9 or more

hours of exercise had a 55% decreased risk of dying from colorectal cancer. The benefit of physical activity was not significantly modified by gender,

body mass index, number of lymph nodes, age, baseline performance status or chemotherapy.2 continued on page 128

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The ASCO Post | MAY 15, 2014

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Integrative Oncology Benefits of Exercise continued from page 127

Similar results were found for men with stage III colorectal cancer in the Health Professionals Study,3 and recent meta-analyses confirm this benefit.4

Guidelines for Physical Activity Sedentary behavior is implicated as an independent risk factor for cancer. The American Cancer Society recommends at least 150 minutes per week of moderate intensity exercise, or greater than 75 minutes per week of vigorous exercise. Ideally, fitness activities are evenly spread throughout the week. Recommendations for cancer survivors are for at least 30 minutes of moderate to vigorous physical activity above usual daily activities, at least 5 days per week5; 40 to 60 minutes of physical activity is preferable. Aerobic activity should be performed for at least 10 minutes and preferably spread throughout the week. The American College of Sports Medicine recommends reaching 55% of maximum heart rate for sedentary persons and 65% for more physically fit individuals. For additional and more extensive health benefits, the Department of Health and Human Services recommends at least 300 minutes (5 hours) per week of moderate-intensity metabolic equivalent (MET) with MET > 3, or 150 minutes per week of vigorous exercise (MET > 6). The elderly or those at risk for falls should incorporate exercises that improve or maintain balance.

Proposed Mechanisms Physical fitness and physical activity trigger multiple mechanisms for cancer prevention.6 For hormoneresponsive cancers, proposed mechanisms include decreased androgen and estrogen synthesis, enhanced sex hormone–binding globulin synthesis producing decreased circulating hormone levels, and decreased body mass index.7 Lower body mass index is associated with decreased leptin and increased adiponectin, which decreases cancer risk. Increased physical activity decreases systemic inflammatory response via decreased tumor necrosis factor–alpha, interleukin (IL)-6 and C-reactive protein synthesis. Multiple mechanisms enhance insulin sensitivity, decrease insulin secretion, decrease insulin C-peptide, and decrease IL-17 levels, thereby decreasing the overall inflammatory response. For other can-

cer types, similar mechanisms are proposed and under active investigation.6

Decreased Physical/Emotional Symptoms During cancer treatment, exercise decreases physical and emotional symptoms. A Cochrane review involving 4,800 patients showed that moderate or vigorous exercise produced better quality of life and physical function, decreased fatigue and anxiety, and enhanced sleep quality compared with less active individuals.8 Ongoing physical activity produces major improvement in muscle strength, aerobic capacity, enhanced quality of life, decreased fatigue, and improved

complementary health practice according to National Health Interview Surveys, and yoga’s popularity is increasing.13 Thirteen million people practice yoga. The physical benefits of yoga in cancer groups include enhanced perceptual and motor skills, increased cardiovascular function, increased flexibility, fitness and muscle strength, balance, improved blood glucose and lipid profiles, decreased fatigue and pain, improved sleep, decreased joint pain and decreased muscular stiffness.5,14 Yoga requires little space and requires no equipment. Vigorous yoga provides benefits similar to those gained with treadmill

Vigorous yoga … provides benefits similar to those of more traditional [exercise] approaches, such as treadmill and weight-bearing resistance, and may help encourage more patients to engage in survivalenhancing physical activity. —Kathleen Wesa, MD

overall emotional status.9 Better functional capacity, decreased chemotherapy-induced nausea, decreased dyspnea, and less memory loss were seen in physically active patients.

Not All Workouts Are Equally Beneficial Fitness programs that combine aerobic and resistance training produce the greatest benefits.10 Aerobic conditioning enhances cardiovascular oxygen delivery and increases oxidative capacity. Resistance exercises decrease muscular weakness, and fitness that combines both aerobic and resistance training provide the greatest benefit in enhancing maximal oxygen consumption.11 Data show that less than 10% of survivors are physically active during treatment, and only 25% will be active after treatment. Support groups and special programs for cancer survivors, such as SHARE and Gilda’s Club, may help enhance fitness participation.12

Yoga: An Increasingly Popular Fitness Choice There are multiple exercise possibilities for patients, such as aerobic training, resistance strength training, stretching, yoga, tai chi, Qi Gong, and so forth. Yoga is the sixth most used

workouts.15,16 It can provide fitness benefits that approach those of treadmill performance in terms of MET expenditure and percent maximum heart rate. While kilocalorie expenditure and maximal oxygen consumption are less than that of treadmill at 3.5 mph (5.6 kph), they are higher than treadmill at 1.9 mph (3.2 kph), and at least 10 minutes of vigorous yoga provides a fitness level at the moderate intensity recommended by the American College of Sports Medicine to improve cardiovascular fitness. Yoga also incorporates weight-bearing resistance. Yoga’s anti-inflammatory effects are well demonstrated. A cross-sectional study of 50 healthy women who were either yoga novices or seasoned practitioners produced additional data. Leptin and adiponectin was measured on three occasions in these women, who were matched on potential confounding factors including body mass index, central adiposity, and cardiovascular fitness. Leptin was 36% higher in the yoga novices vs the experts (P = .08), but the adiponectinto-leptin ratio in yoga experts was nearly twice that of the yoga novices (P = .009).18 Many forms of fitness are available to suit virtually all patient and survi-

GUEST EDITOR

Barrie R. Cassileth, MS, PhD

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 268 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/ about-herbs/id554267162?mt=8. vor preferences. Vigorous yoga is a popular option. It provides benefits similar to those of more traditional approaches, such as treadmill and weight-bearing resistance, and may help encourage more patients to engage in survival-enhancing physical activity. n

Disclosure: Drs. Wesa and Cassileth reported no potential conflicts of interest.

References 1. Steindorf K, Leitzmann M, Friedenreich C: Physical activity and primary cancer prevention, in Ulrich CM, Steindorf K, Berger NA (eds): Exercise, Energy Balance, and Cancer, pp 83-106. New York, Springer, 2013. 2. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527-3534, 2006.

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Integrative Oncology 3. Meyerhardt JA, Giovannucci EL, Ogino S, et al: Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102-2108, 2009. 4. Je Y, Jeon JY, Giovannucci EL, et al: Association between physical activity and mortality in colorectal cancer: A metaanalysis of prospective cohort studies. Int J Cancer 133:1905-1913, 2013. 5. Buffart LM, Galvão DA, Brug J, et al: Evidence-based physical activity guidelines for cancer survivors: Current guidelines, knowledge gaps and future research directions. Cancer Treat Rev 40:327-340, 2014. 6. Courneya KS, Friedenreich CM: Physical activity and cancer: An introduction. Recent Results Cancer Res 186:1-10, 2011. 7. Lynch BM, Neilson HK, Friedenreich CM: Physical activity and breast cancer prevention. Recent Results Cancer Res 186:13-42, 2011. 8. Mishra SI, Scherer RW, Geigle PM, et al: Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev 8:CD007566, 2012. 9. Cramer H, Lange S, Klose P, et al: Yoga for breast cancer patients and survivors: A systematic review and meta-analysis. BMC Cancer 12:412, 2012. 10. Irwin ML: Benefits of aerobic and resistance exercise in cancer survivors, in Berger NA, Steindorf K, Ulrich C (eds): Exercise, Energy Balance and Cancer, pp 199-214. New York, Springer, 2012. 11. Jones LW: Physical activity and lung cancer survivorship. Recent Results Cancer Res 186:255-274, 2011. 12. Bourke L, Homer KE, Thaha MA, et al: Interventions to improve exercise behaviour in sedentary people living with and beyond cancer: A systematic review. Br J Cancer 110:831-841, 2014. 13. Perrgoy JA, Clarke TC, Jones LI, et al: Regional variation in use of complamentary health approaches by U.S. adults, in NCHS Data Brief, no. 146. Hyattsville, Maryland, National Center for Health Statistics, National Institutes of Health, April 2014.

14. Buffart LM, van Uffelen JG, Riphagen II, et al: Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials. BMC Cancer 12:559, 2012. 15. Hagins M, Moore W, Rundle A: Does practicing hatha yoga satisfy recom-

dridge R, et al: Yoga’s impact on inflammation, mood, and fatigue in breast cancer survivors: A randomized controlled trial. J Clin Oncol 32:1040-1049, 2014. 18. Kiecolt-Glaser JK, Christian LM, Andridge R, et al: Adiponectin, leptin, and yoga practice. Physiol Behav 107:809-813, 2012

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MO DEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology. Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Learn More About Herbs, Botanicals, and Other Products

mendations for intensity of physical activity which improves and maintains health and cardiovascular fitness? BMC Complement Altern Med 7:40, 2007. 16. Clay CC, Lloyd LK, Walker JL, et al: The metabolic cost of hatha yoga. J Strength Cond Res 19:604-610, 2005. 17. Kiecolt-Glaser JK, Bennett JM, An-

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

Visit the free About Herbs website at www.mskcc.org/ aboutherbs.

For more information, visit CarolinasHealthCare.org/ModelOfCare

The ASCO Post | MAY 15, 2014

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Pearls in Neuro-oncology

Surgical Resection of Newly Diagnosed Glioblastoma: What Is the Standard of Care? By William T. Curry, Jr, MD

he neurosurgeon is often the gateway provider when patients present with what on magnetic resonance imaging (MRI) appears to be a new glioblastoma. Because histology-based diagnosis is a prerequisite for initiating standard therapy with radiation and chemotherapy, the first question that the neurosurgeon faces is whether to perform a stereotactic biopsy or a craniotomy for resection, which may relieve mass effect and achieve cytoreduction. The surgeon in question takes into account a variety of factors, including the size of the lesion, its location, the presence of midline shift or other markers of mass effect—each of which may correlate with the patient’s neurologic status or Karnofsky performance status.

Glioblastoma Remains Incurable Glioblastoma (grade IV astrocytoma) remains an incurable malignancy, with an expected median overall survival between 14 and 17 months.1,2 While glioblastomas possess most of the canonical hallmarks of malignancy, part of their resistance to local therapies is likely due to their infiltrative nature. From the time in 1923 when neurosurgeon Walter Dandy attempted to cure glioblastoma by hemispherectomy and failed because of contralateral recurrence in the opposite hemisphere, it has been understood that glioblastoma cells infiltrate significant distances across white matter from radiographically and clinically evident primary masses, and

Gross total resection of the contrastenhancing portions of [glioblastoma] tumors appears to be associated with significantly enhanced survival, and adjunctive measures such as intraoperative MRI and fluorescenceguided surgery may be associated with improved outcomes. —William T. Curry, Jr, MD

For decades, Karnofsky performance status has been known to be an independent prognostic indicator of survival for patients with glioblastoma, and, to some extent, a goal of therapy has been to preserve functional status for as long as possible for each patient. With these issues in mind, the surgeon confronting the case specifically asks, “Is this tumor resectable?” In particular, can enough of the tumor be removed without negatively impacting neurologic status and Karnofsky performance status, so that the patient can enjoy the benefits of decompression and cytoreduction? Related questions include: Are the risks of resection worth the potential benefits, and what tools exist to maximize both the extent and safety of resection? William T. Curry, Jr, MD, is Director of Neurosurgical Oncology at Massachusetts General Hospital and Associate Professor of Neurosurgery at Harvard Medical School in Boston.

that, therefore, surgery may not be a centrally important component of care. Despite these facts, glioblastoma today is frequently treated by resection, both at the time of initial presentation and at recurrence. A great deal of effort, technology, and expense is directed toward optimizing craniotomy outcomes, with the parallel and sometimes competing goals of maximizing the extent of removal of the tumor while preserving neurologic function. Historically, the therapeutic value of aggressive surgical resection of glial tumors has been met with skepticism. For patients with large, symptomatic, and peripherally located tumors, surgical debulking has been pursued for its palliative impact, but its survival benefit has been frequently questioned. Over the past 10 to 15 years, we have seen advances in radiographic imaging of brain tumors and in adjuncts to surgery, such as increasingly accurate navigation, functional imaging, neuro-

physiologic mapping techniques, and intraoperative imaging. Similarly, the introduction of temozolomide as an effective chemotherapy in combination with radiation therapy for newly diagnosed patients and the frequent use of bevacizumab (Avastin) for patients with recurrent disease have improved outcomes for glioblastoma patients, with overall survival now between 14 and 18 months. During the same period, evidence supporting the survival value of upfront aggressive resection of newly diagnosed glioblastoma has accumulated, making craniotomy for these patients the current standard of care. The resection of tumors from the brain, however, can be fraught with neurologic morbidity, negatively impacting quality of life and, ultimately, survival itself. Iatrogenic complications, surgical or otherwise, can have a dramatically negative impact.3 Accordingly, significant investigation and debate have addressed the value of aggressive resection of glioblastoma, with a gross total resection defined by removal of 100% of the gadolinium-enhancing material on MRI. As infiltrating astrocytoma cells invariably exist beyond the gadolinium-enhancing core of the tumor and radical resection is not feasible within the central nervous system, it is not intuitive that “100%” or “gross total” resection is a meaningful goal.

Resectability and Survival The question of resectability of glioblastoma tumors is a nuanced one with expected variance in opinion across the spectrum of tumors and surgeons alike. Patient-related factors, including age, Karnofsky performance status, and marital status; tumor-associated characteristics, including size, location, and MRI appearance; and provider-related circumstances, including specialist status, volume of practice, training, experience, and incentives may influence rates of resection, and these can be difficult to disentangle outside of the environment of a randomized study. In a study by Vuorinen et al,4 30 patients aged 65 and older, with presumed newly diagnosed glioblastoma and good performance scores, were randomly assigned to craniotomy vs biopsy. Patients who underwent craniotomy rather than biopsy had significantly improved over-

GUEST EDITOR

Tracy Batchelor, MD

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

all survival and also trended toward longer times to neurologic deterioration. This trial has been criticized because of the specific patient population, the subjects’ relatively poor performance scores, variable postoperative treatments, and small sample size. Also, the authors did not provide information about the extent of resection in patients who underwent craniotomy. The first decade of the 21st century saw the publication of several retrospective single-center studies and database analyses asserting not only that craniotomy produces a survival benefit in glioblastoma patients, but also that a greater extent of tumor removal is associated with relatively better outcomes. It is generally understood that leaving a significant amount of bulky residual tumor after craniotomy may lead to greater perioperative morbidity and neurologic deterioration, related to cerebral edema or intratumoral hemorrhage. The general, though not universal, approach has gravitated toward craniotomy in situations when medical and anatomic factors make it feasible. A randomized study examining intentional subtotal resection vs gross total resection would be considered unethical within the field of neuro-oncology, so there will never be class I evidence addressing the survival impact of surgi-

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Pearls in Neuro-oncology

cally removing all of the radiographically evident tumor. However, the best current evidence supporting the value of gross total resection of glioblastoma tumors comes from randomized studies examining the value of modern adjuncts that help surgeons intraoperatively differentiate glioblastoma tissue from surrounding normal structures.

Fluorescence-Guided Resection In 2006, Stummer et al5 published a randomized trial examining the utility of fluorescence-guided resection of glioblastomas vs standard techniques. 5-Aminolevulinic acid (5-ALA) is a nonfluorescent prodrug that leads to accumulation of fluorescent porphyrins within malignant glioma cells, which can then be identified intraoperatively under blue light. 5-ALA can be administered to glioblastoma patients intravenously or orally prior to craniotomy, and early studies confirmed tumor visualization by operating neurosurgeons. The primary endpoints of this multicenter randomized study were the number of patients in each arm without gadolinium-enhancing tumor on immediate postoperative MRI (ie, gross total resection) and progression-free survival. Enrolled subjects were deemed by study surgeons to have resectable lesions likely to be glioblastoma. The study was terminated at interim analysis because of the significant benefit of fluorescence-guided surgery toward achieving a gross total resection: 65% of patients treated with 5-ALA vs 36% of patients undergoing conventional surgery had no residual contrast-enhancing tumor after craniotomy, independent of age, Karnofsky performance status, or location of the tumor. By multivariate analysis, receipt of 5-ALA and fluorescence-guided surgery was the most important predictive factor. Progression-free survival was better for patients in the 5-ALA group as well: 5.1 vs 3.6 months, independent of Karnofsky performance status and tumor location. The investigators group-stratified protocol patients by postoperative MRI findings, specifically whether a gross total resection had been achieved. Of note, the average amount of residual contrast remaining was very low in the group of subtotally resected tumors. Overall survival was significantly improved for patients who had undergone gross total resection as opposed to having residual contrast postoperatively (17.9 vs 12.9 months). This finding was maintained on multivariate analysis,

which demonstrated that gross total resection, age < 55 years, and Karnofsky performance status > 80 were the most important predictors of overall survival. This study has been criticized because, among other limitations, the postoperative treatments were not necessarily uniform, though all patients received involved-field radiation. Patients who underwent gross total resection were younger and had less frequent eloquent location of their tumors—stratification by these factors showed that the survival advantage for full resection persists regardless of age or eloquent location of tumor.6

Achieving Total Resection The 5-ALA studies serve as the current basis for recommending efforts at gross total resection when it can be achieved safely. The use of 5-ALA as an adjunct effectively randomized the patient population into gross totally resected and subtotally resected groups. 5-ALA is not approved by the U.S. Food and Drug Administration for use in patients undergoing surgery and is available only for investigational use. Intraoperative MRI is a more ex-

pensive and labor-intensive—but increasingly widespread—alternative adjunct toward achieving total resection of brain tumors (Fig. 1). Similar to the 5-ALA story, a randomized clinical trial examining the use of intraoperative MRI has demonstrated the efficacy of the adjunct in achieving gross total resection and better progression-free survival in patients with glioblastoma.7

hazard ratio decreased by 5.2%. Sanai et al9 studied 500 consecutive patients who underwent resection of glioblastoma and observed a significant survival advantage for those who had at least 78% of the contrast-enhancing tumor removed. As increasing amounts of tumor were removed, survival improved, even at the upper limits of resection (ie, between 95% and 100%).

Does Subtotal Resection Improve Survival?

Do All Glioblastomas ‘Respond’ to Gross Total Resection?

An important question that the 5-ALA studies do not address is whether extent of resection is an all-or-none issue. Is all of the impact lost if 95% of the volumetrically measured contrastenhancing tumor is resected, as opposed to 100%? Two recent retrospective studies suggest that there is graded benefit to larger extents of resection for patients with glioblastoma. A study by Chaichana et al8 concluded that the minimum extent of resection associated with prolonged survival for patients with newly diagnosed glioblastoma is 70% and that this factor is key in prognosis. For every 5% increment in extent of resection beyond 70%, the

Although the 5-ALA dataset provides the best contemporary prospective randomized evidence in favor of the survival impact of gross total resection of glioblastoma, the story may continue to evolve. Most of those patients were diagnosed and treated before the regular use of temozolomide chemotherapy, and while the tumors were otherwise fairly well matched, some recently established and impactful molecular features were not studied. Just as temozolomide chemotherapy is more effective against tumors with a methylated O(6)-methylguanineDNA-methyltransferase (MGMT) promoter, surgery may prove to be more useful in certain molecularly defined subgroups of glioblastoma. Mutation of the isocitrate dehydrogenase-1 gene (IDH1) is now understood to be a significant positive predictor of survival for patients with glial tumors, both lowgrade and malignant. For gadolininumenhancing malignant astrocytomas, age, Karnofsky performance status, and IDH1 mutation are independently associated not just with survival, but also with the likelihood of achieving a gross total resection.10 This is the first demonstration of a molecular predictor of resectability in brain tumors. Importantly, that molecular predictor is also associated with better survival. In addition, this study reported that, in IDH1-mutated tumors specifically, resection of the nonenhancing components of the tumor was critical for achieving enhanced survival. The relationship between resectability and survival may be more complex than even currently understood and will require continued study.

In Summary

Fig. 1: Intraoperative confirmation of gross total resection. (A) Preoperative axial T-weighed magnetic resonance imaging with gadolinium showing left-temporal contrast-enhancing lesion, suspicious for glioblastoma. (B) Intraoperative imaging confirming gross total resection of left-temporal glioblastoma.

Defining resectability of glioblastoma tumors is complicated; the tumor biology and cerebral anatomy do not accommodate radical resection of tumors. However, gross total resection of the contrast-enhancing portions of these tumors appears to be associated continued on page 136

XOFIGO® IS INDICATED

for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Not an actual patient. Models used for illustrative purposes only.

Important Safety Information1 for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and • Contraindications: Xofigo is contraindicated in women who are or leukopenia—has been reported in patients treated with Xofigo. may become pregnant. Xofigo can cause fetal harm when administered Monitor patients with evidence of compromised bone marrow reserve to a pregnant woman closely and provide supportive care measures when clinically indicated. • Bone Marrow Suppression: In the randomized trial, 2% of patients Discontinue Xofigo in patients who experience life-threatening in the Xofigo arm experienced bone marrow failure or ongoing complications despite supportive care for bone marrow failure pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with • Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo bone marrow failure was ongoing at the time of death. Among Xofigo, the absolute neutrophil count (ANC) should be the 13 patients who experienced bone marrow failure, 54% required ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin blood transfusions. Four percent (4%) of patients in the Xofigo arm ≥10 g/dL. Prior to subsequent administrations, the ANC should and 2% in the placebo arm permanently discontinued therapy due to be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue bone marrow suppression. In the randomized trial, deaths related Xofigo if hematologic values do not recover within 6 to 8 weeks to vascular hemorrhage in association with myelosuppression were after the last administration despite receiving supportive care observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy of serious infections (10%), and febrile neutropenia (<1%) was similar concomitant chemotherapy with Xofigo have not been established.

600-10-0009-13b

11/13

Printed in USA

Prolong life. Treat bone metastases.

30%

reduction in the risk of death vs placebo (hazard ratio [HR]=0.695)1

The first agent to extend overall survival by exerting an antitumor effect on bone metastases in CRPC1,2 • Exploratory updated analysisa: 3.6-month increase in median overall survival vs placebo (HR=0.695; 95% confidence interval [CI]: 0.581-0.832)1 —14.9 months for Xofigo (95% CI: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8)1

• Prespecified interim analysis: 2.8-month increase in median overall survival vs placebo, P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)1 —14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

• Overall survival benefit supported by delay in time to first symptomatic skeletal event (SSE), favoring Xofigo.b The majority of events consisted of external beam radiation therapy to bone metastases1 • 1-minute intravenous injection every 4 weeks for 6 injections1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b SSEs defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention.

To learn more, visit www.xofigo-us.com

Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients.

The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

Xoﬁgo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the Renal and urinary disorders As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo 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, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | MAY 15, 2014

PAGE 136

Journal Spotlight Thyroid Cancer

Increased Incidence of Thyroid Cancer: An Epidemic of Diagnosis? By Matthew Stenger

n a study reported in JAMA Otolaryngology Head & Neck Surgery,1 Davies and Welch found that the incidence of thyroid cancer has nearly tripled since 1975. However, the increase appears to represent an “epidemic of diagnosis” and to almost exclusively represent increased diagnosis of papillary thyroid cancer. The investigators had previously reported a doubling of thyroid cancer incidence largely due to detection of small papillary cancers. Since these are commonly found in people who have died of other causes and since thyroid cancer mortality had been stable, the investigators had hypothesized that the increased incidence represented overdiagnosis. The current study involved analysis of thyroid cancer incidence, histologic type, tumor size, and mortality using data from 1975 to 2009 from nine Surveillance, Epidemiology, and End Results (SEER) areas (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah) and data on thyroid cancer mortality from the National Vital Statistics System.

Tripled Incidence Since 1975, the incidence of thyroid cancer in men and women aged ≥ 18 years has nearly tripled, from 4.9

The time has come to address the problem of papillary thyroid cancer overdiagnosis and overtreatment. —Louise Davies, MD, MS and H. Gilbert Welch, MD, MPH

to 14.3/100,000 individuals (absolute increase = 9.4 per 100,000, relative rate [RR] = 2.9). More than half this increase (5.1/100,000) occurred during the 7 years since the investigators’ last study. Nearly all of the increase is attributable to a 9.1/100,000 increase in incidence of papillary thyroid cancer (from 3.4 to 12.5/100,000, RR = 3.7). The increase in thyroid cancer in women (14.9/100,000, from 6.5 to 21.4/100,000, RR = 3.3) was near-

Thyroid Cancer Incidence ■■ Since 1975, the incidence of thyroid cancer has nearly tripled, with the increase almost exclusively representing an increase in diagnosis of papillary thyroid cancer. Mortality, however, has remained the same. ■■ The increase in women is nearly four times the increase in men. ■■ The size of diagnosed tumors has decreased over the past 2 decades.

Glioblastoma continued from page 131

with significantly enhanced survival, and adjunctive measures such as intraoperative MRI and fluorescence-guided surgery may be associated with improved outcomes. Nevertheless, neurologic function should not be compromised by surgical efforts at resection, as the Karnofsky performance scale remains an independent prognostic indicator. Patients may also derive survival impact from subtotal resection of glioblastoma, with a possible benefit threshold of approximately 70% volumetric resection of the contrast-enhancing portion of the tumor. Further study may define

subsets of tumors for which resection is particularly valuable. n

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

References 1. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005. 2. Gilbert MR, Dignam JJ, Armstrong TS, et al: A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699-708, 2014. 3. McGirt MJ, Mukherjee D, Chaichana KL, et al: Association of surgically acquired motor and language deficits on overall survival

ly 4 times greater than that in men (3.8/100,000, from 3.1 to 6.9/100,000, RR = 2.2). Diagnosed tumors have gotten smaller. The proportion of tumors ≤ 1 cm has increased from 25% in 1988 to 1989 to 39% in 2008 to 2009. Over the same period, the proportion > 2 cm has decreased from 42% to 33%.

Treatments and Mortality Among the approximately 56,000 Americans diagnosed with thyroid cancer who were treated in 2009, median age at diagnosis was 49 years for women and 53 years for men. More than 90% of both women and men underwent surgery, with approximately half of these patients undergoing radiation therapy, and 50% and 56% had lymph node dissection. The mortality rate from thyroid canafter resection of glioblastoma multiforme. Neurosurgery 65:463-469, 2009. 4. Vuorinen V, Hinkka S, Färkkilä M, et al: Debulking or biopsy of malignant glioma in elderly people—a randomised study. Acta Neurochir (Wien) 145:5-10, 2003. 5. Stummer W, Pichlmeier U, Meinel T, et al: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: A randomised controlled multicentre phase III trial. Lancet Oncol 7:392-401, 2006. 6. Stummer W, Reulen HJ, Meinel T, et al: Extent of resection and survival in glioblastoma multiforme: Identification of and adjustment for bias. Neurosurgery, 62:564-576, 2008. 7. Senft C, Bink A, Franz K, et al: Intraoperative MRI guidance and extent of resection

cer was stable between 1975 and 2009, at approximately 0.5 deaths per 100,000 population. The investigators concluded, “There is an ongoing epidemic of thyroid cancer in the United States. The epidemiology of the increased incidence, however, suggests that it is not an epidemic of disease but rather an epidemic of diagnosis. The problem is particularly acute for women, who have lower autopsy prevalence of thyroid cancer than men but higher cancer detection rates by a 3:1 ratio.” They further stated, “We believe the time has come to address the problem of papillary thyroid cancer overdiagnosis and overtreatment. Providing patients with randomized clinical trial data on an alternative approach—active surveillance of incidentally identified, asymptomatic, small papillary thyroid cancers—is the logical next step. We are pleased to see effort in this direction, both in Japan, where patients have been followed for up to 10 years with favorable results, and in the United States, where Memorial Sloan-Kettering Cancer Center is successfully recruiting patients into an observational cohort.”n

Disclosure: The study was supported by the Department of Veterans Affairs and The Dartmouth Institute for Health Policy and Clinical Practice. The study authors reported no potential conflicts of interest.

Reference 1. Davies L, Welch G: Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 140(4):317322, 2014.

in glioma surgery: A randomised, controlled trial. Lancet Oncol 12:997-1003, 2011. 8. Chaichana KL, Jusue-Torres I, NavarroRamirez R, et al: Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma. Neuro Oncol 2014. 16:113-122, 2014. 9. Sanai N, Polley MY, McDermott MW, et al: An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3-8, 2011. 10. Beiko J, Suki D, Hess KR, et al: IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro Oncol 16:81-91, 2014.

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Director’s Corner Genetics/Genomics

Creating a Comprehensive Catalog of Cancer Genes to Improve Patient Outcomes A Conversation With Eric S. Lander, PhD By Jo Cavallo

n January, Eric S. Lander, PhD, Director of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and his colleagues published the results from their landmark study,1 which explored the feasibility of creating a comprehensive catalog of cancer genes. The researchers collected and analyzed data from the whole-exome sequencing of nearly 5,000 human tumor cancers and their matched normaltissue samples across 21 cancer types. The results of their analysis revealed essentially all known cancer genes in

tated in cancer. Was that surprising to you? Yes. The idea that there were still very large numbers of mutated cancer genes that were unknown was very surprising. We used stringent statistical methods to enumerate candidate cancer genes and then inspected each gene to identify those genes with a strong biologic connection to cancer. These were genes in all sorts of very clear cancer pathways, with just the mutational patterns that you would expect given their function. So, the fact that there were 33 more genes, which

To provide effective combination therapy in cancers, we are going to need to know what pathways are being activated and how. These days, genomic sequencing of tumors is such a straightforward process, I have no doubt that it will become standard of care at some point. —Eric S. Lander, PhD

these cancer types and identified 33 genes—a 25% increase—that were not previously known to be significantly mutated in cancer, including genes associated with proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing, and protein homeostasis. In addition, the study shows that many key cancer genes still remain to be discovered. Dr. Lander estimates that to create a comprehensive catalog of cancer genes necessary to enable physicians to select the best combination therapy for each patient’s cancer, scientists will need to examine 100,000 genes—10 times as many as The Cancer Genome Atlas (TCGA) has analyzed so far—to find most of the genes involved in 50 different cancer types. The ASCO Post talked with Dr. Lander about his study results, what it will take to create a comprehensive catalog of cancer genes, and how such a catalog could guide new drug development, alter clinical trial design, and usher in the era of true precision medicine.

Surprising Findings Your study identified 33 genes that were previously unknown to be significantly mu-

was about a 25% increase in the number of genes known to be significant in those 21 cancer types, was hugely surprising. The study told us that there are a lot of different cancer genes that we still don’t know about but that can be easily found, simply by looking at larger numbers of tumor samples. You are estimating that you will need to analyze 100,000 tumor samples to find most of the genes involved in 50 cancer types? Yes, so that’s about 2,000 samples for each tumor type, which isn’t such a terrifying number. But the number of samples needed will, of course, be different according to the background mutation rate. For example, in lung cancers and melanomas, where the background mutation rate is high, you need about 7,000 tumor samples for each. In cancers where the background rate is much lower, you may only need 1,000, or, more typically, about 2,000 tumor samples. That 2,000-sample estimate is where the 100,000 samples to analyze 50 cancer types comes from.

Catalog of Cancer Genes Please talk about the importance of developing a complete catalog of genes involved in cancer. Having a complete catalog of cancer genes will enable us to look at the biologic pathways of each cancer type and find targets for therapeutic intervention. It lets us recognize what is actually going on in a tumor. For example, there were a number of small GTPase relatives of RAS that were mutated in these cancers. That tells us that there is an important driving force that we did not know about. To provide effective combination therapy in cancers, we are going to need to know what pathways are being activated and how. These days, genomic sequencing of tumors is such a straightforward process, I have no doubt that it will become standard of care at some point. After all, if we are currently spending a couple hundred thousand dollars in the care of a patient with cancer, spending what will probably become $1,000 to understand the mutational pattern of their cancer rather than relying on guesswork and making therapeutic decisions in the dark, strikes me as a no-brainer. How soon will it be before genomic sequencing becomes standard of care in oncology? It is hard to predict exactly, but perhaps within 5 years. I believe that the field should move carefully. What I can say is that if someone I loved had cancer, I would want to have the genomic information on that cancer, and I think that most people are going to feel that way. However, in order to accurately interpret the genomic information on an individual patient’s cancer and prescribe effective therapy, we need a complete catalog of cancer genes and rigorous analytical methods.

Saturation Analysis How will you know when the cancer gene catalog is completed? You keep fishing until the curve flattens out and you don’t find any more genes. This is called saturation analysis. An effective test is to perform “downsampling” to study how the number of discoveries increases with sample size by repeating the analysis on random subsets of samples of various smaller sizes.

In our study, for example, we found that genes mutated at a frequency of 20% or higher have largely been mined out—the curve has flattened out and is not continuing to rise with sample size. However, for genes mutated at lower frequencies, we are finding that the curve is still going up with sample size. So, when the curve bends over and becomes flat, you are done.

Clinical Trial Design How might your study findings impact the design of clinical trials? Most clinical trials will involve genomic analysis for lots of reasons. Companies testing a new therapy in a trial will want to be able to look at the genomic data and determine whether the presence of mutations in any gene correlates with effectiveness of a specific drug. Then patients could be enrolled based on the cellular pathways disrupted in their tumor. It might also be possible to get U.S. Food and Drug Administration approval on new therapies based on many fewer patients’ participation in clinical trials by targeting those patients who will actually respond to the therapy. I think this is the future for clinical trials.

Takeaway Message Do you have any closing thoughts on your research? The big takeaway message from our study is that we clearly have not reached the saturation level in cancer gene identification, and there are a lot of very, very sensible cancer genes still to be found. The good news is it is not going to be that hard to do. The genomic studies of large numbers of tumor samples are no longer prohibitive due to a decrease in the cost of DNA sequencing. Given the devastating effects of cancer on patients and their family members, completing the genomic analysis of this disease should be a biomedical priority. n

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

Reference 1. Lawrence MS, Stojanov P, Mermel CH, et al: Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495-501, 2014.

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American Association for Cancer Research Annual Meeting Genetic Testing Beneficial in Melanoma Treatment, UPCI Study Shows

enetic screening of cancer can help doctors customize treatments so that patients with melanoma have the best chance of beating it, according to the results of a clinical trial by researchers at the University of Pittsburgh Cancer Institute. The trial, funded by the National Institutes of Health, was presented recently at the American Association for Cancer Research (AACR) Annual Meeting 2014. It showed that the cancer immune therapy drug ipilimumab (Yervoy) appears most likely to prevent recurrence in patients whose cancer shows high expression of immune-related genes. “We’ve reached a point in the treatment of melanoma—and cancer in general—where we’re making major improvements in the outcomes of patients through personalized medicine,” said Lead Iinvestigator Ahmad Tarhini, MD, PhD, Associate Professor of Medicine and Translational Science in the Department of Medicine and Clinical and Translational Science Institute, at the University of Pittsburgh. “Anticancer therapy can be associated with significant side effects and economic costs. Therefore, we have a major interest in the development of tests that may allow us to predict which treatment regimen is most likely to help certain patients, while sparing others the unwanted side effects and cost of medications that are unlikely to work.”

recurrence after surgery. “By validating these findings in a large national trial that also will allow us to investigate other significant biomarker data, we’ll seek to develop ‘biomarker signatures’ that doctors can use to customize melanoma treatment

plans. The ultimate goals of therapy are to best treat the cancer in an individualized approach, while avoiding the unnecessary exposure of patients to severe side effects,” said Dr.S:6.875” Tarhini. Additional researchers on this study are Yan Lin, PhD, Hui-Min Lin,

MS, Cindy Sander, BS, William A. La Framboise, PhD, and John M. Kirkwood, MD, all of University of Pittsburgh Medical Center. This research was supported by NIH award P50CA121973 and Bristol-Myers Squibb. n

KADCYLA®: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

KADCYLA contains the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker

Study Details Before and after ipilimumab treatment, Dr. Tarhini and his colleagues obtained tumor biopsies used to run genetic tests on the tumors of 32 patients with advanced, stage III melanoma who were treated by the University of Pittsburgh Medical Center. All patients were given standard-of-care surgery, which included complete surgical removal of an advanced tumor. Tumor specimens were obtained at baseline and at the time of definitive surgery. Patients with tumors that had higher levels of expression of a group of immune-related genes, either before or soon after treatment with ipilimumab, had 63% lower risk of cancer

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

Indication

Additional Important Safety Information

KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated Left Ventricular Dysfunction (LVD) for the treatment of patients with HER2-positive (HER2+), metastatic • Patients treated with KADCYLA are at increased risk of developing breast cancer (MBC) who previously received trastuzumab and a taxane, LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLAseparately or in combination. Patients should have either: received prior treated group and in 3.3% in the comparator group. Permanently therapy for metastatic disease, or developed disease recurrence during discontinue KADCYLA if LVEF has not improved or has declined further or within six months of completing adjuvant therapy. Pregnancy Registry • Advise patients to contact their healthcare provider immediately if Important Safety Information they suspect they may be pregnant. Encourage women who may Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, be exposed to KADCYLA during pregnancy to enroll in the MotHER EMBRYO-FETAL TOXICITY Pregnancy Registry by contacting 1-800-690-6720 • Do Not Substitute KADCYLA for or with Trastuzumab Pulmonary Toxicity • Hepatotoxicity: Serious hepatotoxicity has been reported, • Cases of interstitial lung disease (ILD), including pneumonitis, some including liver failure and death in patients treated with leading to acute respiratory distress syndrome or fatal outcome have KADCYLA. Monitor serum transaminases and bilirubin prior to been reported in clinical trials with KADCYLA. In EMILIA, the overall initiation of KADCYLA treatment and prior to each KADCYLA frequency of pneumonitis was 1.2% dose. Reduce dose or discontinue KADCYLA as appropriate in • Treatment with KADCYLA should be permanently discontinued in cases of increased serum transaminases or total bilirubin patients diagnosed with ILD or pneumonitis • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate Infusion-Related Reactions, Hypersensitivity Reactions left ventricular function in all patients prior to and during • Treatment with KADCYLA has not been studied in patients who treatment with KADCYLA. Withhold treatment for clinically had trastuzumab permanently discontinued due to infusion-related significant decrease in left ventricular function reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in overall frequency of IRRs in patients treated with KADCYLA was 1.4% embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRR reactions, especially during the first infusion © 2013 Genentech USA, Inc. All rights reserved. TDM0001672501 Printed in USA. (07/13)

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Announcements

CancerCare Names Patricia J. Goldsmith Chief Executive Officer

ancerCare recently announced Patricia J. Goldsmith has been named the organization’s Chief Executive Officer. CancerCare is a national nonprofit organization providing free, professional support services to anyone affected by cancer. The announce-

ment comes as the group celebrates 70 years of service to the oncology community. “As CancerCare marks seven decades of helping the cancer community, S:6.875” we are thrilled to have found an exceptional leader in Patricia Goldsmith,” said

Superior efficacy with a single agent

CancerCare National Board of Trustees President Susan Smirnoff. “Patricia is a dynamic oncology visionary with an outstanding record of achievement, and we look forward to expanding CancerCare’s service offerings under her leadership.” Patricia J. Goldsmith

100

30.9 months

90 80

continued on page 140

NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS)

Proportion surviving (%)

7.5”

5.5”

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HR=0.682 95% CI: 0.548, 0.849 P=0.0006

70 60 50

KADCYLA (n=495) No. of events: 149

25.1 months

40 30 20

lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months 485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,2

Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS. For more information on KADCYLA, visit KADCYLA.com.

References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791.

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Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively) • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2 HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

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• The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

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• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1

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Announcements Patricia J. Goldsmith continued from page 139

Ms. Goldsmith brings more than 20 years of nonprofit management and strategic planning experience to her new role. She previously served as Executive Vice President and Chief Operating Officer at the National Comprehensive Cancer Network (NCCN), where she

was responsible for overall operations and provided oversight for a multitude of programs and national initiatives.

Well Positioned for Pending Changes in Health Care “CancerCare is a remarkable organization that does so much good for so many,” said incoming CEO Patricia

Goldsmith. “As the leading social service organization in cancer, CancerCare is well-positioned to support the coming changes in our health-care system directly relating to the psychosocial and financial effectsS:6.875” of diagnosis, treatment and survivorship. I have admired the organization for many years and am honored to have been chosen to

KADCYLA® (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. 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 KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, 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)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA®, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

become the next [Chief Executive Officer]. I look forward to working with the talented staff and Board of Trustees to achieve even greater success in the coming decade.” Watch future issues of The ASCO Post for an in-depth discussion with Ms. Goldsmith regarding CancerCare’s future initiatives. n and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as 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 and 0 or 1+ 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. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

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Announcements

American Association for Cancer Research Inaugurates New Leadership at 2014 Annual Meeting

he American Association for Cancer Research welcomed Carlos L. Arteaga, MD, as President of the Organization for 2014–2015. Dr. Arteaga was inaugurated during the

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

2.0

9.0

4.3

Blood and Lymphatic System Disorders

AACR’s Annual Meeting. Dr. ArteagaS:6.875” is Professor of Medicine and Cancer Biology at Vanderbilt University School of Medicine, where he holds the Donna S. Hall Chair in

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Increased bilirubin

Increased AST

Grade 4 %

Grade 3 %

Grade 4 %

Neutropenia

6.7

Anemia

14.3

4.1

10.5

2.5

Increased ALT

Thrombocytopenia

31.2

14.5

3.3

0.4

Decreased platelet count

1.8

0.2

3.3

0.4

3.3

2.5

Cardiac Disorders Left ventricular dysfunction Eye Disorders Lacrimation increased Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

0 0.4

Gastrointestinal Disorders Dyspepsia

9.2

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5 20.7

Diarrhea

24.1

1.6

79.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration 8.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

Decreased potassium

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)]. 8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.

8.5 Geriatric Use Of 495 patients who were randomized to KADCYLA in the randomized 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients response to KADCYLA. ≥ 65 years old (n=138 across both treatment arms) the hazard ratios A total of 836 patients from six clinical studies were tested at for progression-free survival (PFS) and Overall Survival (OS) were multiple time points for anti-therapeutic antibody (ATA) responses 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post- Population pharmacokinetic analysis indicates that age does not dose time points. The presence of KADCYLA in patient serum at have a clinically meaningful effect on the pharmacokinetics of the time of ATA sampling may interfere with the ability of this assay ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. 8.6 Females of Reproductive Potential KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective Immunogenicity data are highly dependent on the sensitivity and contraception while receiving KADCYLA and for 6 months following specificity of the test methods used. Additionally, the observed the last dose of KADCYLA. incidence of a positive result in a test method may be influenced If KADCYLA is administered during pregnancy or if the patient by several factors, including sample handling, timing of sample becomes pregnant while receiving KADCYLA, immediately report collection, drug interference, concomitant medication and the exposure to the Genentech Adverse Event Line at 1-888-835-2555. underlying disease. Therefore, comparison of the incidence of Encourage women who may be exposed during pregnancy to enroll antibodies to KADCYLA with the incidence of antibodies to other in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see products may be misleading. Clinical significance of anti-KADCYLA Patient Counseling Information (17)]. antibodies is not yet known. 8.7 Renal Impairment No dedicated renal impairment trial for KADCYLA has been 7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have conducted. Based on the population pharmacokinetics, as well been conducted. In vitro studies indicate that DM1, the cytotoxic as analysis of Grade 3 or greater adverse drug reactions and dose component of KADCYLA, is metabolized mainly by CYP3A4 and modifications, dose adjustments of KADCYLA are not needed in to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, adjustment can be recommended for patients with severe renal telithromycin, and voriconazole) with KADCYLA should be avoided impairment (CLcr less than 30 mL/min) because of the limited data due to the potential for an increase in DM1 exposure and toxicity. available [see Clinical Pharmacology (12.3)]. Consider an alternate medication with no or minimal potential to 8.8 Hepatic Impairment inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is In vitro studies in human liver microsomes indicates that DM1 is unavoidable, consider delaying KADCYLA treatment until the strong metabolized by CYP3A4/5. The influence of hepatic impairment on CYP3A4 inhibitors have cleared from the circulation (approximately the pharmacokinetics of ado-trastuzumab emtansine conjugate has 3 elimination half-lives of the inhibitors) when possible. If a strong not been determined. CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical reactions. trials, overdose of KADCYLA has been reported at approximately 8 USE IN SPECIFIC POPULATIONS two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal 8.1 Pregnancy case, the patient incorrectly received KADCYLA at 6 mg/kg and died Pregnancy Category D [see Warnings and Precautions (5.3)] approximately 3 weeks following the overdose; a cause of death and Risk Summary a causal relationship to KADCYLA were not established. KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of 17 PATIENT COUNSELING INFORMATION KADCYLA in pregnant women. No reproductive and developmental • Inform patients of the possibility of severe liver injury and advise toxicology studies have been conducted with ado-trastuzumab patients to immediately seek medical attention if they experience emtansine. Nevertheless, two components of KADCYLA symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (trastuzumab and DM1) are known or suspected to cause fetal harm (especially RUQ abdominal pain), jaundice, dark urine, generalized or death when administered to a pregnant woman. If KADCYLA is pruritus, anorexia, etc. [see Warnings and Precautions (5.1)]. to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

administered during pregnancy, or if a patient becomes pregnant • Advise patients to contact a health care professional immediately while receiving KADCYLA, apprise the patient of the potential for any of the following: new onset or worsening shortness of breath, hazard to the fetus. Patients should be advised to use effective cough, swelling of the ankles/legs, palpitations, weight gain of contraception during treatment with KADCYLA and for 6 months more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)]. following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient • Advise pregnant women and females of reproductive potential that becomes pregnant while receiving KADCYLA, immediately report KADCYLA exposure can result in fetal harm, including embryo-fetal exposure to the Genentech Adverse Event Line at 1-888-835-2555. death or birth defects [see Warnings and Precautions (5.3), Use in Encourage women who may be exposed during pregnancy to enroll Specific Populations (8.1, 8.6)]. in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see • Advise females of reproductive potential to use effective Patient Counseling Information (17)]. contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA [See Warnings and Precautions (5.3) and Human Data Use in Specific Populations (8.1, 8.6)]. In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some • Advise nursing mothers treated with KADCYLA to discontinue associated with fatal pulmonary hypoplasia, skeletal abnormalities nursing or discontinue KADCYLA, taking into account the importance and neonatal death. These case reports described oligohydramnios of the drug to the mother [see Use in Specific Populations (8.3)]. in pregnant women who received trastuzumab either alone or in • Encourage women who are exposed to KADCYLA during pregnancy combination with chemotherapy. In some case reports, amniotic to enroll in the MotHER Pregnancy Registry by contacting fluid index increased after trastuzumab was stopped. In one 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in case, trastuzumab therapy resumed after the amniotic fluid index Specific Populations (8.1, 8.6)]. improved, and oligohydramnios recurred. KADCYLA® (ado-trastuzumab emtansine) Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed

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Carlos L. Arteaga, MD

Dr. Arteaga said. “This is a time when the pace of discovery and progress in cancer research has never been better. Thus, I commit to work tirelessly with the AACR so the organization continues to be a main force and custodian of progress and discovery for the benefit of many patients afflicted with cancer.” Dr. Arteaga’s involvement in the AACR spans more than a decade.

Research Interests Dr. Arteaga’s research interests include oncogene signaling and molecular therapeutics in breast cancer with an emphasis on targeted therapies, mechanisms of drug resistance, translational research, and investigator-initiated clinical trials. Early in his career, he was the first to report the roles of IGF-I receptors and TGF beta in breast cancer progression and their use as therapeutic targets. More recent work has focused on the role of presurgical and neoadjuvant trials to discover molecular biomarkers that inform patient selection in clinical trials and/or for the discovery of mechanisms of drug resistance in breast cancer. Since 2001, he has led the NCI-funded Vanderbilt Specialized Program of Research Excellence (SPORE) in breast cancer. His work has significant implications for novel clinical trials in patients with breast cancer. Additionally, José Baselga, MD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center, was inducted as President-Elect. Charles L. Sawyers, MD, Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, now serves as Past-President. n B:11.5”

7.6

the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

T:10.5”

7.1

Chills

ter Research Network (VICCRN), and Director of Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center in Nashville, Tennesse. “I am extremely honored to be able to serve as President of the AACR,”

S:9.875”

Peripheral edema

Decreased hemoglobin Decreased neutrophils

Breast Cancer Research. Dr. Arteaga serves as Associate Director for Translational/Clinical Research, Director of the Breast Cancer Program, Director of the Vanderbilt-Ingram Cancer Cen-

The ASCO Post | MAY 15, 2014

PAGE 142

Expert’s Corner

Thirty Years of Effort Has Led to the Mainstreaming of Integrative Medicine in Oncology Care A Conversation With Barrie R. Cassileth, MS, PhD By Jo Cavallo interventions to control cancer patients’ physical and emotional symptoms when under treatment and beyond.

Early Research

Barrie R. Cassileth, MS, PhD

hen Barrie R. Cassileth, MS, PhD, began researching complementary medicine and its potential for use in oncology care over 30 years ago, not much was known about the importance of complementary therapies for the well-being of patients with cancer. She chose to conduct her doctoral dissertation research at the University of Pennsylvania Cancer Center’s inpatient leukemia unit. It was there that Dr. Cassileth realized patients with cancer needed more than just access to firstrate medical treatment. They needed relief from the physical and emotional toll of cancer and its treatment. “That put me on this path of researching the effectiveness of complementary therapies and the importance of integrating them into oncology care,” said Dr. Cassileth. Her thesis later became the basis for her first book, The Cancer Patient: Social and Medical Aspects of Care (Williams & Wilkins, 1979), among the earliest to stress the importance of adding rational, helpful

With equal levels of concern about cancer quackery and the prevalent promotion of nonviable “alternatives” to mainstream cancer care, Dr. Cassileth conducted the first national survey of cancer patients’ use of unconventional methods in the 1980s. She continued to study the clinical effects of complementary and alternative medicine on patients. Her research showed that patients were using an array of therapies— some ineffective and potentially harmful, and others that were helpful—but that there was no mechanism in place to alert patients (and clinicians) to the risks involved in using untested therapies along with conventional cancer treatment. Worse still, some patients were forgoing proven cancer therapies altogether for unproven alternative remedies touted as “cancer cures.” In 1999, Dr. Cassileth created the Integrative Medicine Service at Memorial Sloan Kettering Cancer Center, New York, which includes inpatient services at the hospital as well as outpatient services, principally at the Bendheim Integrative Medicine Center. The goal of the department is to provide inpatient and outpatient care, study the ability of specific complementary therapies, such as mind/ body, acupuncture, music, and herbal

therapies, to reduce specific symptoms associated with cancer and cancer treatments, and provide professional education and training. She holds the Laurance S. Rockefeller Chair in Integrative Medicine and is Chief of the Integrative Medicine Service. A prolific writer, Dr. Cassileth has published a dozen books on complementary, alternative, and integrative medicine in oncology care. Her latest book is Survivorship: Living Well During and After Cancer (Spry Publishing, April 2014; see sidebar below). Dr. Cassileth is also a sought-after lecturer on integrative medicine and com-

oncologists can help their patients steer clear of worthless remedies and benefit from integrative therapies that control symptoms associated with mainstream oncology care.

Spread of Integrative Oncology Please talk about the progress you have seen in the integration of complementary practices in conventional oncology care. I think the pivotal change that has occurred over the past 30 years is in the understanding of how important it is to take care of the emotional and physical aspects of having cancer, in addition to

I hope oncologists warn patients to be wary of statements online or in publications that tout “alternatives” to mainstream cancer care. I hope oncologists emphasize the importance of initiating conventional care as soon as possible. —Barrie R. Cassileth, MS, PhD

plementary therapies and will lead an educational session at the 2014 ASCO Annual Meeting on Integrative Oncology: The Evidence Base. The ASCO Post talked with Dr. Cassileth about the progress that has been made over the past 3 decades in the understanding and integration of complementary or integrative therapies in cancer care, the misconceptions about complementary therapies that still exist, the big business of so-called “alternative medicine” scams, and how

treating the disease itself. Cancer is such a difficult problem for patients and their family members to face, as it is for members of the medical community. Today, there is wide recognition and acceptance of the benefits of adjunctive complementary therapies. Virtually all of the comprehensive cancer centers in the United States have an integrative medicine programs, as do many major hospitals. And the good news is that the practice of integrative medicine is spreading also to many countries around the world.

Bookmark Title: Survivorship: Living Well During and After Cancer Author: Barrie Cassileth, MS, PhD Publication Information: Spry Publishing, April 2014, 216 pages, $16.95 This slender-volume survivorship guidebook provides the latest evidencebased information on complementary therapies and is a must-read for both newly diagnosed patients with cancer and survivors living with the short- and long-term side effects of their treatments. Written in easy-to-understand language, the book is organized into three parts. Part One, Information to Start, includes a roadmap for finding quality care, a listing of the 41 National Cancer Institute–designated comprehensive cancer centers in the United States, and a description of integrative medicine. Part Two, Complementary Therapies—The Basics, explains how nutri-

tion, physical activity, acupuncture, mind-body therapies, massage, and creative therapies, such as music, art, and multisensory “dance” therapy, can help restore patients’ sense of control and provide a way to maintain the best possible physical and emotional health throughout cancer treatment and survivorship. Part Three, Symptom Relief With Complementary Therapies, gives information on how such therapies can help patients manage pain, fatigue, anxiety, stress, depression, nausea and vomiting, sexual dysfunction, insomnia, lymphedema, neuropathy, and more. There is also a Scam Alert section, which includes a compilation of alternative approaches that should be avoided; a general resource guide for cancer supportive care services; and a glossary of terms. Helpful informational tips are interspersed throughout the chapters, as are quotes from actual patients on the benefits of integrative care in their personal experience.

ASCOPost.com | MAY 15, 2014

PAGE 143

Expert’s Corner Terminology Problem What are some of the lingering misconceptions about complementary medicine by both physicians and patients? I think the greatest hurdle still to be overcome is the “complementary and alternative medicine” terminology. Twenty years ago, the National Institutes of Health established the Office of Alternative Medicine, which later became the National Center for Complementary and Alternative Medicine. The problem is that the title conflates two very different practices and is especially dangerous in oncology because there are no viable alternatives to mainstream cancer care. So-called “alternative remedies” are bogus. That is one of the great problems we continue to face. Widely promoted unproved “alternative” cancer cures represent a $40 billion dollar a year business in the United States and are big business in other countries as well. The human toll from alternative remedy scams is devastating. Patients use their savings or sell their homes to pay for these bogus treatments because they are terrified of cancer or mainstream treatment. They don’t realize the danger they are putting themselves in. In the

end, these alternative “cures” shorten patients’ lives because they forgo or seriously delay seeking timely, appropriate care at a legitimate cancer center.

Alleviating Side Effects How do complementary therapies in conjunction with conventional cancer treatments help alleviate the physical and emotional effects from cancer and its treatment? That is the key point: Integrative medicine helps alleviate the physical and emotional symptoms associated with cancer and with cancer treatment. Integrative therapies do not treat cancer. They reduce the physical and emotional symptoms associated with cancer and its treatment. Cancer treatment is very difficult to get through and often presents a crisis well beyond the physical manifestations of the cancer itself. Complementary therapy takes advantage of such modalities as acupuncture, massage, meditation, guided imagery, and yoga together with good nutritional guidance and physical exercise to help manage both the short- and long-term effects of cancer therapy, including pain, anxiety, stress, and fatigue.

Latest Book What propelled you to write your new book on survivorship at this time? I kept coming across so many smart, educated patients who asked the most basic questions about cancer treatment and its side effects and what they could do to help themselves. I realized that my previous books were directed toward health professionals or knowledgeable patients. I wanted to provide basic information, readily understandable to all patients, about what complementary therapies can and cannot do and to provide information about scams to steer people away from unproven dangerous therapies. I have several hopes for this book. One is that the book is straightforward and simple enough that everyone will be able to understand the information and come away with a sense that they are not alone. I also hope the book gives readers a sense of empowerment over the devastating effects of cancer and the tools through complementary modalities to help themselves overcome treatment-related side effects. I also wanted to convey the importance of being diagnosed and treated

first at a National Cancer Institute (NCI)-designated comprehensive cancer center. I give a list of the 41 NCI-designated cancer centers nationwide to help patients find a center in or near their home state. And, of course, I wanted to warn people about cancer cure quackery and included a “Scam Alert” section in the book.

Important Messages What should oncologists tell newly diagnosed patients about the experience they may face ahead? First, I hope oncologists warn patients to be wary of statements online or in publications that tout “alternatives” to mainstream cancer care. I hope that oncologists emphasize the importance of initiating proper care as soon as p ossible. Another important message for patients is that while this is a frightening time and there may be unpleasant side effects from the recommended treatment, there are complementary modalities available to help reduce both the emotional effects of cancer such as anxiety, and the severity of physical side effects, such as pain, and keep them comfortable throughout their treatment. n

While botanicals are generally perceived as harmless, many reports in literature indicate that misuse of botanicals can be detrimental. Presented below are a few popular herbs in use today, along with their benefits and risks, especially when taken along with other medications.

To Take Herbs or Not to? —Haiku by Jyothirmai Gubili Soy isoflavones good for breast cancer patients but not in supplemental form

oldest living tree Ginkgo alas, may not help dementia

Turmeric relieves arthritic pain cannot take with blood thinners

Valerian benefits those with insomnia but makes the liver go awry

famed antidepressant St. John’s Wort -plethora of interactions with Rx meds

Russian herb Rhodiola popular adaptogen – keeps fit mind and body does not get along well with antidepressants

Red clover Dong quai Black cohosh help with menopausal symptoms but have side effects …

Berries Acai and Goji super antioxidants best to avoid during cancer treatment

Poems based on information in the “About Herbs” Web site http://www.mskcc.or/aboutherbs Integrative Medicine Service, Memorial Sloan Kettering, New York Illustrations by Angela Donato (Top to bottom, left to right: St. John’s Wort, Rhodiola, Ginkgo, Lycium)

The ASCO Post | MAY 15, 2014

PAGE 144

Clinical Trials Resource Guide Gynecologic Oncology

Ongoing Clinical Trials Actively Recruiting Patients With Ovarian or Cervical Cancers Compiled By Jo Cavallo

he information contained in this Clinical Trials Resource Guide includes details of actively recruiting clinical studies of patients with gynecologic and breast cancers. It also includes the Family Caregiver Palliative Care Intervention study, which is investigating interventions to support caregivers of patients with stage II/IV gastrointestinal, gynecologic, and urologic cancers. All of the studies are listed on the National Institutes of Health website at ClinicalTrials. gov. They include randomized and observational clinical trials.

Study Type: Observational Study Title: Northwestern Ovarian Cancer Early Detection and Prevention Program: A Specimen and Data Study Study Sponsor and Collaborators: Northwestern University, National Cancer Institute Purpose: To improve strategies for detection and prevention of early-stage disease. This study is collecting specimens and data to develop better methods for early detection and prevention of ovarian cancer among the high-risk population and those who have the d isease. Ages Eligible for Study: 18 to 80 years Genders Eligible for Study: Female Accepts Healthy Volunteers: No Primary Outcome Measures: The identification and development of highly sensitive and specific tumor markers for the detection and management of ovarian cancer and other gynecologic malignancies (time frame: outcomes will be assessed at the completion of the study). Principal Investigator: Lee P. Shulman, MD, Robert H. Lurie Comprehensive Cancer Center at Northwestern University; 312-695-1301; cancer@northwestern.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00005095 Study Type: Interventional/randomized/parallel assignment Study Title: Worry, Uncertainty, and Insomnia: A Cognitive-Behavioral Intervention for Cancer Survivors

Study Sponsor and Collaborators: Ohio State University Comprehensive Cancer Center, American Cancer Society, the Lance Armstrong Foundation Purpose: This clinical trial is investigating cognitive-behavioral intervention to treat worry, uncertainty, and insomnia in cancer survivors. Counseling may reduce anxiety and insomnia as well as improve the well-being and quality of life of cancer survivors. This study is also exploring the neuroimmunologic correlates of anxiety and insomnia. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Changes in worry on the Penn State Worry Questionnaire; changes in sleep efficiency on the Insomnia Severity Index; changes in intolerance of uncertainty on the Intolerance of Uncertainty Scale (time frame: from baseline to 6 weeks). Principal Investigator: Sharla WellsDi Gregorio, PhD, Ohio State University Comprehensive Cancer Center; 866-627-7616; sharla.wells@osumc. edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01929720 Study Type: Phase I/interventional/single-group assignment Study Title: A Phase I Study of Carboplatin and Gemcitabine and Stereotactic Body Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer Study Sponsor and Collaborators: Case Comprehensive Cancer Center, National Cancer Institute Purpose: To determine the highest dose of carboplatin and gemcitabine (gemcitabine hydrochloride) that can be given safely to subjects with gynecologic cancer, in combination with stereotactic body radiation therapy. To determine this maximum tolerated dose, patients will receive different amounts of carboplatin and gemcitabine. Ages Eligible for Study: 19 years and older Genders Eligible for Study: Female Accepts Healthy Volunteers: No Primary Outcome Measures: Rate of acute grade 3–5 toxicities following carboplatin/gemcitabine hydrochloride and stereotactic body radiation

therapy graded based on Common Terminology Criteria for Adverse Events, version 4.0 (time frame: within 30 days of completing treatment). Principal Investigator: Steven Waggoner, MD, Case Comprehensive Cancer Center; 216-844-5011; steven. waggoner@uhhospitals.org. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01652794 Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase I Study of Vorinostat in Combination With Paclitaxel and Carboplatin in Solid Tumors (With Focus on Upper Aerodigestive Cancers) in Persons With HIV Infection Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and the best dose of vorinostat when given together with paclitaxel and carboplatin in treating patients with metastatic or recurrent solid tumors, including recurrent ovarian epithelial cancer, and HIV infection. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with paclitaxel and carboplatin may kill more tumor cells. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Incidence of adverse events during paclitaxel and carboplatin treatment according to dose-limiting toxicities, graded using Common Terminology Criteria for Adverse Events, version 4.0 (time frame: 21 days). Principal Investigator: Missak Haigentz, MD, AIDS Associated Malignancies Clinical Trials Consortium; 718-920-4826; mhaigent@montefiore. org. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01249443 Study Type: Interventional/single-

group assignment Study Title: A Biobehavioral Intervention for Patients With Gynecologic or Breast Cancer Recurrence Study Sponsor and Collaborators: Ohio State University Comprehensive Cancer Center, National Cancer Institute Purpose: To study stress reduction in improving quality of life in patients with recurrent gynecologic or breast cancer. Participating in a stress reduction program may help improve quality of life in patients with gynecologic or breast cancer. Ages Eligible for Study: 21 to 85 years Genders Eligible for Study: Female Accepts Healthy Volunteers: No Primary Outcome Measures: Quality of life as assessed by Short Form-36 (time frame: up to 28 weeks). Principal Investigator: Barbara Anderson, PhD, Ohio State University Comprehensive Center; 614-2924236; Andersen.1@osu.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01764789 Study Type: Randomized/interventional/parallel assignment Study Title: A Randomized Trial of a Family Caregiver Palliative Care Intervention Study Sponsor and Collaborators: City of Hope Medical Center, National Cancer Institute Purpose: To study the Family Caregiver Palliative Care Intervention in supporting caregivers of patients with stage II/IV gastrointestinal, gynecologic, and urologic cancers. Education and telephone counseling may reduce stress and improve the well-being and quality of life of caregivers of patients with cancer. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: Yes Primary Outcome Measures: The effects of Family Caregiver Palliative Care Intervention on caregiver burden (time frame: up to 6 months). Principal Investigator: Betty Ferrell, PhD, City of Hope Medical Center; 800-826-4673; bferrell@coh.org. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01846520 n

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Significant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, 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. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis. Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions 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 required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (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 August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | MAY 15, 2014

PAGE 148

Survivorship

Elevated Morbidity/Mortality Risks for Childhood Cancer Survivors Further Increase After Fourth Decade By Charlotte Bath

n analysis of the first generation of childhood cancer survivors, who are now aging into their fourth and fifth decades, shows further increases in the sur-

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. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

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

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

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 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 2 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

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Gregory T. Armstrong, MD, of St. Jude Children’s Research Hospital, Memphis, and colleagues wrote in the Journal of Clinical Oncology.1

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. 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. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

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

The analyses compared the cumulative incidence of a severe, disabling, life-threatening, or fatal health condition among 14,359 patients from the Childhood Cancer Survivor Study and 4,301 of their siblings. The survivors had first been diagnosed when they were younger than 21 years old and received follow-up for a median of 24.5 years after diagnosis. Among the survivors, 5,604 were 35 years old or older, with a range up to 62 years. “Compared with siblings, survivors had an increased cumulative incidence of severe, disabling, life-threatening, or fatal health conditions,” the investigators found. The increase in cumulative incidence at 20 years, which was 16% for cancer survivors vs 3.3% for siblings, increased with age and at 50 years was 53.6% for survivors vs 19.8% for siblings. “Notably, 24-year-old survivors of childhood cancer had the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings,” the investigators stated. Multivariable analysis confirmed that the hazard ratio (HR) for a severe, disabling, life-threatening, or fatal health condition “increased for survivors 35 years old and older compared with survivors 20 to 34 years old [HR = 5.0 vs 3.8; P = .03],” the researchers stated. They concluded: These findings have important implications for cancer screening and prevention. Though the cumulative incidence of events increased across all organ systems, after age 35 years survivors had a disproportionate increase in the incidence of subsequent malignant neoplasms and cardiac events. Although the occurrence of new malignancies has been well documented, we now demonstrate that this profound rise in incidence occurs during an important window of vulnerability, before the age-threshold when general population screening guidelines recommend screenings to start…. Similarly, early detection of cardiomyopathy and medical intervention may mitigate progression to heart failure in survivors exposed to anthracycline chemotherapy or chest directed radiotherapy. Finally, the risk for stroke and myocardial infarction, identified in this study to have increased more than fivefold in survivors older than 35 years, may be modified by promoting a healthy lifestyle that can reduce rates of certain … risk factors. n

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use 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 indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF 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. 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)]. 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. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) 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.

vivors’ morbidity and mortality risks. “By age 50 years, more than half of survivors have experienced a severe, disabling, or Safety:7" life-threatening event, including death,”

Reference 1. Armstrong GT, et al: J Clin Oncol 32:1218-1277, 2014.

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Oncology Worldwide Survivorship

Improving Quality of Life in Cancer Survivors By Eliezer Robinson, MD, Sara Gafni, MA, RN, Ella Muller, MA, RN, and Ronit Leiba, MA On an international scale, according to the International Agency for Research on Cancer (IARC),3 there are over 30 million cancer survivors worldwide, and that number is expected to reach 70 million by 2050.4

Objectives Eliezer Robinson, MD

he number of cancer survivors has been steadily increasing in recent years. According to the Ministry of Health National Cancer Registry, in 2010 there were 254,000 cancer survivors in Israel (3.3% of the population) compared with 15,700 (0.4% of the population, P < .005) in 1975.1 Forty years ago in the United States, cancer survivors made up about 1.5% of the general population (~3 million), whereas currently, about 4% of the U.S. population consists of cancer survivors (~14 million).2

In 2009–2010, we conducted a study at Rambam Medical Center in Haifa, Israel, in which patients with breast and colorectal cancer were asked about needs that emerged during treatment and to what degree they were met. The patients had received adjuvant treatment with radiotherapy or chemotherapy and/or hormonal therapy, and at the time of the study, showed no signs of disease. The patients were interviewed by a nurse, and upon completion of treatment, about 80% reported that most of their medical needs (ie, directly related to medical treatment for cancer) were

Table 1: Frequency Data for Nine Symptoms in Cancer Survivors (N = 198) Frequency Ranking of Symptomsa Symptoms

Upon completion of treatment

After 6 mo

P value

Fatigue

3.30 ± 1.15 (3.7)

2.03 ± 0.83 (2.0)

< .001

Pain

2.30 ± 1.16 (2.3)

1.63 ± 0.69 (1.33)

< .001

Sleep disorders

3.00 ± 1.21 (3.0)

1.84 ± 0.83 (1.67)

< .001

Cognitive functioning

3.38 ± 0.93 (3.7)

2.15 ± 0.71 (2.0)

< .001

Emotional distress/depression

2.08 ± 1.02 (2.0)

1.57 ± 0.55 (1.33)

< .001

Future anxiety

2.19 ± 0.89 (2.0)

1.57 ± 0.40 (1.33)

< .001

Familial changes

2.78 ± 0.96 (2.67)

2.17 ± 0.66 (2.0)

< .001

Financial d ifficulties

1.91 ± 1.15 (1.0)

1.44 ± 0.73 (1.0)

< .001

Weight changes

2.19 ± 1.36 (1.33)

1.63 ± 1.06 (1.33)

< .001

Number of Statements per Patient Indicating Disruptive Symptomsb Upon completion of treatment

After 6 mo

Mean

12.8

5.2

Median

13.0

3.0

Standard deviation

±6.11

±5.61

Minimum

Maximum

27.0

23.0

Mean ± standard deviation (median).

Ranked 3 or higher.

P value

< .0001

Recommendations for Improving Quality of Life in Cancer Survivors ■■ Clinicians should increase their awareness about the difficulties experienced by cancer survivors related to medical disorders, functioning problems, and psychosocial challenges caused by the disease and its treatment. ■■ Survivors’ quality of life can be enhanced by teaching them about nutrition, physical activity, and emotional support, as well as developing psychosocial services for them, while lending assistance with occupational difficulties and making appropriate health insurance coverage available. ■■ Coordinating clinicians need to determine which monitoring checkups to perform and to establish who will oversee and provide instructions for the implementation of these examinations.

met. In contrast, 67% of their needs related to physical functioning (as affected by the disease), 54% of their emotional needs, and only 44% of their practical needs (eg, related to work or financial situation) were met.5

Research Methods In 2012, we resolved to conduct an additional similar survey, to refer survivors to entities that could help them with the needs they revealed, and to redo the survey 6 months after the referral. Thus, upon the completion of treatment, patients were interviewed by an oncology nurse regarding the frequency of their symptoms, and the nurse referred them to an attending entity accordingly. Overall, 198 survivors diagnosed with breast and colorectal cancer participated in the new survey, upon the completion of radiotherapy, radiotherapy combined with chemotherapy, and radiotherapy combined with hormone therapy. All participants showed no signs of the disease. An authorization of the Helsinki Committee of the Rambam Medical Center was completed and obtained as required. Among the 198 patients, 188 were females and 10 were males. The age range was 28.8 to 85.77 (mean, 58.2 ± 12.673). Of the women, 178 were diagnosed with breast cancer, and 10 with colorectal cancer. Almost all (99%) of the patients had undergone radiotherapy, 54% had received chemotherapy, and 64% had been given hormone therapy.

Questionnaire and Variables The questionnaire encompassed nine symptoms that are frequently seen among survivors,6-9 according to our survey of the scientific literature (fatigue, pain, sleep disorders, cognitive

dysfunction, emotional distress/depression, future anxiety, familial changes, financial distress/difficulties, weight changes). Patients were asked three questions about each symptom by the interviewing nurse, totaling 27 questions per each survivor. The answers were ranked from 1 to 5 according to the Likert scale (1 = never, 2 = rarely, 3 = sometimes, 4 = frequently, and 5 = always). Reverse questions were arranged and scored accordingly (for example, to address familial changes, patients were asked to express their level of agreement with the statement, “I feel comfortable among household members”; to assess weight changes, they were asked to rank the statement, “I am at peace with my current look”). Symptoms for which the resulting frequency ranking exceeded 2—occurring sometimes, frequently, or always— were considered disruptive.

Results Table 1 shows the frequency ranking of the nine symptoms upon completion of treatment and after 6 months, and the statistical differences for each one of the symptoms. With the exception of financial distress, all the remaining symptoms were ranked higher than 2, indicating symptoms that are sometimes or frequently disruptive. No symptom was reported as being disruptive all the time. The average number of statements indicating disruptive symptoms for patients upon completion of treatment was 12.8 ± 6.11 (median, 13). After 6 months, there was a significant drop in the number of responses suggesting disruptive symptoms (mean, 5.2 ± 5.6; median, 3; P < .001). continued on page 150

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Oncology Worldwide Improving Quality of Life in Cancer Survivors continued from page 149

Education and Referrals Training on nutrition, physical activity, and emotional support were delivered to between 73% and 80% of the survivors (Table 2). About half the survivors were referred to a family practitioner, a dietitian, and support activity provided by the Israel Cancer Association. We see that most of the patients contacted a consultant who gave them advice upon completion of treatment: 96% contacted a family practitioner after having been referred, 94% contacted the Israel Cancer Association after having been referred to the organization upon completion of treatment, 93% contacted a dietitian after being referred upon completion of treatment (Table 3).

Discussion In 1985, Fitzhugh Mullan, MD, a U.S. physician who had recovered from cancer, described the way he felt, in The New England Journal of Medicine, with these words: “It is as if we have invented sophisticated techniques to save people from drowning, but once they have been pulled from the water, we leave them on the dock to cough and splutter on their own in the belief that we have done all that we can.”10 As a result of this experience, Dr. Mullan became the founding President of the National Coalition for Cancer Survivorship in the United States, aimed at supporting cancer survivors. The Coalition acts on behalf of cancer survivors and endeavors to promote their well-being. The percentage of patients with a 5-year survival during the early years of the Coalition was around

Table 2: Training Sessions and Referrals to Address Symptoms/Problems Upon Completion of Cancer Treatment Symptoms/ Problems

Training

Referral

Professional/Organization to Which the Patient Is Referred

Physical a ctivity

158 (80%)

40 (25%)

Physiotherapist

Psychomedical issues

155 (78%)

25 (16%)

Oncologist

74 (48%)

Family practitioner

20 (13%)

Social worker

73 (47%)

Israel Cancer Association

41 (26%)

Rehabilitation consultant in oncology

Nutrition

145 (73%)

86 (59%)

Dietitian

Sun exposure

111 (56%)

10 (9%)

Dermatologist/ Israel Cancer Association

Smoking (10% of all patients)

48 (24%)

20 (41%)

Family practitioner/ Israel Cancer Association

Table 3: Implementation of Referrals After 6 Months Referral Upon Specialist to Symptoms/ Completion Whom Patient Problems of Treatment Was Referred Nutrition 86 (59%) Dietitian 40 (25%) Physiotherapist Physical a ctivity Smoking (10% 20 (41%) Family practitioner/ of all patients) Israel Cancer A ssociation Dermatologist/Israel Sun exposure 10 (9%) Cancer Association Psychosocial 25 (16%) Oncologist issues 74 (48%) Family practitioner 20 (13%) Social worker 73 (47%) Israel Cancer A ssociation 41 (26%) Rehabilitation consultant in oncology

Patients Who Contacted Specialist After 6 mo 80/86 (93%) 34/40 (85%) 12/20 (60%)

4/10 (40%) 19/25 (76%) 71/74 (96%) 15/20 (75%) 69/73 (94%) 30/41 (73%)

55%, and today it has reached 69%.11,12 Dr. Mullan’s article apparently did not make great waves. But about 20 years later, in 2005, the U.S. Institute of Medicine—which, albeit an independent research institute, is counted among the health policymakers in the United States—published a paper entitled From Cancer Patient to Cancer Survivor: Lost in Transition. The authors recommended efforts to increase awareness of the difficulties experienced by survivors, in terms of medical, functioning, and psychosocial problems derived from cancer and its treatment. They further recommended enhancing survivors’ quality of life by developing psychosocial support services.13,14 Within the context of the current study, we observed that patients with breast and colorectal cancer who showed no signs of these diseases upon completion of treatment suffered from other disorders. In most cases, the patient does not tell the physician about these symptoms and problems because, the way the patient sees it, the physician is busy with the medical problem and shouldn’t be bothered; this finding was also validated by research conducted in the United States. For this reason, we asked the nurse to interview the patients and refer to the 27 statements pertaining to quality of life. Responses suggesting a disorder were reported for 12 of those statements. Following the initial survey, the nurse provided the survivors with support and/or referred them to entities that could provide them with assistance. This same nurse interviewed the patients 6 months later. After 6 months, it emerged that the mean number of problematic statements dropped to 5. This is not a controlled study, and it is possible that some of the disorders would have resolved without any assistance. In our opinion, however, there is no doubt that patients have problems that should be clarified, and they should be provided with assistance, as required, while they are on the road to recovery.

Conclusions It is important to monitor survivors,14-16 and there are numerous objectives to keep in mind: (1) detection of disease recurrence at an early stage, (2) treatment of side effects that can appear early or later as a result of treatment and/or the disease per se, (3) early detection of a secondary tumor that may emerge, and (4) assisting patients in coping with psychosocial challenges. There are many ways to monitor sur-

vivors—by the oncologist in the oncology ward or by the family practitioner, in survivorship clinics or in clinics by disease type and location (eg, in breast or hematologic diseases). No prospective research has established which method is most effective, and there is always the need to review patients’ and caregivers’ wishes, as well as costs of each and every method. However, some studies have shown that survivors prefer to continue receiving support at the oncology support center where they were treated, while updating their family practitioner.17,20 Collaborative monitoring by the family practitioner and the attending oncologist, with the oncology nurse intermediating, appears to be the most cost-effective and efficient method. Therefore, it is essential that the family physician receive a detailed summary from the attending oncologist, describing the treatment summary of the survivor, including, inter alia, indication of late side effects that may derive from treatment. Forms for conveying this type of information were prepared by Ido Wolf, MD, with assistance from the Israel Cancer Association, and were coordinated with representatives of the Israeli Society for Clinical Oncology. n

Disclosure: This study was partially financed by the Israel Cancer Association. The authors reported no potential conflicts of interest.

References 1. Keinan-Boker L: Deputy Director of the National Center for Disease Control of the Israel Ministry of Health [personal communication]. October 6, 2013. 2. Howlader N, Noone AM, Krapcho M, et al: SEER Cancer Statistics Review, 1975-2009. Bethesda, Maryland, National Cancer Institute, 2012. 3. Ferlay J, Shin HR, Bray F, et al: GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. Lyon, France, International Agency for Research on Cancer, 2010. Available at http://globocan.iarc.fr. 4. World Cancer Research Fund/ American Institute for Cancer Research. Cancer survivors, in Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, pp 342347. Washington, DC, AICR, 2007. Available at http://www.dietandcancerreport. org/cancer_resource_center/downloads/Second_Expert_Report_full.pdf. 5. Robinson E: Cancer survivors: A challenge to healthcare systems worldwide. International symposium. Panel discussion presented at 46th ASCO Annual Meeting, June 4-8, 2010. 6. Hsu T, Ennis M, Hood N, et al: Quality of life in long term breast cancer survi-

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Oncology Worldwide vors. J Clin Oncol 31:3540-3548, 2013. 7. Helwick C: NCCN Clinical Practice Guidelines in Oncology: 2013 Updates. ASCO Post 4(8):3-10, 2013. 8. Mustian KM, Sprod LK, Janelsins M, et al: Multicenter randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol 31:3233-3241, 2013. 9. Hollingworth W, Metcalfe C, Mancero S, et al: Are needs assessments cost effective in reducing distress among patients with cancer? A randomized controlled trial using the distress thermometer and problem list. J Clin Oncol 31:3631-3638, 2013. 10. Mullan F: Seasons of survival: Reflections of a physician with cancer. N Engl J Med 313:270-273, 1985.

11. American Cancer Society: Cancer Facts & Figures, 2013. Atlanta, American Cancer Society, 2013. 12. Hausman JH, Ganz PA, Sellers TP, et al: Journey forward: The new face of cancer survivorship. J Oncol Pract 7(3 suppl):e50s-e56s, 2011. 13. Hewitt M, Greenfield S, Stoval E: From cancer patient to cancer survivor: Lost in transition. Washington, DC, National Academies Press, 2006. 14. Jean-Pierre P, Winters PC, Ahles TA, et al: Prevalence of self-reported memory problems in adult cancer survivors: A national cross-sectional study. J Oncol Pract 8:30-34, 2012. 15. Furman MJ, Lambert LA, Sullivan ME, et al: Rational follow-up after curative cancer resection. J Clin Oncol

31:1130-1133, 2013. 16. Rosales AR, Byrne D, Burnham C, et al: Comprehensive survivorship care with cost and revenue analysis. J Oncol Pract 7:945-949, 2013. 17. Rechis R, Beckjord EB, Nutt S: Potential benefits of treatment summaries for survivors’ health and information needs: Results from a LIVESTRONG survey. J Oncol Pract 7:973-976, 2013. 18. Shalom MM, Hahn EE, Cassillas J, et al: Do survivorship care plans make a difference? A primary care provider perspective. J Oncol Pract 7:314-318, 2011. 19. Virgo KS, Lerro CC, Klabande CN: Barriers to breast and colorectal cancer survivorship care: Perceptions of primary care physicians and medical oncologists in the United States. J Clin Oncol 31:2322-2366, 2013.

20. Roordo C, Berendsen JA, Howenkamp, et al: Discharge of breast cancer patient to primary care at the end of hospital follow-up: A cross-sectional survey. Eur J Cancer 49:1836-1844, 2013.

Dr. Robinson is Professor of Oncology at Rambam Medical Center, Haifa, Chairman of the National Council for Oncology, and Chairman of the Israel Cancer Association, Givatayim. Ms. Gafni is a nurse in the Radiation Oncology Department at Rambam Medical Center. Ms. Muller is Director of Nursing in the Oncology/Hematology Division and Specialist in Palliative Care at Rambam Medical Center. Ms. Leiba is a statistician in the Quality Improvement Unit at Rambam Medical Center.

MEDICAL DIRECTOR, QUALITY DEPARTMENT The American Society of Clinical Oncology (ASCO) is recruiting the Medical Director for its critically important and growing Quality Department. Headquartered in Alexandria, VA, the non-for-profit ASCO (www.asco.org) currently has more than 280 dedicated full-time staff to manage its growing number of programs, services, and interests in cancer public health issues. ASCO’s Quality Department was formed in 2011 and is one of 12 ASCO Departments. A total of 75 individuals are being assembled to staff the Quality Department under the leadership of Robert Hauser, PharmD, Ph.D. The Medical Director will lead a team of 35-40 individuals to advance the following programs: • The Quality Oncology Practice Initiative (QOPI) • QOPI Practice Certification (QCO) • Practice Guidelines • Performance Measures and Practice Improvements • CancerLinQ, ASCO’s learning healthcare system for oncology The ideal candidate will be a board-certified physician with a good working knowledge of electronic health records and knowledge of current trends in health IT, familiarity with data collection and analytics, and a solid background in performance measurement and practice improvement activities.

Spencer Stuart has been retained to assist with this important recruitment. Spencer Stuart and ASCO respect the importance of maintaining confidentiality. Letters of application, with resumes, and letters of nominations should be submitted by e-mail to: Lmedoff@spencerstuart.com

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Health Disparities

Personalizing Outreach to Address Asian Cancer Health Disparities

n an effort to reduce cancer health disparities among Asian Americans, UC Davis Comprehensive Cancer Center now offers individual, in-language education and culturally sensitive materials for every Asian American cancer patient. New brochures and 5-minute videos were debuted during the National Minority Cancer Awareness Week in April. These were designed to inform Asian Americans about the importance of engaging in cancer research. The educational efforts also are part of the Asian American Cancer Education Study (AACES), a UC Davis program aimed at increasing awareness of clinical trials and the importance of donation of biospecimens such as blood, saliva, or tissue.

“There are a lot of myths within Asian communities,” said Angela Sun, PhD, who oversees education outreach activities for AANCART and developed the clinical trials materials. “It’s critical that we educate our community on the importance of participating in cancer

research in a culturally appropriate way.” Research revealed many Asian American cancer patients hesitated to participate in clinical trials because they believed if they were placed into the control group, their regular treatment would end. To address this concern, AANCART tailored

the materials by explaining how trials are conducted to assure patients that proper cancer treatment would continue. Additionally, Asian American patients commonly opted out of participation because they believed they would be treated as mere test subjects. To counter this per-

Asian Americans Underrepresented in Research Asian Americans are consistently underrepresented in cancer research. Studies show that language barriers, mistrust of the medical system, and cultural differences often create misunderstandings about the nature and purpose of clinical trials and biospecimen donation, discouraging participation. “Asian-Americans are the only racial group for whom cancer is the leading cause of death, so we are highly motivated to increase their involvement,” said Professor Moon S. Chen, Jr, PhD, MPH, the cancer center’s Associate Director for Cancer Control. UC Davis researchers have found that less than 5% of all clinical trials participants in the United States include minorities, less than 2% of clinical cancer research studies focus on non-white ethnic or racial groups, and biospecimen collection among diverse populations lags far behind that of non-Hispanic whites.

Ethnically Specific Outreach The Asian American Network for Cancer Awareness and Training (AANCART), headquartered at the UC Davis Comprehensive Cancer Center, developed the brochures and DVDs based on extensive research using ethnically specific community outreach programs in Honolulu, Los Angeles, Sacramento, and San Francisco. Through community focus groups and surveys conducted in Vietnamese, Chinese, Korean, Tagalog, and Hmong, AANCART sought to understand existing cultural barriers and misconceptions about participation in cancer research. They found many causes of confusion, from pervasive cultural beliefs to language problems, such as inaccurate translation of certain terms and phrases.

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Health Disparities

ception, AANCART focused on the positive impact of participation, specifically highlighting participants’ key role in helping to advance discovery of effective cancer treatments for other Asian Americans. Changing the language of the brochures on clinical trials from the English version, “I can help find new treatments for cancer,” to “We can help find new treatments

for cancer” emphasizes the collectivistic view of Asian American cultures. To understand additional barriers, AANCART team members also interviewed physicians. “We learned that physicians want to approach patients, but language and culture barriers hindered effective patient/ provider communication,” said Julie

Dang, MPH, CHES, Administrative Core Director at AANCART. The oneon-one educational sessions with patients provide detailed information about research opportunities. Patients eligible to participate in a trial after discussing it with their doctor are then assigned a bilingual “patient navigator” who helps them through every step of the clinical trial.

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“Asian Americans’ participation in cancer research is important both for their benefit and to help scientists develop better cancer drugs and protocols for future generations,” said Dr. Chen. He added that biospecimen collection to obtain appropriate genetic material is critical. Additional information is available at www.aancart.org. n

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Announcements

Becky L. DeKay, MBA, Becomes President of ACCC

ecky L. DeKay, MBA, became President of the Association of Community Cancer Centers (ACCC) at its 40th Annual National Meeting in April. She is Director of Oncology Services at the Feist-Weiller Cancer Center at Louisiana State University (LSU)

Health Shreveport, in Louisiana. “I am honored to serve as President of the Association of Community Cancer Centers during this transformative time in health care,” said Ms. DeKay. “ACCC has long been an advocate for ensuring patient access to quality care.

We know that the continuous delivery of quality cancer care is a journey, not a destination. And I can think of no better partner for this journey than ACCC.” Ms. DeKay has been active in ACCC since joining the staff of LSU

Health Shreveport in 2003. She has served on the Governmental Affairs Committee, chaired both the Membership and the Strategic Planning Committees. More recently, she served as ACCC Treasurer for 2 years. n

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Announcements

Bert Howard O’Neil, MD, Joins Indiana University Simon Cancer Center

ert Howard O’Neil, MD, has been named the inaugural Joseph W. and Jackie J. Cusick Professor of Oncology and a Professor of Medicine at the Indiana University (IU) School of Medicine, in Indianapolis. He is also the Phase I Director and Director of the Gastro-

Bert Howard O’Neil, MD

intestinal Cancer Research Program at the IU Melvin and Bren Simon Cancer Center, and he will represent the cancer center on the Big Ten Cancer Research Consortium steering committee. As the Phase I Director, Dr. O’Neil will oversee phase I clinical trials for all

areas of cancer treatment. Dr. O’Neil’s primary area of expertise is in gastrointestinal cancers, with a particular concentration on pancreas, colorectal, and hepatocellular carcinomas. He also has considerable expertise in targeting new

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continued on page 156

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Announcements Bert Howard O’Neil, MD continued from page 155

drugs to specific molecular targets on tumors. “Finding new and better agents to treat cancer, particularly gastrointestinal cancers, is a major focus of the IU Simon Cancer Center,” said Patrick J. Loehrer, MD, Director of the IU Simon

Cancer Center. “There is no one that I know in the country who is better suited for this role than Dr. O’Neil.” Dr. O’Neil was most recently an Associate Professor of Medicine and Director of the Gastrointestinal Malignancies Research Program at the University of North Carolina at Chapel Hill. He also was the Medical Director of the UNC Lineberger

Comprehensive Cancer Center’s clinical protocol office where he designed and conducted clinical and translational studies. Dr. O’Neil earned his medical degree from the University of California, Los Angeles, and he completed his internal medicine residency and fellowship in hematology/oncology at the University of California, San Francisco. n

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ASCOPost.com | MAY 15, 2014

PAGE 157

In the Clinic

Ofatumumab Plus Chlorambucil for Previously Untreated CLL in Patients Not Treatable With Fludarabine-Based Regimens 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.

n April 17, 2014, ofatumumab (Arzerra) received regular approval for use in combination with chlorambucil (Leukeran) in previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate.1,2 Ofatumumab was granted accelerated approval for use in CLL refractory to fludarabine and alemtuzumab (Campath) in 2009.

Pivotal Study Approval was based on an open-label trial in which 447 patients for whom fludarabine-based therapy was considered inappropriate by investigators (eg, due to advanced age or comorbidities) were randomly assigned to receive ofatumumab/chlorambucil (n = 217) or chlorambucil alone (n = 227). Ofatumumab was given as an infusion at 300 mg on day 1 of cycle 1, 1,000 mg on day 8 of cycle 1, and 1,000 mg on day 1 of all subsequent 28-day cycles. Chlorambucil was given at 10 mg/ m2 orally on days 1 to 7 every 28 days. Prior to each infusion of ofatumumab, patients received premedication with acetaminophen, an antihistamine, and a glucocorticoid. Overall, patients had median age of 69 years, with 69% of patients in both

OF NOTE

fatumumab’s Fab domain binds to CD20, and its Fc domain mediates immune effector functions, resulting in B-cell lysis in vitro. Cell lysis mechanisms may include complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

groups aged ≥ 65 years, 63% were male, 89% were white, 72% had at least two comorbidities, 48% had creatinine clearance < 70 mL/min, and 72% had beta-2 microglobulin levels > 3,500 µg/L. Median progression-free survival, the primary endpoint, was 22.4 months in the ofatumumab/chlorambucil group vs 13.1 months in the chlorambucil group (hazard ratio [HR] = 0.57, P < .001). Objective response occurred in 82.4% (complete response in 12%) vs 68.6% (complete response in 1%) of patients (P = .001), and median duration of response was 22.1 vs 13.2 months.

How It Works Ofatumumab is a CD20-directed cytolytic monoclonal antibody that binds specifically to both the small and large extracellular loops of the CD20 402 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B lymphocytes) and on B-cell CLL and is neither shed from the cell surface nor internalized following antibody binding. The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions, resulting in B-cell lysis in vitro. The potential mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

How It Is Given The recommended dosage of ofatumumab in previously untreated CLL is 300 mg on day 1 (at an initial infusion rate of 12 mL/h) followed 1 week later by 1,000 mg (25 mL/h) on day 8 (cycle 1), followed by 1,000 mg (25 mL/h) on day 1 of subsequent 28-day cycles for a minimum of 3 cycles and until best response or a maximum of 12 cycles. Patients should receive premedication with oral acetaminophen at 1,000 mg (or equivalent), oral or intravenous antihistamine (diphenhydramine at 50 mg or cetirizine at 10 mg or equivalent), and intravenous corticosteroid (prednisolone at 50 mg or equivalent) 30 minutes to 2 hours prior to each infusion. In the absence of an infusion-related reaction, the rate of infusion can be in-

Ofatumumab/Chlorambucil for CLL ■■ Ofatumumab (Arzerra) has received regular approval for use in combination with chlorambucil (Leukeran) in previously untreated patients with chronic lymphocytic leukemia (CLL) who cannot be given fludarabine-based therapy. ■■ The recommended dosage of ofatumumab in previously untreated CLL is 300 mg on day 1, followed 1 week later by 1,000 mg on day 8 (cycle 1), followed by 1,000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles, until best response or a maximum of 12 cycles.

creased at 30-minute intervals to 25, 50, 100, 200, and 400 mL/h for the day 1, cycle 1 dose and to 50, 100, 200, and 400 mL/h for other doses. Infusion should be interrupted for reactions of any severity.

OF NOTE

fatumumab carries boxed warnings for hepatitis B virus reactivation, hepatic failure, progressive multifocal leukoencephalopathy, and death in some cases.

If the reaction resolves or remains no higher than grade 2, treatment can be resumed at half the previous infusion rate after grade 1 or 2 reactions and at 12 mL/h after grade 3 or 4 reactions. Permanent discontinuation should be considered if severity of the infusion reaction does not resolve to grade 2 or lower despite adequate clinical intervention.

Safety Profile In the randomized trial, the most common clinical adverse events of any grade in the ofatumumab/chlorambucil group were infusion reactions (67% vs 0% in chlorambucil group), neutropenia (27% vs 18%), asthenia (8% vs 5%), headache (7% vs 3%), leukopenia (6% vs 2%), and herpes simplex (6% vs 4%). The most common grade 3 or 4 adverse events were neutropenia (26% vs 14%), infusion reactions (10% vs 0%), and leukopenia (3% vs < 1%). Grade 3 or 4 hematologic abnormalities consisted of neutropenia in 29% vs 24%, lymphopenia in 29% vs 7%, and leukopenia in 23% vs 4%.

Ofatumumab carries boxed warnings for hepatitis B virus reactivation, which has resulted in fulminant hepatitis, hepatic failure, and death in some cases, and for progressive multifocal leukoencephalopathy resulting in death. Ofatumumab also has warnings/ precautions for infusion reactions, tumor lysis syndrome, and cytopenias. Tumor lysis syndrome should be anticipated in high-risk patients, and premedication with antihyperuricemic agents and hydration should be performed. Late-onset and prolonged neutropenia have been observed. Complete blood counts should be monitored at regular intervals. n References 1. U.S. Food and Drug Administration: Ofatumumab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm393823.htm. 2. ARZERRA® (ofatumumab) injection prescribing information. GlaxoSmithKline, April 2014. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2014/125326s060lbl.pdf.

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

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

The ASCO Post | MAY 15, 2014

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Announcements

Irving Bone Marrow Transplant Unit Opens at NewYork-Presbyterian/Columbia

ewYork-Presbyterian/Columbia University Medical Center has opened the Irving Bone Marrow Transplant Unit, a state-of-the-art facility for comprehensive bone marrow transplant (BMT) care. The new unit features 18 inpatient rooms, a

high-tech nurses station for individual patient monitoring, and a specialized airflow system to help protect patients with weakened immune systems. The unit is supported by a $20 million gift from Herbert and Florence Irving.

Combined Transplantation Procedures In addition to its use in blood cancer treatment, BMT and other forms of cellular therapies can be used to custom-tailor a patient’s immune system. The pioneering work of Megan

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2013 Incyte Corporation. All rights reserved. Issued: November 2013 RUX-1326 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Sykes, MD, Director of the Columbia Center for Translational Immunology, has demonstrated that combined bone marrow transplantation and organ transplantation can induce tolerance and allow acceptance of the donor organ without the use of longterm immunosuppressant therapy. The new BMT unit will be at the forefront of efforts to make these novel combined transplant procedures the clinical standard. The unit is being led by BMT clinician-scientist Markus Mapara, MD, Director of the Blood and Marrow Transplantation Program at NewYork-Presbyterian/Columbia University Medical Center, and Professor of Medicine at Columbia University Medical Center.

Improving Patient Outcomes In addition to his interest in combined bone marrow and solid organ transplantation, Dr. Mapara is aiming to develop new approaches to improve the outcomes of patients undergoing autologous and allogeneic hematopoietic stem cell transplantation by preventing and/or reducing the treatment-related complications such as graft-vs-host disease, as well as preventing recurrence of the underlying disease. A particular focus of his research is the ability to perform mismatched transplants in patients who do not have matched donors. “NewYork-Presbyterian/Columbia is in the midst of a revolution in cancer care,” said Gary Schwartz, MD, Chief of Hematology/Oncology at NewYork-Presbyterian/ Columbia. “This new state-of-the-art

Gary Schwartz, MD

bone marrow transplant facility offers our patients the latest advances in cancer care by providing new therapeutic approaches for the treatment and cure of cancer,” he added. n

ASCOPost.com | MAY 15, 2014

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Issues in Oncology Humanism

Schwartz Center Rounds® Programs Foster Clinical Teamwork and Enhance Patient Care By Jo Cavallo

n the fall of 1994, 40-year-old Kenneth B. Schwartz, a health-care lawyer, was diagnosed with lung cancer. Radiation and chemotherapy failed to stop progression of the disease, and 10 months later he died. During his treatment, Mr. Schwartz wrote about the ordeal of coming to grips with the inevitability of his fate in The Boston Globe Magazine.1 He also wrote about the gratitude he felt toward his oncologist, Thomas J. Lynch, Jr, MD, as well as the nurses and other medical staff that cared for him and showed him such compassion while he was being treated at Massachusetts General Hospital (MGH) in Boston. “These acts of kindness—the simple human touch from my caregivers— have made the unbearable bearable,” wrote Mr. Schwartz.

Patient-Caregiver Connection The article became a blueprint for the creation in 1996 of the Schwartz Center for Compassionate Healthcare, a nonprofit organization designed to strengthen the relationship between patients and their health-care providers. The follow-

programs in their institutions. In contrast to the traditional medical, morbidity and mortality, or ethics rounds, which focus on medical problems, clinical strategies, or ethical issues, Schwartz Center Rounds sessions provide a forum for medical personnel to discuss the social, emotional, and interpersonal issues they experience caring for patients. “The goal of the Rounds is to get doctors and other medical caregivers to focus on the connection between patients and their professional caregivers,” said Dr. Lynch, a cofounder of the Schwartz Center for Compassionate Healthcare, and now Director of Yale Cancer Center and Physician-in-Chief of Smilow Cancer Hospital at Yale– New Haven in Connecticut. “Most people go into medicine because they enjoy people and they want to help them,” he continued. “But there are so many stressors in our system that try to wring out that essential humanity and minimize the importance of it. The Rounds is all about bringing that connection between the patient and caregiver back to the center of the work we do all day, and that’s important.”

Most people go into medicine because they enjoy people and they want to help them. But there are so many stressors in our system that try to wring out that essential humanity and minimize the importance of it. The Rounds is all about bringing that connection between the patient and caregiver back to the center of the work we do all day. —Thomas J. Lynch, Jr, MD

ing year the Schwartz Center launched the Schwartz Center Rounds at the MGH Cancer Center. The program is dedicated to improving communication between patients and their professional caregivers and providing emotional support to every member of the medical team, including physicians, nurses, social workers, psychologists, physical therapists, and chaplains. Today, more than 350 health-care facilities nationwide— including 40 cancer centers—have implemented Schwartz Center Rounds

Improved Teamwork Established at Yale Cancer Center in 2006, Dr. Lynch said the Rounds program draws between 60 and 100 clinical staff members to each of its 11 1-hour sessions held throughout the year. After listening to a presentation on a specific patient case or topic, audience members are encouraged to share their perspectives on the case as well as broader related issues and concerns. “The program has been instrumental in breaking down traditional role barriers

How the Schwartz Center Rounds Program Works

he Schwartz Center Rounds program utilizes a case-based format to present information about an identified topic and stimulate discussion among Rounds participants. A physician leader and planning committee choose a case and topic and identify a panel of professional caregivers to share their perspectives on the social and emotional challenges raised by that case. A trained facilitator then encourages dialogue among participants from diverse disciplines, including physicians, nurses, social workers, psychologists, allied health professionals, and chaplains. Most health-care institutions conduct the program on a monthly or bimonthly basis. At many Schwartz Center Rounds sites, physicians, nurses, and social workers are eligible to receive continuing education credits for attending. Requirements vary by state. Attendance at Rounds sessions can also help satisfy Accreditation Council for Graduate Medical Education core competency requirements for postgraduate residency programs. n

between doctors and nurses and other staff members and gives each of the different caregivers a window into the professional lives of their colleagues,” said Dr. Lynch. That insight is resulting in improved teamwork, increased understanding of the nonclinical aspects of patient care, and greater emotional support in the institutions implementing the programs. In a survey2 of medical personnel conducted by the Goodman Research Group and published in 2008: • 93% of respondents said Rounds gave them a better appreciation for the roles and contributions of their colleagues • 90% reported better communication with their coworkers about nonclinical aspects of care • 86% said they were more focused on the effects of illness on patients’ lives • 84% felt more compassionate toward patients and their families • 76% reported feeling less alone in their work with patients “Our survey showed that after participating in Rounds for a while, medical staff from every discipline felt better able to communicate with patients and families, gained new ideas about how to handle difficult patient situations, and felt less stressed and burned out,” said M arjorie Stanzler, Senior Director of Programs and a cofounder of the Schwartz Center for Compassionate Healthcare. Another positive outcome of the Rounds, according to Ms. Stanzler, was that some institutions changed policies or practices to make care more patientcentered. “The most commonly cited

change was that clinicians began referring patients earlier and more often to palliative care,” said Ms. Stanzler.

Marjorie Stanzler

Bringing the Program to Your Institution Institutions interested in establishing the Schwartz Center Rounds must first become a member of the Schwartz Center for Compassionate Healthcare and sign a letter of agreement detailing both the institution’s and the Schwartz Center’s responsibilities in conducting the program. For more information, visit www .theschwartzcenter.org. n Disclosure: Dr. Lynch and Ms. Stanzler reported no potential conflicts of interest.

References 1. Schwartz KB: A patient’s story. Boston Globe Magazine, July 16, 1995. 2. Lown BA, Manning CF: The Schwartz Center Rounds: Evaluation of an interdisciplinary approach to enhancing patient-centered communication, teamwork, and provider support. Acad Med 85:1073-1081, 2010.

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ASCO State Affiliates Connecting to ASCO Through the State Affiliate Council By Ray D. Page, DO, PhD, FACOI

SCO’s State Affiliate Council is composed of the State Society Presidents and/or designated physician Council Representatives as well as the Executive Directors of each

state and/or regional oncology society. The Council convened in late February to address the most relevant issues affecting oncology practices today.

For many years, ASCO has had a strong desire to bolster representation of the domestic membership on the ASCO Board of Directors. There are now three community oncology

Building a Pipeline of Possibilities in Oncology For more than 25 years, Gilead has worked to develop medicines in areas of unmet medical need for patients worldwide. We are now conducting approximately 15 ongoing clinical trials in oncology, studying 4 small molecules and 2 monoclonal antibodies. Our pipeline comprises novel, targeted investigational agents across many pathways to treat a wide range of cancers. Together with our scientific and medical partners, we share a common focus—advancing the discovery, development, and delivery of new medications for people around the world.

Learn more about our oncology pipeline at http://www.gilead.com/ research/pipeline

representatives on the ASCO Board, as well as designated representatives on the Nominating Committee. ASCO recognizes the importance of the community oncologists’ voice in shaping vision, directives, and policy. To that end, the State Affiliate Council was formed in 2011, specifically to strengthen two-way communications. The Council now has direct access to the ASCO Board in addition to having Sandra Swain, MD, FACP, ASCO’s Immediate-Past President, serving as a liaison.

Finding Solutions to Saving Community Practices At the recent State Affiliate Council meeting, Tom Barr, MBA, General Manager of Oncology Metrics, along with a four-physician panel discussed important concepts related to practice survival in 2014. The physicians, representing diverse practice environments, expressed a broad array of concerns, including such topics as accountable care organizations creating competition and patient steerage, implementing electronic health records, covering all the “quality measures” while efficiently managing patients, optimizing hospital employment relationships and contracting, ICD-10 implementation, uninsured patient populations and working with health-care exchanges, experience with the Community Oncology Medical Homes (COME HOME) innovation grant, and what shared cost savings may look like in the near future. Mr. Barr provided some overarching tips to conceptually manage and enhance oncology practices going forward. Among those tips: learn to love Medicare rates, manage your drugs effectively, expect competition, embrace technology, empower the team concept, and don’t abuse your labor (yourself, that is). Dr. Page is a community hematologist/ oncologist at The Center for Cancer and Blood Disorders in Fort Worth, Texas, where he serves as President and Research Director. He is an Adjunct Professor of Medicine and Pharmacology at the University of North Texas Health Science Center. Dr. Page is the current Chair of the State Affiliate Council and is President-Elect of the Texas Society of Clinical Oncology.

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ASCO State Affiliates Payment reform models were discussed at length. With our nation’s unsustainable debt driven partly by escalating health-care costs, Congress is looking at multiple methods of cutting health-care spending. Oncology is a particular target, with new healthcare technologies, expensive cancer drugs, and more intensive therapies contributing to a dramatic growth in costs.

Congress Passes 1-Year SGR Patch Tremendous progress has been made over the past year to repeal the sustainable growth rate (SGR) system through the bipartisan, bicameral SGR Repeal and Medicare Provider Payment Modernization Act of 2014 (H.R. 4015/S. 2000), which ASCO has endorsed. Unfortunately, partisan politics over how to cover the cost of repeal stalled this bill, and instead, Congress patched rather than permanently repealed the flawed payment system. With a 23% Medicare physician

payment cut scheduled to take effect on April 1, the House and Senate acted at the last minute to enact the Protecting Access to Medicare Act of 2014 (H.R. 4302), which provides a yearlong patch to the flawed SGR system. H.R. 4302 provides a 0.5% provider payment update through the end of 2014 and a 0% update for the first 3 months of 2015. It also includes a 1-year delay in the transition from ICD9 to ICD-10 code sets. It pays for the patch with provider payment cuts, including cuts to payments for diagnostic laboratory tests, advanced imaging, and “misvalued” codes under the physician fee schedule.

Developing Alternative Payment Models It is extremely important that ASCO, and all other oncology stakeholders, explore alternative payment models that provide evidence-based, high-quality, value-driven access to care. ASCO and the Community Oncology Alliance (COA) published a

I strongly encourage ASCO members to get engaged in their state societies and make use of their resources. I also suggest that members contact their State Affiliate Council representative about practice concerns and issues that may need to be addressed on a national level. —Ray D. Page, DO, PhD, FACOI

May Is National Skin Cancer Awareness Month

ccording to the Skin Cancer Foundation, more than 3.5 million cases of skin cancer are diagnosed each year, with the incidences of skin cancer outnumbering all cases of breast, colon, lung, and prostate cancers combined. Of the three most common types of skin cancer—basal cell carcinoma, squamous cell carcinoma, and melanoma—melanoma causes the vast majority of deaths from skin cancer. Individuals most at risk for skin cancer include those with blonde or red hair, individuals who possess lighter skin naturally, and those with a family history of melanoma or other skin cancers.

Tips to Protect Against Skin Cancer • Avoid peak hours. Avoid being in the sun during the peak hours between 10:00 AM and 4:00 PM when ultraviolet rays are at their strongest. • Use sunscreen. Wear a broad-spectrum (UVA/UVB) sunscreen with a 15 SPF or higher every day. • Cover up. Cover up exposed areas of skin by wearing a wide-brimmed hat, sunglasses, and appropriate clothing to cover arms and legs. • Avoid indoor tanning. Tanning beds, tanning booths, or sunlamps should be avoided. n

Left to right: James Frame, MD, FACP, Chair-Elect, Thomas Marsland, MD, Immediate Past Chair, Joseph DiBenedetto, Jr, MD, Dorothy Green Phillips, Ray Page. DO, PhD, FACOI, Chair, Karen Beard, CPC, CPCO

joint statement in this regard encouraging the development of promising payment structures, such as the Oncology Medical Home and Treatment Month Payment. These can work with Episodes of Care and Shared Cost Savings designs, as well as, Merit-Based Incentive Payment Systems. The ASCO Dashboard Initiative was discussed by James Frame, MD, FACP, West Virginia Council representative and Council Chair-Elect. The ultimate purpose of the Dashboard is to enhance communication of trends and data as a mechanism to increase prospective systematic feedback from A SCO’s State Affiliates. This information will be shared with the ASCO Board and Committees in a way that assists in identifying and tracking practice, legislative, and other rising trends throughout the country. The Dashboard will increase engagement within the Council and permit the State Affiliate Council to

evolve its service mission in a rapidly changing environment. The Dashboard can form strategic and tactical decision-making for ASCO leadership. There is also the potential to augment and supplement current informal grassroots reporting and periodic survey tools for the domestic membership.

Getting Involved The State Affiliate Council serves to identify and create positive actions for ASCO members. As a practicing hematologist/oncologist, I strongly encourage members to get engaged in their state societies and make use of their resources. I also suggest that ASCO members contact their State Affiliate Council representative about practice concerns and issues that may need to be addressed on a national level. To find your representative, visit http:// www.asco.org/about-asco/affiliatesmap. n

Don’t Miss These Important Reports in This Issue of The ASCO Post Leonard Saltz, MD, on Optimal Treatment of Rectal Cancer see page 86

William T. Curry, Jr, MD, on Surgical Resection of Glioblastoma: Standard of Care see page 130

Eduardo Cazap, MD, PhD, FASCO, on Clinical Research in South America see page 168

Walter F. Baile, MD, on the Dos and Don’ts of Delivering Bad News see page 211

Visit The ASCO Post online at ASCOPost.com

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ASCOPost.com | MAY 15, 2014

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In the Clinic

Ramucirumab for Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma 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.

n April 21, 2014, ramucirumab (Cyramza) was approved for use as a single agent in the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy.1,2

Pivotal Study Approval was based on the demonstration of improved overall survival in the multinational phase III double-blind REGARD trial, in which 355 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned 2:1 to receive intravenous infusion of ramucirumab at 8 mg/kg (n = 238) or placebo (n = 117) every 2 weeks, with both groups also receiving best supportive care.2,3 Patients had disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy and had to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with bilirubin ≥ 1.5 mg/ dL, uncontrolled hypertension, or major surgery within 28 days or who were receiving chronic antiplatelet therapy other than once-daily aspirin were excluded. Randomization was stratified by weight loss over the prior 3 months

OF NOTE Ramucirumab binds VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D, thereby inhibiting ligandinduced proliferation and migration of endothelial cells.

(≥ 10% vs < 10%), geographic region, and location of the primary tumor (gastric vs gastroesophageal junction). Baseline characteristics were similar between treatment groups. Overall, median age was 60 years, 70% of patients

were men, 77% were white and 16% were Asian, ECOG performance status was 0 for 28% and 1 for 72%, 91% of patients had measurable disease, and 75% had gastric cancer and 25% gastroesophageal junction adenocarcinoma. In total, 85% had disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy consisted of a platinum/fluoropyrimidine combination in 81%, fluoropyrimidine-containing regimens without a platinum agent in 15%, and platinum-containing regimens without a fluoropyrimidine in 4%. Patients received a median of four doses (range = 1–34) of ramucirumab or a median of three doses (range = 1–30) of placebo. Median overall survival in the ramucirumab group vs the placebo group was 5.2 vs 3.8 months (hazard ratio [HR] = 0.78, P = .047). Median progression-free survival was

How It Is Given The recommended dose of ramucirumab is 8 mg/kg every 2 weeks as an IV infusion over 60 minutes, with treatment continued until disease progression or unacceptable toxicity. All patients should be premedicated with an intravenous histamine H1 antagonist (eg, diphenhydramine hydrochloride) prior to each infusion. Patients who have experienced a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen prior to each infusion. Dose modifications or interruptions are required for infusion-related reactions, hypertension, proteinuria, and wound-healing complications. Ramucirumab should be permanently discontinued in patients who experience arterial thromboembolic events, gastrointestinal perforation, grade 3 or 4 bleeding, or reversible posterior leukoencephalopathy syndrome.

Ramucirumab for Gastric/Gastroesophageal Junction Cancer ■■ Ramucirumab (Cyramza) was approved for use as a single agent in the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy. ■■ The recommended dose of ramucirumab is 8 mg/kg every 2 weeks as an IV infusion over 60 minutes.

also prolonged in the ramucirumab group (2.1 vs 1.3 months, HR = 0.48, P < .001). Recently reported findings of another study (I4T-IE-JVBE) in 665 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma indicate a survival advantage for the combination of paclitaxel plus ramucirumab vs paclitaxel plus placebo.

How It Works Ramucirumab is a recombinant human IgG1 monoclonal antibody that acts as a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. It specifically binds VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D. As a result of receptor blockade, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells. Ramucirumab was shown to inhibit angiogenesis in animal models.

Safety Profile The safety of ramucirumab as a single agent has been evaluated in 570 patients, including the 236 patients in study I4TIE-JVBD. In this study, the most common adverse events of any grade that occurred more frequently in the ramucirumab group were hypertension (16% vs 8% in the placebo group), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%). The most common grade 3 or 4 adverse events occurring more frequently in the ramucirumab group were hypertension (8% vs 3%), abdominal pain (6% vs 3%), and hyponatremia (3% vs 1%). The most common serious adverse events in ramucirumab patients were anemia (4%) and intestinal obstruction (2%). Red blood cell transfusions were given to 11% vs 9% of patients. Other clinically relevant adverse events reported in 1% to 5% of patients receiving ramucirumab were neutropenia (5% vs 1%), epistaxis (5% vs 1%), rash (4% vs 2%), and arterial thromboembolic events (2% vs 0%). On labora-

tory assessment, proteinuria occurred in 8% vs 2% of patients and resulted in discontinuation of ramucirumab in two patients. Gastrointestinal perforation occurred in 0.8% and infusion-related reac-

OF NOTE Ramucirumab carries a boxed warning for hemorrhage, including severe and sometimes fatal hemorrhagic events.

tions in 0.4% of ramucirumab patients. A total of 33 (7%) of 443 patients receiving ramucirumab in clinical trials have tested positive for anti-ramucirumab antibodies on an enzyme-linked immunosorbent assay. However, this figure may not be a reliable indicator of rate of antibody development, since the assay has limitations in the detection of anti-ramucirumab antibodies in the presence of ramucirumab. Neutralizing antibodies were detected in one of the patients testing positive for anti-ramucirumab antibodies. Ramucirumab carries a boxed warning for hemorrhage, including severe and sometimes fatal hemorrhagic events. It also has warnings/precautions for arterial thromboembolic events (including serious, sometimes fatal events), hypertension, infusion-related reactions, gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with cirrhosis (including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome in patients with Child-Pugh B or C cirrhosis), and reversible posterior leukoencephalopathy syndrome. Based on its mechanism of action, ramucirumab may cause fetal harm. Blood pressure should be routinely monitored in patients receiving ramucirumab, and treatment should be withheld prior to surgery. n References 1. U.S. FDA: Ramucirumab. Available at www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm394260.htm. 2. CYRAMZATM (ramucirumab) injection prescribing information. Eli Lilly, April 2014. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2014/125477lbl.pdf. 3. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD). Lancet 383:31-39, 2014.

The ASCO Post | MAY 15, 2014

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Oncology Worldwide A Vision of Independent Clinical Research in South America By Eduardo Cazap, MD, PhD, FASCO

linical research is vital for the development and improvement of methods designed to prevent and treat cancer. The majority of clinical trials take place in the developed world through sponsored pharmaceutical research companies.1 The corresponding lack of research in developing countries results in two unmet needs related to cancer treatment: First, recommended treatments do not reflect ethnic (genetic), cultural, environmental, and resource differences between developed and developing countries. Second, there is little research conducted on common tumors found primarily in developing countries. Consequently, the ability to diagnose and treat these diseases is impaired in many parts of the world.

countries, with training of research professionals at all levels (data managers, research nurses, etc) according to the local context, and identification of innovative resources to fund research. It is also critical to develop new models to answer questions that are relevant to our own patient populations and clinicians, being at the same time useful and cost-effective for each health-care system.3 Cancer research must be framed in a locoregional context because, frequently, the extrapolation of methodologies

This differs from the goals of pharmaceutical and biotechnology companies—rapid evaluation of their innovative products and market authorization if they demonstrate effectiveness, with a secondary aim of finding the best integration of active new agents into cancer treatment regimens for a variety of cancer sites, age groups, and clinical scenarios.5 These differences arise because drug approval and profitable return on investment are the fundamental objectives of pharmaceutical companies,

Research Barriers

Further Benefits of Publicly Funded Trials

The most frequent barriers to successful clinical research in South America are the lack of national or regional organizations linked to cancer research, lack of public recognition, and lack of funding capabilities, coupled with a heavy dependence on pharmaceutical companies that perform clinical research and scarcity of funding outside these companies.2 Nevertheless, it is critical to promote clinical research in developing Dr. Cazap is founder and first President of the Latin American and Caribbean Society of Medical Oncology (SLACOM), Buenos Aires; former President of the Union for International Cancer Control (UICC), Geneva; a member of the International Clinical Trials Working Group (ICTW-ASCO), Alexandria, Virginia; and a member of the Board of Directors of the National Cancer Institute of Argentina (INC). The author would like to thank Simon Gozar (SLACOM Chief Executive Officer), Daniel Campos (SLACOM Director of Research), Martine Piccart-Gebhardt (ESMO President), Alexandru Eniu (ESMO Emerging Countries Committee Chair), and Christian Dittrich (ESMO Faculty Group Coordinator for Principles of Clinical Trials and Systemic Therapy) for their helpful comments on earlier drafts of this manuscript. A special recognition goes to Margaret (Peg) Mastrianni, Deputy Director and Chief Program Officer of The Breast Cancer Research Foundation, Larry Norton, MD, and Cliff Hudis, MD, from Memorial Sloan Kettering Cancer Center for their support of S LACOM research activities.

to different resource levels. The development of evidence-based guidelines and recommendations for clinical practice are highly dependent on local conditions, so it is also imperative to promote independent research for this purpose at the national level. Publicly funded trials can determine whether interventions found to be effective in other countries are also effective in one’s own country. We know that health-care systems vary from country to country and that national populations vary by age structure, comorbidity, and genetic background. Particularly with the newer generation of biologic agents, we need to establish whether treatment effect or toxicity varies according to population genetics.

Fig. 1: Structure of the SLACOM Clinical Research Institute. NCIs = National Cancer Institutes, SLACOM = Latin American and Caribbean Society of Medical Oncology.

from developed countries may not be fully applicable, and the interpretation of results from the international literature may sometimes be erroneous when applied to different ethnic and regional populations.4 It is also necessary to promote not only clinical research, but also basic, translational, epidemiologic, and implementation research. This is essential not only for patient care, but also for the development of national cancer plans and the creation of better health-care systems.

Publicly Funded Clinical Trials The most important objective of a publicly funded clinical cancer trial is the identification of optimal therapies.

whereas independent research may have broader objectives, including the answer to clinical questions or the validation of scientific hypothesis. Many important cancer trials do not contain experimental agents and therefore lack a pharmaceutical sponsor. This is also true for studies that intend to answer a purely clinical question, epidemiologic studies, and, more recently, implementation research. Another critical objective for publicly funded trials is to identify the most effective treatments that national health-care systems should make available (and, likewise, to identify ineffective treatments that health-care systems should not support). In this context, health-care coverage should be adapted

Institutional participation in clinical trials improves quality of care for all patients treated at that site. Doctors and nurses who participate in clinical trials are more likely to adopt effective innovations into routine practice, as well as to practice cancer care more rigorously. Another potential benefit from publicly funded trials is the incorporation of translational research components into cancer trials. These additional elements may include epidemiology, development and validation of prognostic markers, evaluation of biologic mechanisms, novel imaging, cost-effectiveness, and efficacy of interventions in selected populations. All these extra components have the potential to add great value to an individual trial. In many cases, pharmaceutical companies may not be willing or able to support these added objectives. Publicly funded trials facilitate the translation of research discoveries from academia into clinical practice. Too often, investigators at publicly funded research institutes and universities are not able to bring new discoveries into clinical evaluation because they do not have easy access to clinical trials and may not be able to stimulate interest from pharmaceutical and biotechnology companies in performing them. In addition, publicly funded trials can expand the opportunities for evaluation of novel interventions from industry. Often, companies may only be able to underwrite evaluation of their novel agents in the most common cancers. By collaborating with a publicly

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Oncology Worldwide funded network, companies can facilitate the evaluation of their new agent in less common cancers, as well as in age groups that are more difficult to study, such as children and the elderly. Typically, companies see other firms as rivals and do not consider combination strategies. Publicly funded cancer networks can encourage the evaluation of a combination of novel agents from several different companies and foster collaboration. The presence of an international publicly supported clinical trials group attracts interest from international pharmaceutical companies both for potential collaboration and to increase market share for their new agents. Companies are attracted by the existence of a clinical trials network with proven capability and expertise. Regional and national data collected by the network can also be useful for developed countries, for example, by being applicable to minorities living in many parts of the world.

Conducting Clinical Trials Globally The world distribution of cancer patients shows that 61% live outside the United States, Europe, and Japan. Latin America has 10% of the world cancer patient population, 30% are in Asia, and 28% in China.6 Thus, the issue of trial placement has become increasingly complex. Research costs are rising, and

accrual is strongly related to the size of the population. In this regard, the international patient population represents an extraordinary source of information. It is also important to consider that regulatory processes are evolving and that harmonized regulatory requirements should be promoted. Global trials include demographics and epide-

several aspects related to medical research: good clinical practices, dossier review, regulatory authorization, quality control systems, and established processes. Independent research and publicly funded trials can promote innovative regulatory processes, facilitating the development of studies that are not just focused on drug approval.

Cancer research must be framed in a locoregional context because, frequently, the extrapolation of methodologies from developed countries may not be fully applicable, and the interpretation of results from the international literature may sometimes be erroneous when applied to different ethnic and regional populations. —Eduardo Cazap, MD, PhD, FASCO

miology together with ethnicity issues. Today, it is possible to perform trials faster and better on a global scale. At the local level, knowledge and technology transfer are improved, and local expertise, together with global and local publications, are stimulated. Additional reasons to conduct clinical trials globally are improvements in

Global efforts promoting independent clinical research should include an increase in participation in phase I and II studies, explore opportunities for early-phase drugs, strengthen collaboration with academic cancer research centers, increase partnership with other cancer research organizations, and further continuous education and train-

ing programs. In addition, investment must be expanded in exploratory and proof-of-concept trials, especially those that are relevant for the different world populations and that reflect various resource levels.7

Changing the Paradigm The Latin American and Caribbean Society of Medical Oncology (SLACOM) is a regional organiza tion with more than 2,000 members (Fig. 1). Founded in 2002, SLACOM is headquartered in Buenos Aires, and it has a Board of Directors constituted by representatives from six countries of the region. Like the European Society for Medical Oncology (ESMO) or the American Society of Clinical Oncology (ASCO), SLACOM is a scientific society with individual membership, and its main activities are related to producing scientific knowledge and providing medical education. The existing difficulties and barriers for independent research were the principal factors in SLACOM’s decision to develop a model adapted to regional conditions and feasible to implement with existing resources and capabilities. This decision resulted in the launch of a Clinical Research Institute in 2008. The usual model for clinical research has pharmaceutical companies acting as sponsors and, in order to facilitate the process, clinical research organicontinued on page 172

Research Groups in South America

lthough cancer research in South America has been largely led by the pharmaceutical industry, a number of independent research groups are active in the region.

Peru: GECOPERU and INEN The Peruvian Oncology Clinical Studies Group (Grupo de Estudios Clínicos Oncológicos Peruano, or GECOPERU [gecoperu.org]) was founded in March 2005 as a nonprofit academic organization, interested in the development of basic research, epidemiology, translational research, and clinical trials. It works to discover new treatments and set standards in the management of cancer and to translate this knowledge by increasing the chances of cure and survival of cancer patients. It has a central operating office and partnerships with several international groups (CIBOMA, IBCSG, BIG, and others).

The National Institute for Neoplastic Diseases (Instituto Nacional de Enfermedades Neoplásicas, or INEN [www.inen.sld.pe/portal/investigacion.html]) is the governmental body for cancer control and policy in Peru. Basic and clinical research activities are an important component of INEN’s strategic planning.

Chile: GOCCHI The Chilean Cooperative Group for Oncological Research (Grupo Oncológico Cooperative Chileno de Investigación, or GOCCHI [www. gocchi.org]) is a nonprofit corporation registered in Chile since 1998. GOCCHI is conducting academic clinical trials in oncology based on the highest scientific, methodologic, and ethical standards. The principles and goals of GOCCHI are to plan, promote, and develop oncologic research in Chile, to

promote and optimize the cooperative work of the clinical and investigational centers of the private and public sector as well as between the Ministry of Health and the universities, and to prepare and present reports and studies related to oncology. The network of clinical centers affiliated with GOCCHI consists of more than 20 private and public institutions across the country, with 210 affiliated members, including medical oncologists, radiotherapists, oncologic surgeons, pathologists, and basic science researchers.

Brazil: The LACOG Group The Latin American Cooperative Oncology Group (LACOG [www. lacog.org.br]) was founded in 2008 by medical oncologists from several Latin American countries. It is a nonprofit organization and legal entity for academic cancer research in Latin

America, developing a network of investigators in oncology for epidemiologic and clinical studies in cancer. LACOG has 47 members in 39 sites from 10 countries in the region. Currently, the group has seven ongoing studies.

Argentina: GOCS, IATTGI, and GAICO The South Cooperative Oncology Group (Grupo Oncológico Cooperativo del Sur, or GOCS [www. gocsbhb.com.ar/archivos/gocs_principal.html]) was founded in 1978 by medical oncologists from Neuquén and Bahía Blanca, Argentina, with the objective of improving patient care through the development of clinical research and professional and public education. Today, more than 10 institutions involved in cancer patient care (members and affiliates) from continued on page 173

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

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Oncology Worldwide Clinical Research in South America continued from page 169

zations contracted for all operational matters, logistics, and administrative support. SLACOM integrates all clinical trial players—sponsor, researchers, clinical research organizations, and patients—in a coordinated and

efficient way, avoiding duplications, facilitating processes, lowering costs, and bridging gaps. Patients and researchers are central components of the strategy in SLACOM’s research activities. Other important factors in the equation are the quest to answer clinical questions, provide good epidemiologic informa-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

tion, understand ethnic and regional variations, and address issues related to affordability, sustainability, and applicability. The evaluation of new therapeutic strategies is frequently a key area of interest for independent groups involved in the process.8 SLACOM’s approach allows that the sponsor (or a consortium of spon-

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

sors), working alone or in partnership with other interested partners (governments, academies, health-care systems, pharmaceutical companies, etc), may be included in a hybrid model. Additional sponsors can be integrated, if they agree to follow the criteria and methodology of SLACOM researchers. Under this structure, the clinical research organization’s work is coordinated with the group of researchers. In this context, it is important to understand that the relationship with the researcher is managed not only through the clinical research organization representative (a frequent situation in developing countries). In addition, SLACOM’s Clinical Research Institute team has continuous contact with clinical research organization members and researchers in a coordinated, personal, and functional way.

Feasibility Assessments Prestudy feasibility analysis is a vital element in our strategy. We only select researchers who are expert in a given disease with high possibilities of patient accrual. We develop our own databases and conduct data analysis with information from more than 12 countries in Latin America. The data include each center’s capabilities, potential patient availability, and real possibilities of accrual to avoid or diminish incorrect estimations. It is well known that the cost of a trial increases exponentially with the number of sites. Therefore, we perform a very careful analysis of the number of sites with respect to the total necessary number of patients and countries. A timeline assessment is also included in our feasibility estimations. The use of “megasites”—specialized cancer centers with a high number of patients and more possibilities for fast accrual—selection of countries according to a very strict evaluation process, and involvement of researchers who are committed to the study are the backbone of our strategy. We also perform a thoughtful analysis of competing studies—two or more investigations competing for the same target population—to avoid these situations. All activities are simplified in a practical and operational manner, lowering costs and improving efficiency, accrual, and quality. All the processes that are part of the research are reformulated and monitored. All contracts, drug supplies, logistics, images, hospital costs, research fees, and other expenditures are carefully managed and take into consideration the best option in terms of price-performance ratio.

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Oncology Worldwide Currently, we are launching the first multinational randomized phase III study in Latin America, designed to answer a clinical question and funded only though private resources. In this case, SLACOM is the only sponsor. The

search must be encouraged. We need less expensive and faster models but, most importantly, studies that will answer clinical questions relevant to the different needs of world populations. Drug development and science are cru-

Better cancer research should be based not only on the efforts of pharmaceutical companies. Researchers, governments, nongovernmental organizations, the private sector, patient organizations, and society as a whole must be part of this process. —Eduardo Cazap, MD, PhD, FASCO

next steps on our agenda are the development of our own data management team, database, and tumor bank.

In Conclusion Clinical research must be promoted globally for the benefit of the international community of cancer patients. The development of experiments and efforts trying to advance innovative models and different strategies for re-

Research Groups in South America continued from page 169

different cities in Argentina and other countries participate in GOCS clinical studies and educational activities. Since its founding, the GOCS group has devoted a great deal of effort to clinical investigations of breast cancer, lung cancer, biochemical modulation in colorectal cancer, and, to a lesser extent, research areas such as prognostic factors and supportive care. All member institutions follow a uniform method of data collection, registration, and management (which allows for the presentation of reliable information) and a peer-review system. Every GOCS center has a computerized database, and all of these systems are interconnected by means of telecommunications. This enables

cial; however, it is also critical to have additional information that will improve cancer care and make health-care systems more efficient. The responsibility for better cancer research should be based not only on the efforts of pharmaceutical companies. Researchers, governments, nongovernmental organizations, the private sector, patient organizations, and society as a whole must be part of this process. the daily exchange of information as well as the monitoring of studies in progress. The GOCS sponsors scientific meetings, lectures by renowned personalities in oncology, and training fellowships for Argentine and foreignborn oncologists. In addition, six annual plenary meetings are held at different locations. The group is also involved in educational activities and provides information and support to cancer patients. GOCS has published more than 60 peer-reviewed publications and collaborates with the Oncology Institute of Bari, Italy.

Argentina: IATTGI The Argentine Intergroup for the Treatment of Gastrointestinal Tumors (Intergrupo Argentino para

We strongly believe that if our research model is successful, it will improve the performance and competitiveness of South American research groups, provide information from, and for, our own patient population, and allow us to answer questions that will otherwise remain difficult or impossible to resolve. In addition, we hope that our Clinical Research Institute, run and managed by a regional oncology society, will serve as an inspiration for similar models to be considered, expanded upon, and adapted in other regions of the world. n Disclosure: Funding for the phase III study is provided by a research grant from The Breast Cancer Research Foundation (BCRF).

References 1. U.S. National Cancer Institute: Find international clinical trials. Available at www.cancer.gov/clinicaltrials/international/collaborate/findtrials/findtrials. Accessed April 24, 2014. 2. Sergua B, Sadikov A, Cazap EL, et al: Barriers and challenges to global clinical can-

Tratamiento de Tumores Gastrointestinales, or IATTGI [www.iattgi.org]) is a cooperative group from Argentina dedicated to care, research, and teaching related to gastrointestinal tumors. This nonprofit organization was founded in 1983 and is constituted by gastroenterology, surgery, radiology, radiotherapy, pathology, oncology, and palliative care researchers. IATTGI participates in clinic trials through the recruitment of patients from different institutions of Argentina, working in clinical research with pharmaceutical industry funding and on some independent research projects. The group has published more than 30 studies in peer-reviewed journals.

Argentina: GAICO Founded in 2007, the Argen-

cer research. Oncologist 19:61-67, 2014. 3. Kerner JF, Cazap E, Yach D, et al: Comprehensive cancer control-research & development: Knowing what we do and doing what we know. Tumori 95:610622, 2009. 4. Piccart M, Goldhirsch A, Wood W, et al: Keeping faith with trial volunteers. Nature 446(7132):137-138, 2007. 5. Trimble EL, Abrams JS, Meyer RM, et al: Improving cancer outcomes through international collaboration in academic cancer treatment trials. J Clin Oncol 27:5109-5114, 2009. 6. U.S. National Institutes of Health: ClinicalTrials.gov. Clinical trials, trends, charts, and maps. Available at www.clinicaltrials.gov. Accessed April 24, 2014. 7. Siegfried N, Steinhausen K, Ren J, et al: Global core competencies for clinical trials. Lancet 380:728, 2012. 8. Organisation for Economic Co-operation and Development: OECD recommendation on the governance of clinical trials. Available at www.oecd.org/sti/scitech/oecdrecommendationonthegovernanceofclinicaltrials.htm. Accessed April 24, 2014.

tine Group for Clinical Research in Oncology (Grupo Argentino de Investigación Clínica en Oncología, or G AICO [www.gaico.org.ar]) is composed of 15 cooperating groups and includes various health professionals from public and private institutions. The group designs and develops clinical research studies, whether investigator-initiated or in collaboration with academic institutions and the pharmaceutical industry. GAICO also has disease committees, provides training for its members, and releases standard operating procedures. It collaborates with regional and international societies (GECOPERU, BIG, and CIBOMA, among others) and organizes an annual meeting. n

Narratives in Oncology

A Special Supplement to The ASCO Post Narratives in Oncology is a special edition of The ASCO Post featuring personal profiles about oncology leaders who have made an important contribution to the clinical research and care of patients with cancer. Watch for your issue of Narratives in Oncology mailing with the June 10, 2014* issue of The ASCO Post. Or visit The ASCO Post at ASCO’s Annual Meeting, booth 24091, for your advance copy of this limited special edition. *The ASCO Post will be published two times next month, June 10 and June 25.

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Society of Surgical Oncology Cancer Symposium Issues in Oncology

An Oncologic Surgeon Discusses the Pros and Cons of Pursuing a Business Degree A Conversation With Martin J. Heslin, MD, MSHA By Ronald Piana

s pursuing a Master of Business Administration (MBA) degree a good idea for ambitious surgical oncologists who want to advance their careers? The ASCO Post recently spoke with Martin J. Heslin, MD, MSHA, Chief, Section of Surgical Oncology, University of Alabama at Birmingham (UAB) Medical Center, about pursuing the degree. Dr. Heslin gave a presentation at the 2014 Society of Surgical Oncology Cancer Symposium titled, “Should I Get a Masters of Business Administration as Part of a Career Development Plan?”

When to Pursue an MBA Going back to school for a business degree is a big commitment in terms of time and money. How does a doctor know when it’s the right time? There are a couple of options. A

The Business of Health Care We tend to think that community oncologists dealing with complex administrative and billing burdens could benefit from pursuing an MBA in order to run a profitable practice. But you make a case for using the degree in academic medicine. Why? Times have changed. Health care has become a business. Academic medicine used to be shielded from the business side of health care. Physicians on the academic side tended to make less money than those in private practice, and there was more focus on research and education. Generally, the clinical recompense gained if you contracted with a hospital could support your efforts. Not anymore. It is all about fundedeffort reporting now. Either you’re generating revenue from grants or contracts or you’re working with the administrative

[A business degree] broadens your knowledge base in topics generally not taught in regular training, such as healthcare law, health policy, and strategic planning. As to whether a degree will help a doctor get promoted faster, the answer depends on the institution. —Martin J. Heslin, MD, MSHA

leadership development course is good for a physician at the trainee level; it’s typically shorter and more condensed. If a doctor is still in training, the best approach is to group vacation days together and do the course work through a society. However, if you’re going to do a full executive business program, which is what I focused on, before committing you must be able to dedicate 10 to 15 hours per week. You need to be online and have free time during nights and weekends. For a practicing surgical oncologist, I think the best time to pursue a business degree is during midcareer. As an assistant professor, you understand the working relationships between doctors and administrators. In other words, you’ve gained the background knowledge to justify working toward the degree and maximizing its benefits.

group figuring out how to save money. So you need to provide high-quality cancer care while running a profitable, cost-effective institution. The degree can provide the foundational business, financial, and operational knowledge necessary for today’s academic institution challenges.

Surgeon Executives As an oncologic surgeon with a business leadership degree, do you feel that combining the skill sets of a CEO with an oncologist is the best way for institutions to deliver cost-effective high-quality cancer care? The short answer is yes. The physician-surgeon CEO model has a couple of advantages. Surgeons are usually fairly decisive people, and a surgeon executive manages a typically difficult group to organize, namely surgeons, who are always disappearing into the OR and conse-

Questions Before Committing to a Business Degree Program ■■ Can I afford it? ■■ Will this degree get me promoted faster? ■■ What are the potential job options outside academia or the typical departmental structure? ■■ Will this degree help me get increased compensation? ■■ Is there an opportunity for surgeons?

quently rarely available for meetings. Surgeon executives can also generate revenue in the OR, as long as they can package their time appropriately. And the degree can provide the management tools that may actually improve the level and efficiency of an oncology program. Given the time an oncologic surgeon spends in the OR, do you see fewer surgeons in MBA programs than other specialties? The percentage of surgeons in the executive business program compared with medical doctors is quite small. The reason for that is that most centers believe that a surgeon can generate more revenue in the OR than in an executive role. The adage is that you keep the administrators in the office and the surgeons in the OR. Unless you’re talking about a center’s CEO or other top positions, having surgeons in midlevel administrative positions doesn’t usually make economic sense. That’s one of the reasons that we see so few surgeons in business programs. The trend seems to be changing, however.

Career Path How does a business degree help your career path? On a personal level, I’ve found it broadens your knowledge base in topics generally not taught in regular training, such as health-care law, health policy, strategic planning, and so forth. As to whether a business degree will help a doctor get promoted faster, the answer depends on the institution. If you belong to a pure, hard-core academic institution with an R01 grant– funded mentality, you need multiple grants to be promoted with tenure, so an executive management degree might not have value in your career path. How-

ever, if your institution values quality, safety, and business acumen, then the time and money needed for a degree should help accelerate your career. Please give readers a snapshot of your career and your decision to pursue an executive business degree. I went to medical school at the State University of New York Health Science Center at Syracuse, New York. I did my residency at New York University Medical Center and spent 4 years at Memorial Sloan Kettering Cancer Center—2 in a clinical fellowship and 2 in a research fellowship. In 1996, I was recruited to UAB, and I relocated with my family to Birmingham, where we’ve lived for the past 18 years. My old boss told me that opportunity exists for those who are not geographically paralyzed. But remaining at one institution has allowed me to pursue career goals and raise a family at the same time. That said, if you remain at one institution, you need to make sure that you maximize your skills and value in order to advance your career. Career change happens primarily as a result of crisis or attrition, and neither happens often enough for your career needs. So you need to move horizontally in the medical center, either through administration of the cancer center, as I do, or via management of quality and safety on the hospital side. To advance your career, you need to be fresh, seek new internal opportunities, and meet people you’d never encounter if you stayed in your one little safety zone. So when I got the executive MSHA, it gave me a way to wear multiple hats and broaden my career as an administrator surgeon. In the end, deciding to pursue a business degree is a highly personal choice. For me, it was certainly worth it. continued on page 176

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Announcements

Duquesne University Awarded $1.4 Million NIH Grant

uquesne University’s newly established biomedical engineering initiative has received a $1.4 million, 5-year grant from the National Institutes of Health’s National Cancer Institute to detect, capture and analyze circulating melanoma cells. John Viator, MD, Biomedical Engineering Program Director at Duquesne, and a specialist in medical lasers, will use this technology to analyze patients’ blood samples in hopes of detecting the spread of this potentially fatal skin cancer months or even years before it could be identified by conventional imaging.

ticular cancer and how it’s spreading,” explained Dr. Viator. “Instead of blindly prescribing chemotherapies, if you capture the individual cells that are spreading, you can verify the type of melanoma that responds well to a certain drug.”

Duquesne’s grant not only supports refining the method and studying the basic science of melanoma and cancer biology, but will provide for a study of cancer patients to predict and observe the disease state and the response to therapy.

Dr. Viator will collaborate with his former colleagues from the University of Missouri and researchers at the University of Pittsburgh in the work, which also will involve the UPMC Hillman Cancer Center. n

Serendipitous Finding The focus on melanoma arose while Dr. Viator was working on separate research to use lasers in a noninvasive way to determine the severity of a burn injury. A surgical oncologist colleague asked if the method could be used to find melanoma cells circulating in the bloodstream, as it attempts to spread throughout the body. The duo then developed a method of zapping a blood sample as it circulated through a system. If even a single cell contains melanoma, a high frequency sound wave identifies it as cancerous—leading to possible early, personalized intervention. “Once you capture these individual cancer cells, you can do molecular tests, genetic tests, image them under a microscope, and learn more about that par-

Activated T Cell Inactivated T Cell

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

Pursuing a Business Degree continued from page 175

Medicaid Challenges To end on a business note, how’s the fiscal health of the UAB Comprehensive Cancer Center? Our biggest current challenge is Medicaid, because we are in that unenviable position of having a governor who is not expanding the program as an exchange under the Affordable Care Act, and the disproportionate share hospital payments—by which the U.S. government provides funding to treat indigent patients—are going to be lost. It’s estimated to be an issue on the order of $20 million to $50 million over the next year or two. We have to decide whether to go at-risk for Medicaid ourselves (become our own managed care company) or bring in a for-profit managed care company contracted by the state. But other than that, everything at UAB is great. n

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

Artist’s interpretation based on scanning electron microscopy.

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Announcements

The Leukemia & Lymphoma Society Surpasses $1 Billion Investment in Blood Cancer Research

he Leukemia & Lymphoma Society (LLS) has announced that it has passed the $1 billion mark in research investment, a significant milestone in the cancer research landscape

as the Society continues its 65-year pursuit of advancing breakthrough therapies, finding cures, and ensuring access to life-saving therapies for all blood cancer patients.

This announcement came during a recent conference the Society held in Washington, DC, featuring a research symposium, “Bridging the Gap from Bench to Bedside: The Road to

Discover PD-1: An immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

Cures” and a panel discussion titled, “What is a Cure?”

Greater Efforts Still Needed “For 65 years, LLS has been leading the way, moving us closer to a world without blood cancers,” said Louis J. DeGennaro, PhD, Interim President as well as CEO and Chief Mission Officer, LLS. “While the $1 billion research investment is helping to save lives today and extending survival rates for many patients, there are still few, if any, means for preventing or early screening for most blood cancers. More than one-third of blood cancer patients do not survive more than 5 years after diagnosis. We can do better, and we must do better to save more lives.” The panel discussion on defining a cure features the experiences of patients, families, clinicians, and an FDA official. It also features insights from renowned blood cancer researchers who are advancing promising new therapies and identifying changes in the development and regulatory processes that are needed to help bring live-saving treatment options to patients faster.

Access to New Therapies Access to new treatments is also a focus of the LLS conference. More than 500 LLS advocates met with legislators urging them to support legislation that improves access to innovative blood cancer therapies and limits the use of “specialty tier” drug designations, thereby increasing affordability for patients. n

The ASCO Post

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2. References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. 2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. 3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565. 5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477. 6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

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2014-2015 Oncology Meetings May ASPHO’s 27th Annual Meeting May 14-17 • Chicago, Illinois For more information: www.aspho.org Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences 2014 State of the Art Radiation Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org Association of Oncology Social Work 30th Annual Conference May 28-30 • Baltimore, Maryland For more information: www. aosw.org/imis201/AOSWMain/ Conferences-Programs/2014/aosw2014-conference.aspx

4th International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma June 7 • Santa Monica, California For more information: www.cme.ucla.edu/courses/eventdescription?event_id=2245469 National Coalition of Oncology Nurse Navigators 5th Annual Conference: Setting the Course for Improved Cancer Care June 12-14 • Atlanta, Georgia For more information: www.nconnconference.com Targeting VEGF-mediated Tumor Angiogenesis in Cancer Therapy June 19-20 • New York, New York For more information: www.nyas.org/Events The Win 2014 Symposium— Winning Combinations for Precision Cancer Medicines June 23-24 • Paris, France For more information: www.winsymposium.org MASCC/ISOO International Symposium on Supportive Care in Cancer June 26-28 • Miami, Florida For more information: www.mascc.org/symposium

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June 2nd Annual Prostate Symposium: Challenges and Solutions June 6-7 • Winston-Salem, North Carolina For more information: http:// northwestahec.wfubmc.edu

European Conference of Oncology Pharmacy 2 June 26-28 • Krakow, Poland For more information: http://ecop2014.wordpress.com 6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/

2014-2015

16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

July Best of ASCO in Japan July 5-6 • Kobe, Japan For more information: www.jsmo.or.jp/en/ 23rd Biennial Congress of the European Association for Cancer Research July 5-8 • Munich, Germany For more information: http://eacr23.eacr.org 8th International Conference on Teenage and Young Adult Cancer Medicine July 7-8 • London, United Kingdom For more information: www.teenagecancertrust.org/whatwe-do/international-conference/ NCCN Policy Summit: The Impact of Health Care Reform on Academic Oncology Practice July 10 • Arlington, Virginia For more information: www.nccn.org/professionals/ meetings/oncology_policy_program/ impact_health_care_reform.aspx

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

Breast Cancer: New Horizons, Current Controversies July 10-12 • Boston, Massachusetts For more information: www.hms-cme.net/341279/

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org

The 12th Annual Scientific Meeting of Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/

ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/

July 21-25, 2014

The Kohala Coast, Hawaii

Abstract Submission Deadline: Early Registartion Deadline:

April 11, 2014 May 20, 2014

u n m c . e d u/p a np a c i fi c l y m p h o m a

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2014-2015 Oncology Meetings Hematology and Medical Oncology Best Practices August 14-21 • Arlington, Virginia For more information: smhs.gwu.edu/ cehp/activities/courses/hemonc

2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9

Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org

American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org

16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au 6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org 6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org

Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

2014-2015

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety. org.uk/index. cfm?task=meetings&meetingid=37 11th Meeting of the Eurpean Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/ breastcancer/pages/index.aspx 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home. aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com 20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com continued on page 180

The ASCO Post | MAY 15, 2014

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2014-2015 Oncology Meetings continued from page 179

December

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747 Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306 EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014 Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

2014-2015

The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11 - 15 • San Diego, California For more information: www.asbmt.org Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ 46th Annual Meeting on Women’s Cancer March 28 - 31 • Chicago, Illinois For more information: www.sgo.org

April American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org

March 37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

SAVE THE DATE

NP FOR YO s AND UR PA s

October 30TH – November 2ND Loews Royal Pacific Hotel at Universal Orlando, FL

A CE/CME/CEU Conference for Advanced Practitioners in Oncology

apsho.org/jadprolive

13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

May ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

June NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6 - 10 • Baltimore, Maryland For more information: www.snm.org

July Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

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The ASCO Post | MAY 15, 2014

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Perspective Clifford A. Hudis, MD, FACP continued from page 1

investment improves our lives by enabling the development of more effective treatments that benefit everyone. Engaging all members of society in this discussion should help increase the priority of scientific research investment, which is the underpinning of all of our shared progress.

Looking Back Five decades ago when ASCO was founded, there were only a handful of chemotherapy drugs to treat cancer, and most of them were only modestly effective. In the ensuing years, the United States has led the world in investing in cancer research, which has yielded dramatic improvements in our ability to prevent, detect, and treat cancer. In 2013 alone, the U.S. Food and Drug Administration approved 18 new chemotherapeutic agents, bringing the total number now available to more than 170. The result of our progress has been a dramatic decline in overall cancer deaths, with nearly 14 million American cancer survivors alive today and more than 18 million projected by 2022. However, surviving is just the beginning. Not only are the patients we treat living longer, they are often able to enjoy high-quality, productive lives thanks to advances in better symptom management and targeted treatments that improve outcomes while limiting overall side effects.

Unprecedented Challenges Among my goals for the year leading up to our 50th Annual Meeting was to critically reflect on the progress we have made but, more importantly, to carefully consider what ASCO needs to do going forward to best serve our members and their patients. Our recent Board of Directors Retreat focused, in essence, on reimagining ASCO for the 21st century. If we had a blank slate, what would ASCO need to do and look like to be a successful force for good around the world? True to our mission, what more can and should we be doing to increase the pace of global control and cure for cancer? ASCO’s landmark report, The State of Cancer Care in America: 2014 shows that even as we make exciting scientific gains we simultaneously face unprecedented challenges in the near future. The convergence of the growing demand for services as the population ages—by 2025, demand for cancer care is expected to increase by 42%— and a concurrent projected shortage of nearly 1,500 physicians over the next

decade; changes in health-care delivery systems that may limit access for some; the financial pressures on independent oncology practices, threatening their survival; and the loss of research support are all conspiring to thwart patient access to high-quality, high-value cancer prevention and treatment services today and in the future. The severe budget cuts to the National Institutes of Health and the National Cancer Institute are a particular long-term danger as they hinder our ability to continue making the advances in cancer care that inspire us and

community practices while encouraging high-quality care. • Ending persistent financial threats to community practices caused by uncertain funding such as sequesterrelated cuts to Medicare physician payments, and by the sustainable growth rate (SGR) formula, Medicare’s current reimbursement system. The latter has become a source of tremendous instability within the health-care system and a threat to millions of seniors. Repeal of SGR is an obtainable goal with bipartisan support already established.

It is an exciting time to be a doctor, especially one who treats patients with cancer. We are seeing advances being made at an unprecedented level, and they hold the promise of evolution and revolution in terms of the expected outcomes after a diagnosis of cancer for millions of patients around the world. —Clifford A. Hudis, MD, FACP

make our careers rewarding and exciting (along with patient care) at a time when, ironically, the pace of scientific advance has never been greater. It’s as if we can see the opportunities but can’t quite reach them. Overcoming these challenges will not be easy, and there may be additional obstacles to confront, but I am confident that ASCO and its members have the skills, insights, and fortitude to do so. Indeed, we must succeed so that every American, and indeed every cancer patient anywhere, benefits as fully as possible from the advances in cancer care we have developed and will bring forward in the near future.

Developing Solutions In addition to continually pressing the public and our elected officials for a significant increase in research support, we also need to address broader issues of value and how we deliver care. In this regard, our recent State of Cancer Care in America report included ASCO’s suggestions on steps we can take to address emerging threats and called on federal policymakers and other stakeholders in the oncology community to help create an environment where quality patient care can thrive. They include: • Developing and testing new healthcare delivery and payment models that preserve the viability of small

• Embracing and supporting physicianled quality initiatives, such as ASCO’s Quality Oncology Practice Initiative (QOPI®) and CancerLinQ™, ASCO’s rapid-learning health system.

Improving Quality and Value of Care QOPI was launched in 2006 to provide oncologists with a tool to improve the quality, consistency, and value of care their patients receive. Today, with the cost of oncology care in the United States projected to rise to $173 billion by 2020,1 having one standard set of common quality measures in cancer care has never been more urgent. Across industries, it is generally true that standardization improves quality and reduces cost. In oncology, we have increased opportunities to apply this principle without threatening the sanctity of the patient-physician relationship and professional judgment in choosing among care options. Doing so will not only increase measurable quality, but also preserve resources, allowing us to serve more patients well. Doing this requires measures, and this is where QOPI has been so critical. I am happy to report that since QOPI’s inception, more than 850 oncology practices have registered in the program. A recent analysis of QOPI data has found consistently high lev-

els of performance in many areas of cancer care and has demonstrated the favorable impact of program participation on adherence to standards. For example, an analysis of more than 150 participating practices showed high scores (greater than or equal to 90%) in complying with recommendations for postoperative (adjuvant) chemotherapy standards in breast, colorectal, and non–small cell lung cancers. QOPI participants have also shown demonstrable improvements in end-oflife care for adult patients with advanced cancers. The result is that fewer patients are receiving ineffective treatments in the last 2 weeks of life. The incorporation of molecular testing has also been shown to rapidly improve in appropriate disease areas as assessed by QOPI. We are very, very proud of QOPI. But QOPI will continue to rapidly evolve, and the next step in that process is the CancerLinQ initiative. This is a “big data” learning health system comprising a knowledge-generating computer network that will collect and analyze cancer care data from millions of patient visits and expert guidelines and feed that knowledge back to oncologists at the point of care. The program was conceived in response to the Institute of Medicine’s recommendations for establishing a “learning health system” for health care, and with CancerLinQ, all patients treated in any oncology office in the country will have the potential to access vetted state-of-the-art care and research without leaving their local communities. In 2013, ASCO demonstrated an operational prototype, which gathered deidentified data from more than 177,000 patients with breast cancer who received treatments at hospitals and practices nationwide. Based on that early success, we plan to make the first components of CancerLinQ available to physicians in 2015. This will include relevant data on all types of cancer and will eventually provide access to millions of de-identified patient records, as well as expert guidelines and relevant scientific literature to enable a faster learning cycle from real-world patient experiences. There are many approaches to responsibly controlling the costs of health care. One of them is to continually reevaluate conventional approaches to care, and during 2013, ASCO contributed a second set of recommendations to the American Board of Internal Medicine Foundation’s Choosing Wisely ® campaign. In doing so, we joined professional societies across the spectrum to look critically at which

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Perspective

components of our day-to-day practices add value and which do not. To extend our communications internationally, we also launched ASCO International. This ambitious program is aimed at accelerating our global effort to bridge the gap in health equity among different racial and economic groups in cancer prevention, diagnosis, and treatment around the world. We have made a commitment to double our international programs over the next 4 years.

Looking Ahead This year has been a great joy for me. It has been my honor to serve as President of ASCO during its 50th Anniversary year and when there is so much potential and excitement in the scientific and clinical realms. The next year promises to present even greater challenges and opportunities for advancements in many areas of cancer prevention and treatment, and we hope these are reflected in the 2014 Annual Meeting Education Program. This year’s program includes multidisciplinary sessions that emphasize collaborative care in the management of

different cancers; topics relevant to daily practice; tools for delivering high-quality care; global health challenges in oncology; and understanding molecular path-

Peter P. Yu, MD

ways and genomics. You will also find discussions on the cost and value of cancer care integrated into many sessions. In addition to celebrating the 50th anniversary of ASCO’s founding, we are also celebrating the inauguration of Peter P. Yu, MD, as ASCO President. Dr. Yu, Director of Cancer Research at Palo Alto Medical Foundation and a member of the Alliance for Clinical Trials in Oncology and the Gynecologic Oncology Group, is well known in the oncology community for his knowledge and understanding of how health

information technology can advance the prevention, diagnosis, and treatment of cancer care. His interest and expertise in this area will be invaluable as we move forward in the big data digital age of health care. I also want to congratulate Julie M. Vose, MD, MBA, FASCO, on her election. Dr. Vose will take office as President-Elect during the Annual Meeting and begin her 1-year term as President in June 2015. It is an exciting time to be a doctor, especially one who treats patients

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

Julie M. Vose, MD, MBA, FASCO

with cancer. We are seeing advances being made at an unprecedented level, and they hold the promise of evolution and revolution in terms of the expected

The ASCO Post SALUTES

The American Society of Clinical Oncology on its

50TH Anniversary 1964 –2014

outcomes after a diagnosis of cancer for millions of patients around the world. I chose a career in cancer medicine about 25 years ago because, even then, it was obvious to me that this field offered the possibility of transformative, science-driven changes in clinical outcome coupled with the opportunity to work closely with patients and families coping with one of the most universally feared illnesses we confront. Everything I expected turned out to be true, except that the reward was even greater than I imagined. For younger physicians entering the field, I believe that the future will be even more exciting than it was for me. Given our talent and accomplishments, I’m looking forward to another year of great progress for our members and the patients and families we serve. n

Reference 1. Mariotto AB, Yabroff KR, Shao Y, et al: Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst 103:117-128, 2011.

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva (see Warnings and Precautions). Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva (see Warnings and Precautions and Adverse Reactions). WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently (see Contraindications and Adverse Reactions). Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Contraindications, Adverse Reactions, and Patient Counseling Information in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRyO-FETAL TOxICITy: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time (see Use in Specific Populations). ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia (see Warnings and Precautions) • Osteonecrosis of the Jaw (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. 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 other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater.

Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

xgeva n = 2841 %

Zoledronic Acid n = 2836 %

GASTROINTESTINAL Nausea Diarrhea

31 20

32 19

GENERAL Fatigue/ Asthenia

INVESTIGATIONS Hypocalcemiab Hypophosphatemiab

18 32

9 20

NEUROLOGICAL Headache

RESPIRATORy Dyspnea Cough

21 15

18 15

Body System

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations). • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53) (See Warnings and Precautions). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva (see Warnings and Precautions). Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology in full Prescribing Information). USE IN SPECIFIC POPULATIONS: Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology in full Prescribing Information). Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology in full Prescribing Information). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Specific Populations). Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology in full Prescribing Information). Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva [see Use in Specific Populations and Patient Counseling Information]. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy (see Contraindications and Warnings and Precautions) • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2013 Amgen Inc. All rights reserved. Printed in USA. 68257-R4-V1

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CELEBRATING

ASCO’s History, 1964–2014 T

he last 50 years have been marked by significant advances in cancer research and in more effective therapy for patients. Once viewed as a largely untreatable, fatal disease, today a number of cancers are being converted into chronic diseases that can be managed for long periods of time. The result is that there are now nearly 14 million cancer survivors in the United States, compared to just 3 million in 1971. The Cancer Progress Timeline at the bottom of these pages gives a quick chronology of the history of cancer care and includes the work of some of the pioneers who have made pivotal contributions to advancing

Building Bridges to Conquer Cancer Sandra M. Swain, MD ASCO President, 2012-2013

ne of the pleasures during my year as President was the ability to bring personal and professional passions and a sense of what really matters into focus for the work of our membership. My Presidential theme, Building Bridges to Conquer Cancer, reflected my particular interest in outreach to partners and possibilities that lie beyond the work of our daily practices. This is an extraordinary time in oncology, one in which we will gain new knowledge to empower us to deliver the best outcomes for our patients. An explosion of new data comes weekly. The digital age is changing our world at a rapid pace, democratizing both information and education. There has never been more opportunity and there has never been a greater need to collaborate to achieve our common goal of conquering cancer. During my Presidency I focused on three things: the possibilities and promise of global health equity; the need to strengthen future generations of leaders and practitioners; and the vision for a rapid learning system in oncology. The solutions for all have at their core the need for connection. Success is made possible by collective effort, by neighbor helping neighbor, and by learning from those who have gone before us. Nowhere is this truer than in oncology. The promise of science, the power of technology, and the strength of an increasingly global community can be leveraged to produce a world free from the fear of cancer. Clearly, there is no shortage of challenges deserving our attention. The three issues I mentioned earlier: advancing global health equity; mentoring the next generation of leaders; and the implementation of a rapid learning system, still belong squarely on our radar screens. n

CANCER PROGRESS TIMELINE From ASCO’s Cancerprogress.net Visit CancerProgress.net to view the interactive timeline.

the ultimate goal of curing cancer. To view an interactive version of the timeline, visit ASCO’s CancerProgress.Net As a Society, ASCO has also progressed from its original seven founding members in 1964 to 35,000 members today (See “ASCO’s Visionary Founders,” on pages 201–202.) As ASCO commemorates its 50-year history at this year’s Annual Meeting, The ASCO Post presents reflections from some of the Society’s past Presidents on the evolution of the Society and the progress they have seen in cancer care. For a complete list of past ASCO Presidents, see page 206.

Collaborating to Conquer Cancer Michael P. Link, MD ASCO President, 2011-2012

erving as ASCO’s President was one of the most exciting years of my professional career. Although that year presented a number of challenges, it also marked a number of accomplishments, including a record number of new ASCO members, which then reached more than 30,000 in 122 countries (today, there are approximately 35,000 ASCO members). We celebrated the 40th anniversary of the National Cancer Act, and we can be proud of what has been achieved in cancer care since then, including a dramatic increase in the number of cancer survivors, nearly 14 million today, up from just 3 million in the 1970s. And not only are cancer survivors living longer, they are living better quality of lives. The theme of my Presidential year was Collaborating to Conquer Cancer, which I took from the lessons we have learned from our experiences of pediatric oncology. My view is that the remarkable successes we have had in pediatric oncology, including a nearly 80% 5-year survival rate, would not have been possible without collaborations, and that our collective goal to conquer cancer depends more than ever on partnering within and across specialties. Developing curative regimens and other advances in pediatric oncology has demonstrated what can be accomplished through collaboration and through the understanding of multidisciplinary care. The lessons we learned in pediatric oncology can be applied in medical oncology as well. I believe that pediatric oncology can serve as a model for the future, a future in which we achieve the goal of conquering cancer for all patients. n

1880s Use of Radical Mastectomy Surgeon William Halsted pioneers a new approach in removing breast tumors, in which the entire breast, surrounding lymph nodes, and chest muscles are removed.

1903 Radiation Is Used to Treat Cancer Doctors report the first successful use of radium to treat two Russian patients with skin cancer.

1943

Introduction of the Pap Test The Pap test, named for its inventor George N. Papanicolaou, MD, PhD, enables doctors to detect and treat cervical cancers or precancerous cells before they spread. Since the 1950s, the Pap test has helped reduce U.S. cervical cancer deaths by nearly 70%. continued on page 192

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CELEBRATING ASCO’s History Past Presidents continued from page 191

The Promise of Genomics George W. Sledge, Jr, MD ASCO President, 2010-2011

y year as President of ASCO was one of momentous change, not just for ASCO, but for health care and for cancer biology as well. The theme of my Presidency was Patients, Pathways, and Progress. “Pathways” referred to the molecular pathways that are becoming increasingly important in the targeted treatment of cancer and to the research pathways through which new drugs are developed. “Progress” referred to the advances that have been made in the treatment of cancer, but also took into account our future commitments to our patients through our continued passion for clinical cancer research, the increased understanding of cancer molecular biology that lead to research advances, and our strong belief that progress requires continued commitment from governments around the world to support cancer research in the lab and in the clinic. During my Presidential address at ASCO’s 47th Annual Meeting, I talked about meeting the challenges of the genomic era as a profession in several ways, including through a well-trained and motivated workforce, a vibrant clinical trials system, and a rapid learning system for oncology. I stated that as we go forward in this genomic era, we must also look back. Back to the humane standards that have forever guided our profession. Back to our belief that patients always come first. Back to the realization that the pathways forward always flow from that which is best in the human spirit: our thirst for useful knowledge, our compassion for our fellow beings, and our belief in their essential dignity. n

Personalizing Cancer Care Richard Schilsky, MD ASCO President, 2008–2009

uring my Presidency we completely revamped the way the ASCO Board of Directors works by creating various subcommittees and a much more deliberate strategic planning process. In effect, the Board members took more ownership of ASCO’s agenda, planning the future of the Society rather than dealing with its multiple operational aspects. It was an important change for ASCO. My theme was Personalizing Cancer Care and I was pleased that my Presidential speech was enthusiastically received. However, as I was leaving the hall a patient advocate stopped me

1947 First-ever Remission of Pediatric Leukemia Sidney Farber, MD, achieves the first partial remission of pediatric leukemia in a 4-yearold girl using the drug aminopterin.

1949

First Chemotherapy Drug Approved Nitrogen mustard is approved by FDA in the treatment of Hodgkin lymphoma.

and said that she was very disappointed with my speech. I asked why? She said all I talked about was molecular pathology and genotyping. To her, personalized medicine meant that the doctor gets to know each patient as an individual and delivers the kind of personalized care they need. As physicians, our goal is to understand the needs of each patient and then provide a treatment plan built around a set of personalized needs and goals. The “Sometimes in our desire to patient advocate’s comment made me rereach a scientific understanding member that sometimes in our desire to of cancer, we forget that our reach a scientific understanding of canmain objective is to connect with cer, we forget that our main objective is and care for the patient.” to connect with and care for the patient. I’ll never forget that encounter. n

One Community

Nancy E. Davidson, MD ASCO President, 2007–2008

y Presidential theme was One Community. I think that theme continues to express much of our goal in oncology, which is to make sure that all members of the cancer care team work together—oncologists, nurses, scientists, nutritionists, psychologists, social workers, administrators, and others. I also had the privilege to be the first President to work an entire term with our CEO, Dr. Allen Lichter. Allen and I talked a lot about the likelihood that cost was going to be ever more important in the overall discussion of how we deliver health care in this country. Some ASCO members felt that doctors and patients shouldn’t talk about money; they should only focus on care. However, we decided that it was unrealistic to avoid that conversation. “As health-care providers it is our So we launched the Cost of Care Task obligation to talk about costs Force, and its first challenge was to with our patients.” tackle something I brought up, which was that cost is a side effect, just like losing your hair or having low blood cell counts, and as health-care providers it is our obligation to talk about costs with our patients. I’m proud of the role that ASCO is continuing to play in advocating ways to provide the highest quality of oncology care in the most cost-effective manner. n

1958

Combination Chemotherapy Achieves Remissions in Leukemia NCI scientists demonstrate that combination chemotherapy can cause remissions in both children and adults with acute leukemia.

1950s-1960s Cancer Is Linked to Smoking Studies begin linking smoking as a major cause of cancer, especially lung cancer.

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CELEBRATING ASCO’s History Multidisciplinary Interactions Gabriel N. Hortobagyi, MD, FACP ASCO President, 2006–2007

conferences, and the training of young oncologists. Looking forward, ASCO Presidents should use their bully pulpit to emphasize issues of quality of care, rapid translation of research into practice, championing the rights of cancer patients, and partnering with patient advocates to positively influence the political process. Despite the regulatory maze and increased bureaucracy, oncology continues to be the greatest of professions, enormously rewarding for those who practice for the right reasons—combinB:8.25” ing patient care, research, and the training of our next generation of cancer care T:7.5” providers. n S:6.75”

s my Presidency gradually fades into the past, it is sobering to reminisce on how exciting it was. ASCO is a great organization with an amazing staff and a solid mission. Chairing the Board meetings was clearly a highlight of my Presidency because of the vast talent and collective wisdom that is brought to bear with each issue under discussion. Cabozantinib is not approved for Recruiting Allen Lichter, MD, as under investigation in this trial. CEO was a thrill. In partnership with Allen, we took the first steps to make ASCO less dependent on Pharma support. Future ASCO Presidents should continue to seek alternative sources of revenue for our Society, to avoid the appearance of any conflict of interest. My theme was Multidisciplinary Interactions and the emphasis on serving all ASCO constituencies, especially the international member-

the use

INVESTIGATIONAL PHASE 3 TRIAL CURRENTLY ACCRUING

Cabozantinib vs everolimus phase 3 trial in metastatic renal cell carcinoma (RCC)

“Today, thanks to a vigorous International Affairs Committee, ASCO influences oncology services on all four corners of the world, and partners with multiple regional societies in educational conferences, and the training of young oncologists.” ship, which had been an “orphan” contingent for many years. Today, thanks to a vigorous International Affairs Committee, ASCO influences oncology services on all four corners of the world, and partners with multiple regional societies in educational

1960 Philadelphia Chromosome Is Linked to Leukemia Researchers in Philadelphia identify a chromosomal abnormality linked to many leukemias. A decade later, it is discovered that the abnormality occurs when chromosomes 9 and 22 switch places in a process called translocation. continued on page 194

KEY ELIGIBILITY CRITERIA • Diagnosis of RCC with a clear cell component

• Presence of measurable disease • Progression after prior treatment with a VEGFR-targeting tyrosine kinase inhibitor (TKI)

PRIMARY ENDPOINT Progression-Free Survival SECONDARY ENDPOINTS Overall Survival Objective Response Rate RCC (N=650) • Clear cell histology • Measurable disease (RECIST 1.1) • Progression after prior treatment with a VEGFR-targeting TKI

Cabozantinib 60 mg QD Randomization (1:1)

Global, randomized, open-label, controlled trial

Everolimus 10 mg QD

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CELEBRATING ASCO’s History Past Presidents

FDA-Approved Drugs to Use as Single Agents or in Combination Chemotherapy

continued from page 193

Quality Cancer Care Margaret A. Tempero, MD ASCO President, 2003-2004

en years ago, at ASCO’s Annual Meeting, we were celebrating 40 Years of Quality Cancer Care. We have certainly seen many improvements in cancer care quality since then, especially in more effective agents and patient-centeredness care. When I joined ASCO in 1984, I never imagined that I would be President of what is now the leading organization of clinical oncologists in the world. Certainly we have to credit the vision of the Founders and the subsequent hard work of thousands of ASCO volunteers for our success. In 2004, we were celebrating the clinical research and innovation that enabled three new targeted therapeutics, cetuximab (Erbitux), gefitinib (Iressa), and bevicizumab (Avastin), to receive FDA approval, strengthening hope of safer and more effective cancer treatments for our patients. So far this year, a number of agents have been approved by FDA in the treatment of cancer. Last “Our job is to give back the best year, there were 13 new chemotherawe have: The highest quality care peutics approved, so we are witnessing and the latest innovations.” rapid advancements in more targeted cancer therapy for our patients. (See sidebar at right.) When I gave my Presidential address a decade ago, I quoted the words Arnoldus Goudsmit used to describe the true center of ASCO’s mission, the “improved diagnosis, treatment, well being, and longevity” of patients with cancer. Fifty years later, that sentiment remains the cornerstone of ASCO’s mission. Our patients are our precious gift. They teach us and inspire us every day. They advance our knowledge by participating in clinical trials, often knowing that their most important benefit is a societal one, the gift of information. Our job is to give back the best we have: The highest quality care and the latest innovations. This way, we can truly help our patients walk in hope—not in fear— and as long as we remain true to our purpose, we will not fail. n

1965 Chemotherapy Regimen Leading to Eventual Cure in Hodgkin Lymphoma

EARLY 1970s Use of Radioactive “Seeds” Is Increased Increased use of radioactive “seeds” targets prostate and other cancers, delivering highdose radiation to the tumor while leaving healthy tissue relatively unaffected.

Research led by Vincent DeVita, MD, finds that MOPP chemotherapy cures up to 50% of patients with advanced Hodgkin lymphoma.

2014 Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic NSCLC with disease progression on or who are intolerant to crizotinib; mercaptopurine as a 20 mg/mL oral suspension for the treatment of acute lymphoblastic leukemia as part of a combination regimen; siltuximab for the treatment of patients with multicentric Castleman’s disease who are human immunodeficiency virus-negative and human herpesvirus-8-negative; ofatumumab in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate; ramucirumab as a single agent in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma; ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukemia (ibrutinib was approved in 2013 for the treatment of mantle cell lymphoma); trametinib and dabrafenib for use in combination in the treatment of unresectable or metastatic BRAF V600E or V600K mutation metastatic melanoma.

2013 Crizotinib for ALK-positive advanced non-small cell lung cancer; i brutinib and lenalidomide in the treatment of mantle cell lymphoma; obinutuzumab for use in combination with chlorambucil in the treatment of chronic lymphocytic leukemia; pertuzumab injection for use in combination with trastuzumab and docetaxel as neoadjuvant treatment for HER2-positive breast cancer; paclitaxel in combination with gemcitabine for first-line treatment of advanced adenocarcinoma of the pancreas; afatinib and erlotinib for the first-line treatment of EGFR exon 19 deletions or exon 21 substitution mutations metastatic non– small cell lung cancer; trametinib for BRAF V600E or V600K mutation advanced melanoma; dabrafenib for BRAF 600E mutation metastatic melanoma; ado-trastuzumab emtansine as a single agent in HER-2 positive advanced breast cancer patients who received prior therapy with trastuzumab and a taxane; doxorubicin hydrochloride liposome injection for advanced ovarian cancer and for AIDS-related Kaposi’s sarcoma; bevacizumab for use in combination with fluoropyrimide-irinotecan or fluoropyrimidine-oxaliplatin-based chemotherapy for metastatic colorectal cancer.

LATE 1960s -EARLY 1970s Screening Tests for Colorectal Cancer Reduce Deaths Guaiac fecal occult blood test, flexible sigmoidoscopy, and colonoscopy are introduced, enabling physicians to detect precancerous growths and early-stage cancers in the colon.

1971

National Cancer Act Becomes Law President Richard M. Nixon signs the National Cancer Act, which led to a major expansion of cancer research in the United States.

Vincent DeVita, MD

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CELEBRATING ASCO’s History Cancer Prevention

Quality of Cancer Care

Paul A. Bunn, Jr, MD ASCO President, 2002–2003

Joseph S. Bailes, MD ASCO President, 1999–2000

ne highlight of serving as ASCO President is working with the outstanding staff—to name just a few, Executive Vice President Charles M. Balch, MD; Chief Operating Officer Ron Beller, PhD; Jean Colvard; Roseanna Thoman; and all the Department heads. During my Presidency, we undertook some very exciting initiatives. One was the elevation of the Cancer Prevention Task Force to full committee status, which allows the Society to focus more effectively on the creation of cancer education and prevention initiatives. Part of ASCO’s strategic planning was to be-

nder my leadership as President, ASCO initiated the largest quality of cancer care study ever done. Called the National Initiative for Cancer Care Quality (NICCQ), we looked at more than 60 quality measures for stage I to III breast cancer and stage II to III colorec-

“We set about revising the ASCO tobacco control policy; the ultimate goal was the global elimination of tobacco products.” come the authoritative resource for cancer. Since lung cancer is the number one cancer killer worldwide, I thought that we should lead in prevention initiatives. So we set about revising the ASCO tobacco control policy; the ultimate goal was the global elimination of tobacco products. In part, the policy called for efforts to increase tobacco taxes, expand prevention programs, limit promotions, and impose trade restrictions. It was a bold move, and one that I am proud of. n

You wouldn’t accept ambiguity here. Why would you in a breast cancer recurrence test? 1970s CT Scanning Provides Clearer Images of Tumors and Guides Radiation Researchers perform the first CT scan on a human, a woman with a suspected brain tumor. Over the following decades, CT scanning enables doctors to assess the size, shape, and location of many types of tumors, and to target radiation and surgery without harming healthy tissue. continued on page 196

Intermediate…now what? The answer is MammaPrint®. With binary Low Risk/High Risk classiﬁcatons, MammaPrint provides up to 39% more deﬁnitve results1. No wonder MammaPrint is the fastest growing breast cancer recurrence assay2.

Convenient online ordering available at www.agendia.com

Come visit us at ASCO booth #16025

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CELEBRATING ASCO’s History Science vs Practice

Past Presidents continued from page 195

tal cancer. We identified areas in need of improvement and suggested follow-up efforts to target and improve the quality of cancer care. Supported largely by Susan G. Komen for the Cure, the study was a major undertaking that actually became the “It was very important to get springboard for ASCO into cancer care our international colleagues quality research and education. invested in ASCO so that we Now, the Society is globally recogcould increase the organization’s nized as the leader in cancer care qualglobal status. And we have.” ity. If I reflect back on my Presidency, I think my part in launching NICCQ was the highlight of an extremely rewarding year. And the reason that ASCO continues to grow is that we are viewed as an evidence-based international organization that puts the patient with cancer first. n

AACR–ASCO Transition George P. Canellos, MD ASCO President, 1993–1994

y Presidency was a transitional year; it was the first time that ASCO had a meeting separate from the American Association for Cancer Research. Since ASCO was thought to be simply a science-light organization that focused solely on clinical trials, the pressure was on to establish an independent scientific presence. I planned for our Annual Meeting to have more science than usual, and ASCO has continued to maintain that solid scientific presence. A contract group was managing ASCO at the time, and it became apparent that we needed to take a permanent role in the organization’s continuous activities. So we offered Dr. John Durant the position of Executive Vice President, and he was later confirmed in the position by my successor. ASCO’s road to indepen“Since ASCO was thought dence and eventually to self-publishing the to be simply a science-light Journal of Clinical Oncology had begun. organization that focused solely Also during my term, Dr. Bernard on clinical trials, the pressure was Fisher was wrongly accused of running on to establish an independent an organization that had some problems scientific presence.” with its data. Breast cancer advocates were up in arms; the NCI was upset—a real mess. Dr. Fisher was subsequently vindicated. At the ASCO Annual Meeting that I chaired, there were inquiries about having him speak at the Plenary Session. Naturally the presentations were already booked, but we altered the session, eliminating certain talks to make room for Dr. Fisher. I gave him a big hug when he stepped to the lectern, and it set off a roaring ovation from the packed hall. He did a marvelous job. n

Bernard Fisher, MD ASCO President, 1992-1993

My year as President was a busy one. Aside from continuing my research and directing the activities of the National Surgical Adjuvant Breast and Bowel Project, I was drowned by the vast amount of information that was sent to me by ASCO headquarters. At the onset of my Presidency, I discovered that a crisis was brewing regarding ASCO’s mission. Since subsequent Annual Meetings of the Society were no longer to be held in conjunction with the American Association for Cancer Research, many members felt that ASCO was abandoning its scientific objectives and directing its course toward private-practice issues. On the other hand, private-practice oncologists were concerned that ASCO was not providing them with a platform for discussing their problems related to reimbursement, government affairs, and education of oncologists. During my tenure, I was more concerned with ASCO’s relation with research. I firmly believed that the future vitality, integrity, and justification for the Society would depend on how well research enveloped its membership. I thought that a widening gap between physicians and investigators could not only threaten the welfare of patients, but as clinicians got further away from science, the hope for “ASCO members must base progress in curing and preventing cantherapeutic decision-making cer would diminish. In my Presidential on information obtained using address, I noted a statement by Nobel scientific methodology.” Laureate Sir Peter Medewar, indicating that to deride any aspect of science, be it fundamental, basic, or clinical, is the ultimate foolishness, the last word in poverty of spirit and meanness of mind. While I was less than enthusiastic about ASCO’s role in the public issues arena, I did believe that ASCO should be used as a bully pulpit to express its positions on selected public issues related to its major goal, ie, promoting medical care based on science. Two decades later, I still maintain that all members of ASCO must have the same objectives relating to the prevention and cure of cancer: They must base therapeutic decision-making on information obtained using scientific methodology rather than empiricism, anecdotalism, and inductivism, which, unfortunately, continue to be used by too many physicians. n

1975–1976 First Adjuvant Chemotherapy Increases Cure Rates for Breast Cancer Drs. Bernard Fisher and Gianni Bonadonna show that chemotherapy given after surgery prolongs the lives of women with early-stage breast cancer. Adjuvant chemotherapy later becomes a cornerstone of care for other common cancers, including colon and lung cancer.

Bernard Fisher, MD

Gianni Bonadonna, MD

1986 Late 1970s Growing Use of Mammography Saves Lives Mammography becomes increasingly common, resulting in early detection of breast cancer, and contributing to a 27% reduction in breast cancer mortality in women since 1975.

Tamoxifen Reduces Breast Cancer Recurrence Tamoxifen is approved by FDA as adjuvant therapy, reduces breast cancer recurrence, and dramatically increases survival.

Early 1990s 3D Radiation Increases Precision, Safety of Therapy 3D radiation treatment plans increases precision and safety of therapy, minimizing the damage to healthy tissue.

Cancer Deaths Begin to Decline For the first time since recordkeeping began in the 1930s, cancer mortality rates begin to decline. Between 1991 and 2008, the death rate has fallen by 18%.

ASCOPost.com | MAY 15, 2014

PAGE 197

CELEBRATING ASCO’s History Journal of Clinical Oncology Emil J. Freireich, MD ASCO President, 1980–1981

During my Presidency, we decided to increase ASCO’s size to give clinical investigators a better position in the medical world. To that end, I decided that the Society needed its own journal. At that time, we sent our papers to Blood or Cancer Research, where, in my estimation, they received poor treatment. I charged the Science and Publications Committee to develop a plan for the new journal. Led by Emil Frei III, MD, the committee worked long and hard to design guidelines for the journal and to select its first editor, Joseph R. Bertino, MD. The Journal of Clinical Oncology was born, and its continued success as one of the nation’s top-ranked journals is very satisfying. I also felt that ASCO needed to generate more income than it was getting from membership dues. I decided to bring in commercial exhibits, which helped transform the Society. For one, we now had enough money to support our publica“My advice to young oncologists tion and help us initiate grants and educoming into this great field is to cational programs. retain a sense of urgency!” Unlike other scientific societies, ASCO focused on patient-oriented studies. It’s great to cure mice and treat cell lines and isolate genes, but if we’re going to cure cancer, it is going to take talented physicians working at the bedside and in clinical trials. All of our patients are battling a lethal disease, and my advice to young oncologists coming into this great field is to retain a sense of urgency!

■

The Consequence Is Cure Vincent T. DeVita, Jr, MD ASCO President, 1977–1978

y Presidency was the first year that the Annual Meeting hit 10,000 attendees, which at the time we thought was a huge number—it seemed that we’d hit the ceiling. It was about 9 years after we published the results from our study of combination chemotherapy (MOPP) in the treatment of advanced Hodgkin’s disease, which was the first example of the ability to cure advanced can“The most important cer in adults consequence of using with drugs. So I titled my Presidential chemotherapy for Hodgkin’s speech “The Consequences of the Chedisease was its cure.” motherapy of Hodgkin’s Disease.” Given

Sentinel Lymph Node Biopsy Determines Cancer Spread This surgical technique becomes a less invasive way to assess whether cancer has spread in patients with early-stage melanoma. Sentinel lymph node biopsy is later used in women with breast cancer.

The Camaraderie of ASCO James F. Holland, MD ASCO President, 1976–1977

ncologists are occupied with an unusual kind of medicine, and, as a result, we are exposed to enormous personal stress and strain, because patients we care for are profoundly sick “Part of being able to sustain with potenoneself in oncology is to have tially fatal disthe camaraderie of fellow eases. As a oncologists.” group, we deal with the possible mortality of those for whom we are responsible far more than physicians of most other specialties. So, an important part of being able to sustain oneself in oncology is to have the camaraderie of fellow oncologists, kindred souls who have the same experiences, who are facing the same challenges, and who understand. It is not that misery loves company, but rather that there is strength in union. ASCO has served wonderfully for me and for many others to maintain the recognition that we are all in this long and difficult chore together. n

1997

Antiemetic Drug Ondansetron Is Approved Ondansetron is approved by FDA to prevent vomiting caused by chemotherapy and radiation.

the use of the word “consequences,” everyone in the audience assumed that I was going to speak about the bad effects of the chemotherapy. Remember, at that time most people were still skeptical about the curative value of chemotherapy. The title turned out to be an interesting play on words, because the central point of the speech was that the most important consequence of using chemotherapy for Hodgkin’s disease was its cure. To give the speech’s meaning historical perspective, the original paper we published in 1970 on MOPP was the most cited paper in the history of the Annals of Internal Medicine. It took another 11 years for MOPP to fully diffuse into the practice of oncology, so when I gave my Presidential speech it was not fully out there. Nevertheless, it remained the standard of care for 25 years. n

1992-1994 Taxanes Emerge as a Vital Chemotherapy Option Paclitaxel is approved for advanced ovarian cancer. Over the next decade the drug also proves effective for breast cancer, extending lives and delaying disease progression

First-Ever Targeted Cancer Drug, Rituximab Is Approved The first molecularly targeted cancer drug, rituximab, is approved by FDA to treat patients with B-cell non-Hodgkin lymphoma that no longer responds to other treatments.

Surgery Cures Some Patients With Advanced Colon Cancer

Late 1990s Prophylactic Surgery Helps Prevent Breast and Ovarian Cancers in High-Risk Women Researchers discover that prophylactic surgery in women with BRCA mutations can reduce breast and ovarian cancer risk by 90% or more.

Researchers find that some patients with colon cancer whose cancer has spread to the liver only can be cured with surgery. continued on page 201

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ďŹ&#x201A;ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2 Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs placebo (47% vs 53%, respectively)1 37% reduced risk of death • HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Learn L earn m more ore a att X XtandiHCP.com tandiHCP.c com

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARYOF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 (%) Grade 3-4 (%)

General Disorders Asthenic Conditionsa 50.6 Peripheral Edema 15.4 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 Arthralgia 20.5 Musculoskeletal Pain 15.0 Muscular Weakness 9.8 Musculoskeletal Stiffness 2.6 Gastrointestinal Disorders Diarrhea 21.8 Vascular Disorders Hot Flush 20.3 Hypertension 6.4 Nervous System Disorders Headache 12.1 Dizzinessb 9.5 Spinal Cord Compression and 7.4 Cauda Equina Syndrome Paresthesia 6.6 Mental Impairment Disordersc 4.3 Hypoesthesia 4.0 Infections And Infestations Upper Respiratory Tract 10.9 Infectiond Lower Respiratory Tract And 8.5 Lung Infectione Psychiatric Disorders Insomnia 8.8 Anxiety 6.5 Renal And Urinary Disorders Hematuria 6.9 Pollakiuria 4.8 Injury, Poisoning And Procedural Complications Fall 4.6 Non-pathologic Fractures 4.0 Skin And Subcutaneous Tissue Disorders Pruritus 3.8 Dry Skin 3.5 Respiratory Disorders Epistaxis 3.3 a b c d e

Placebo N = 399 Grade 1-4 (%) Grade 3-4 (%)

9.0 1.0

44.4 13.3

9.3 0.8

5.3 2.5 1.3 1.5 0.3

24.3 17.3 11.5 6.8 0.3

4.0 1.8 0.3 1.8 0.0

1.1

17.5

0.3

0.0 2.1

10.3 2.8

0.0 1.3

0.9 0.5 6.6

5.5 7.5 4.5

0.0 0.5 3.8

0.0 0.3 0.3

4.5 1.8 1.8

0.0 0.0 0.0

0.0

6.5

0.3

2.4

4.8

1.3

0.0 0.3

6.0 4.0

0.5 0.0

1.8 0.0

4.5 2.5

1.0 0.0

0.3 1.4

1.3 0.8

0.0 0.3

0.0 0.0

1.3 1.3

0.0 0.0

0.1

1.3

0.3

Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fallrelated injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology]. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology ]. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology ]. USE IN SPECIFIC POPULATIONS Pregnancy- Pregnancy Category X [see Contraindications]. XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, 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 Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 and over, while 25 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). • Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. • Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of treatment with XTANDI. • Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. • Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. • Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI. Manufactured by: Manufactured for and Distributed by: Catalent Pharma Solutions, LLC, Astellas Pharma US, Inc., St. Petersburg, FL 33716 Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Issued: August 2012 12A005-ENZ-BRS Rx Only © 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 0131-076-8930

The ASCO Post | MAY 15, 2014

PAGE 202

CELEBRATING ASCO’s History

Fred J. Ansfield, MD, FASCO

Robert W. Talley, MD, FASCO

Jane Cook Wright, MD, FASCO

Arnoldus Goudsmit, MD, PhD, FASCO

ganizing a membership committee and recruiting new members into ASCO.

William Wilson, MD, FASCO

Herman A. Freckman, MD, FASCO

phosphamide, 5-FU, methotrexate, and prednisone in advanced breast cancer. During the formation of ASCO, Dr. Ansfield was responsible for outlining a long-range plan for the institution of clinical oncology as a specialty in medicine, with a primary focus on the training of specialists in the field. Dr. Ansfield served as ASCO’s third President, from 1966 to 1967. Harry F. Bisel, MD, FASCO Dr. Bisel was born on June 17, 1918, in Manor, Pennsylvania. He received his medical degree from the University of Pittsburgh in 1942 and did graduate work at the University of Pennsylvania and Harvard Medical School. Dr. Bisel was the first formally trained oncologist hired by the Mayo Clinic. He went on to found the Mayo Clinic Section of Medical Oncology and was chairman from 1963 to 1972. He retired from the Mayo Clinic in 1983. Dr. Bisel was an early researcher in advanced breast cancer, investigating the efficacy in clinical trials of combinations of

2004 FDA Approves the First AntiAngiogenic Drug, Bevacizumab Bevacizumab is approved to treat colon cancer. It has since become an important treatment for patients with advanced lung, ovarian, and kidney cancers, and for certain brain tumors.

Harry F. Bisel, MD, FASCO

agents, including 5-FU, cyclophosphamide, and prednisone with or without vincristine, among others. As a founding member of ASCO, Dr. Bisel was charged with outlining a longrange plan for the institution of clinical oncology as a specialty in medicine. He also conceptualized the idea that “one full day … be held annually for scientific meetings.” Dr. Bisel was elected the first President of ASCO, serving from 1964 to 1965. Herman A. Freckman, MD, FASCO Dr. Freckman was Director of Cancer Chemotherapy at The Christ Hospital in Cincinnati and an early researcher in such chemotherapeutics as intra-aortic infusion of 5-FU and cyclophosphamide in the treatment of lung cancer; chlorambucil and prednisolone for disseminated breast carcinoma; and intra-aortic infusion of 5-FU, methotrexate, cyclophosphamide, vinblastine, and vincristine, alone or in combination for advanced colorectal cancer. Dr. Freckman was responsible for or-

2004, 2006 Two Targeted Drugs for Advanced Colon Cancer Are Approved Cetuximab and panitumumab are approved to treat metastatic colon cancer.

Arnoldus Goudsmit, MD, PhD, FASCO A native of Amsterdam, Dr. Goudsmit earned his medical degree in 1931 from the University of Amsterdam and moved to New York 2 years later to study at Cornell University Medical College, where he received his PhD degree in biochemistry. He later studied internal medicine at the Mayo Clinic in Rochester, Minnesota. As an internist in Youngstown, Ohio, in the 1950s, Dr. Goudsmit was the first physician there to use nitrogen mustard to treat a woman with cancer. Dr. Goudsmit credited his experience as the first President of the Ohio chapter of the American Society of Internal Medicine with helping him to establish ASCO. A pioneer in advancing the field of chemotherapy, Dr. Goudsmit published a report of studies of heparin and cyclophosphamide in the treatment of lung cancer while he was organizing the launch of ASCO, drafting its constitution and organizational bylaws, and arranging for the Society to be incorporated. Dr. Goudsmit remained dedicated to advancing research in chemotherapy throughout his career, and as late as the 1980s, he was involved in an Eastern Cooperative Oncology Group study of combinations of chemotherapy agents for advanced gastric cancer.

2006 First Vaccine Is Approved to Prevent Cervical Cancer The FDA approves the first vaccine to prevent infection with two high-risk strains of HPV that cause about 70% of all cervical cancers. Studies have also linked HPV infection to head and neck, vulvar, and anal cancers.

Robert W. Talley, MD, FASCO When Dr. Goudsmit was planning for the establishment of ASCO, he asked Dr. Talley to be responsible for the area of “clinical science,” including the development of a comprehensive list of contemporary drugs and their application in the treatment of cancer. The list compiled by Dr. Talley was used to develop scientific programming for the ASCO Annual Meeting and other Society-sponsored educational initiatives. William Wilson, MD, FASCO At the early organizational meetings in the establishment of ASCO, Dr. Wilson was tasked with proposing a budget that would address the creation of a Society journal and other educational initiatives, including the Annual Meeting. Jane Cook Wright, MD, FASCO The only woman and the only African American among the original ASCO founders, Dr. Wright served as the Secretary-Treasurer during the formation and early years after ASCO’s establishment. Dr. Wright was the last surviving member of the original seven founders, and she died on February 19, 2013, at the age of 93. In recognition of Dr. Wright’s contribution to cancer research, ASCO and the Conquer Cancer Foundation created the Jane C. Wright, MD, Young Investigator Award in 2011. To read Dr. Wright’s full biography, see the Pioneers in Oncology feature on page 204. n References 1. DeVita VT, Chu E: A history of cancer chemotherapy. Cancer Res 68:8643-8653, 2008. 2. Krueger GM, Alexander LI, Whippen DA, et al: Arnoldus Goudsmit, MD, PhD: Chemotherapist, visionary founder of the American Society of Clinical Oncology, 19092005. J Clin Oncol 24:4033-4036, 2006.

2010, 2011 Ipilimumab Is Shown to Improve Survival for Patients With Advanced Melanoma Ipilimumab is found to improve survival and delay disease progression in patients with advanced melanoma. The drug is approved in early 2011.

continued on page 204

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CELEBRATING

ASCO’s History, 1964–2014 ASCO’s Visionary Founders By Jo Cavallo

n April 9, 1964, seven physicians—Jane Cooke Wright, MD, FASCO; Arnoldus Goudsmit, MD, PhD; Fred J. Ansfield, MD, FASCO; Harry F. Bisel, MD, FASCO; Herman H. Freckman, MD, FASCO; Robert W. Talley, MD, FASCO; and William Wilson, MD, FASCO—met for lunch at the Edgewater Beach Hotel in Chicago. They wanted to discuss the formation of a medical organization that focused on the clinical care of cancer and gave physicians treating patients with cancer a forum to share ideas and information. At the time of that initial meeting—the first of four organizational meetings— there were not many physicians treating cancer. In fact, oncology was not yet a recognized discipline, and attending physicians were all general medicine doctors. Treatment for the disease centered on surgery and radiotherapy, and pessimism about making progress in cancer was high, but cure rates were low.1 Although the term “chemotherapy” had been coined more than half-a-century before by German chemist Paul Ehrlich to describe the use of chemicals to treat disease, the era of chemotherapy did not begin until 1942, when physicians at New Haven Hospital in Connecticut successfully used nitrogen mustard to treat a patient with advanced lymphosarcoma. A decade later, Dr. Goudsmit used nitrogen mustard to treat a woman diagnosed with cancer at the Cleveland Clinic. Told by the institution’s physicians that there was no therapy available for her disease, she sought treat-

1998, 2006 Trastuzumab Has Major Impact on Breast Cancer Care In 1998, the FDA approved trastuzumab after research showed that adding the monoclonal antibody to chemotherapy dramatically increases survival for women with advanced breast cancer that over-produces HER2. In 2006, the drug was approved as part of adjuvant therapy for women with early-stage HER2-positive breast cancer.

ment from Dr. Goudsmit, an internist in Youngstown, Ohio. She lived for at least another 10 years. Dr. Goudsmit, along with Dr. Ansfield, is largely credited with organizing the effort to establish the Society.2 It was his belief that the advent of drugs in the treatment of cancer called for a new breed of physicians who focused on chemotherapy. They would later become known as medical oncologists. “If it hadn’t been for the drugs, there would have never been an organization as what we have now,” said Dr. Goudsmit. “It’s only when … anticancer drugs became available that there was an opportunity for the oncologists.”

ASCO’s Defining Goals Initially called the American Association of Clinical Oncologists—Dr. Wright later suggested the new organization be called the American Society of Clinical Oncology—the founders held the fourth and final organizational meeting on November 5, 1964, at the Lakeshore Hotel in Chicago. They sent invitations to join ASCO to 134 physicians. The invitations included a copy of Dr. Goudsmit’s essay, “Some Considerations Relative to the Present Status of Clinical Oncology,” in which he outlined shifting attitudes about the diagnosis and treatment of cancer and “the trend toward a greater patient-related orientation,” necessitating the need for an organization such as ASCO. Although some physicians declined the invitation to join the fledgling clinical oncology organization, claiming the

formation of a new society was unnecessary, 90 physicians joined ASCO, and 51 charter members attended the Nov ember meeting. During the meeting, Dr. Goudsmit announced six ambitious goals he had developed for ASCO: • Provide the form, meeting ground, and means for formal and informal communication and mutual education for and among clinically oriented individuals with special knowledge and training in the field of human neoplastic diseases. • Provide physicians with proper professional educational background material and the opportunity to facilitate their own improved management of neoplastic diseases. • Sponsor or cosponsor the publication of photographs, books, and/or articles on the subject of clinical oncology. The publication of a special journal … is particularly appropriate. (The Journal of Clinical Oncology was launched January 1, 1983.) • Collaborate with other medical and research organizations, national and otherwise, with a view of enhancing professional education in the area of diagnosis and treatment of patients with neoplastic diseases. • Initiate, coordinate, and cooperate in projects of investigation of human neoplastic disease. • Provide a corporate framework for the pursuit of these and related activities.

ASCO’s Evolution ASCO’s first scientific Annual Meeting was held the following year on April

9, 1965, in the Bellevue Stratford Hotel in Philadelphia. More than 70 members and invited guests attended the inaugural event, which featured three presentations on leukemia and multiple myeloma. Today, ASCO has grown to become the world’s leading professional society of multidisciplinary medical professionals who treat people with cancer. Among ASCO’s 35,000 members, including those in the United States and internationally, are clinical oncologists from all oncology disciplines and subspecialties; physicians and other healthcare professionals participating in approved oncology training programs; oncology nurses; and other practitioners with an interest in oncology. Each year, ASCO’s Annual Meeting, which is now held over the course of 5 days, attracts more than 25,000 oncology professionals and features the presentation of more than 4,000 scientific abstracts.

Meet the Founders Fred J. Ansfield, MD, FASCO Along with Dr. Goudsmit, Dr. Ansfield is considered the driving force behind the founding of ASCO. At the time of the formation of ASCO, Dr. Ansfield was Associate Professor of Surgery, Cancer Research Hospital at the University of Wisconsin in Madison. An early pioneer in the use of chemotherapy, Dr. Ansfield led early clinical studies of fluorouracil (5-FU) in patients with several types of advanced solid-tumor cancers. He later studied the effect of adding vincristine to cyclo-

2001 FDA Approves Imatinib Research by Brian J. Druker, MD, lead to quick approval of imatinib after studies show it halted the growth of chronic myelogenous leukemia. Just weeks later, imatinib was found to also be effective against GIST.

2003 Scientists Decode the Human Genome Scientists announce they have mapped the 3 billion DNA letters in the human genome

2003, 2004 First Targeted Drugs for Lung Cancer Are Approved The FDA approves the first targeted drugs for advanced non-small cell lung cancer, erlotinib and gefitinib.

Dr. Brian Druker

continued on page 202

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

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CELEBRATING

ASCO’s History, 1964–2014 Pioneers in Oncology

ASCO Cofounder Jane Cooke Wright, MD, Defied Racial/Gender Barriers and Helped Usher in the Modern Age of Chemotherapy By Jo Cavallo

Jane Cooke Wright, MD

hen Jane Cooke Wright, MD, met with six other oncologists at the Edgewater Beach Hotel in Chicago on April 9, 1964, to discuss the creation of American Society of Clinical Oncology, the first medical society dedicated to bringing patient-oriented issues to clinical oncology, the Civil Rights Act of 1964 banning discrimination in public places was still 2 months away from being signed into law. The only woman and African American at the table that day, Dr. Wright was used to breaking gender and color barriers in the pursuit of her career in medicine, a career that was perhaps preordained.

Family Dynasty Born on November 30, 1919, in New

York, Dr. Wright was born into something of a medical dynasty. Her paternal grandfather, Dr. Ceah Ketcham Wright, born into slavery, attended Meharry Medical College in Nashville, Tennessee, the first medical school in the South open to African Americans. Her step-grandfather, Dr. William Fletcher Penn, was the first African American to graduate from Yale Medical School. Her father, Louis Tompkins Wright, was one of the first black graduates of Harvard University Medical School and one of the country’s first black surgeons. An early pioneer in cancer research, he established the Harlem Hospital Cancer Research Foundation in 1948 with the goal of encouraging more studies of chemotherapy, then an emerging concept in cancer care. A stellar student, Jane Cooke Wright attended the Ethical Culture School and later the Fieldston School in New York and graduated from Smith College, where she was an art major before turning her sights on medicine. After graduating from Smith in 1942, Dr. Wright received a full scholarship to New York Medical College, where she graduated with honors in 1945 after an accelerated 3-year program. She interned at Bellevue Hospital in New York and completed her residency at Harlem Hospital. Perhaps in honor of

her mother, Corinne Cooke Wright, an elementary school teacher, Dr. Wright became a staff physician with the New York public school system before joining her father at the Harlem Hospital Cancer Research Foundation.

Career Marked by Firsts It was there that the father and daughter team began experimenting with potential anticancer agents both in tissue cultures and in patients, pioneering combinations of chemotherapy, and researching the efficacy of administrating a series of chemotherapeutic drugs in a specific order. They were among the first to test triethylenemelamine, a nitrogen mustard– like compound, as well as the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various types of solid tumor and blood cancers. In their study, seven different folic acid antagonists were administered as single agents or in combination, with most patients experiencing some improvement. Among the seven agents tested, aminopterin and amethopterin (methotrexate) appeared to produce the greatest effect, providing the first evidence of the efficacy of methotrexate against solid tumor cancers.

“Jane played a pivotal role in the development of methotrexate among other chemotherapeutics, and this is a drug that today is among the greatest of all cancer drugs ever developed,” said Clifford A. Hudis, MD, FACP, President of ASCO and Chief, Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center. “Methotrexate forms the backbone of the first curative treatments for breast cancer and other cancers, as well as treatment for other serious diseases such as rheumatoid arthritis. And Jane did all this in the premodern era of molecular biology.”

Imagining Personalized Medicine After the death of her father in 1952, Dr. Wright became the Director of the Harlem Hospital Cancer Research Foundation, and in 1955 she joined the faculty of the New York University Medical Center as Director of Cancer Research, where she focused on correlating the responses of tissue cultures to anticancer drugs with the responses of patients. In a paper describing her study,1 Dr. Wright and her coauthors concluded that primary tissue culture might be a valid method for screening and selecting the most effective checontinued on page 206

Visit CancerProgress.Net to View the Interactive Timeline. Timeline continued from page 202

2012 2011 Second Targeted Melanoma Drug, Vemurafenib, Is Approved The FDA approves vemurafenib in the treatment of patients with advanced melanoma and BRAF mutation.

Two Targeted Drugs in Addition to Chemotherapy Are More Potent for HER2-Positive Breast Cancer Researchers find that using two targeted drugs, pertuzumab and trastuzumab, in combination with standard chemotherapy are more potent than one targeted drug for women with HER2-positive breast cancer, substantially slowing cancer growth.

2013–2014 FDA Approves Multiple Novel Agents for Treating Cancer See sidebar on page 194.

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CELEBRATING ASCO’s History Jane Cooke Wright continued from page 205

motherapy agent for specific tumors in individual patients, a precursor to the concept of personalized medicine. Excited by the possibility of drug de-

“Dr. Wright’s story is unbelievably inspiring and even astounding. Imagine an African American woman sitting with six white men in 1964 and dreaming of an organization that would be focused on the clinical care of patients with can-

Dr. Wright’s story is unbelievably inspiring and even astounding. Imagine an African American woman sitting with six white men in 1964 and dreaming of an organization that would be focused on the clinical care of patients with cancer. What’s amazing about Jane is first simply that she was there. —Clifford A. Hudis, MD, FACP

velopment in the treatment of cancer, Dr. Wright joined the American Association for Cancer Research (AACR) in 1954 to share her research in chemotherapeutics and to learn from other researchers how best to extend the lives of patients with cancer. It was this desire to focus her energies on the clinical care of patients that led her to the Edgewater Beach Hotel and her meeting with the other six founding members of ASCO: Fred J. Ansfield, MD, Harry F. Bisel, MD, Herman H. Freckman, MD, Arnoldus Goudsmit, MD, PhD, Robert Talley, MD, and William Wilson, MD. In addition to being a founding member of ASCO, Dr. Wright also served as its Secretary/Treasurer until 1967.

cer,” said Dr. Hudis. “What’s amazing about Jane is first simply that she was there. Being a woman in that situation then was a breakthrough, and being an African American was a breakthrough, but to be both was unbelievable.” That same year, President Lyndon B. Johnson named Dr. Wright to the President’s Commission on Heart Disease, Cancer, and Stroke. The commission’s recommendations, including an emphasis on better communication among doctors, hospitals, and research institutions, resulted in the establishment of a national network of cancer treatment centers. In addition to having a full and rewarding professional career, Dr. Wright had a fulfilling personal life, marrying

David D. Jones, Jr, a lawyer, in 1947, and raising two daughters, Jane Wright Jones and Alison Jones. Mr. Jones died in 1976.

Lifetime of Achievements In 1967, Dr. Wright was named Professor of Surgery, Head of the Cancer Chemotherapy Department, and Associate Dean at New York Medical College, making her the highest ranking black woman at an American medical institution. Four years later, Dr. Wright became the first woman president of the New York Cancer Society. After a 40-year career in medical oncology, Dr. Wright retired in 1987. On February 19, 2013, Dr. Wright died in her home in Guttenberg, New Jersey. She was 93. Although the existence of African American physicians, especially African American women physicians, was rare in the United States in the early- and mid-20th century, numbering just a few hundred, Dr. Wright discounted any speculation that she was a victim of racial prejudice. According to her obituary in The New York Times,2 Dr. Wright said in an interview with The New York Post in 1967, “I know I’m a member of two minority groups, but I don’t think of myself that way. Sure, a woman has to try twice as hard, but racial prejudice? I’ve met very little of it.” And then she added, “It could be I met it—and wasn’t intelligent enough to recognize it.”

Lasting Legacy To commemorate the contribution Dr. Wright has made to clinical care and

cancer research, in 2006 the AACR established the AACR–Minorities in Cancer Research Jane Cooke Wright Lectureship, which recognizes outstanding scientists who have made meritorious contributions to cancer research and furthered the advancement of minority investigators in cancer research. In 2011, ASCO and the Conquer Cancer Foundation recognized Dr. Wright’s life achievements to the field of oncology with the creation of the Jane C. Wright, MD, Young Investigator Award. “The Young Investigator Award is a wonderful way to perpetuate Jane’s view and vision of how life and scientific advances should be accomplished. We know that most of the award winners go on to have remarkably productive careers as measured by their scientific contributions and service, and that is the best way to honor her memory,” said Dr. Hudis. “There is a real reward in a lifetime of dedication to a goal, and I think that’s what Jane’s life was all about. She did it in a way that was inspirational to our oncology community, but also to her family, and her children were so proud of her for this. Jane set an example for all of us of how to live a rewarding life.” n References 1. Wright JC, Cobb JP, Gumport SL, et al: Investigation of the relationship between clinical and tissue response to chemotherapeutic agents on human cancer. N Engl J Med 257:1207-1211, 1957. 2. Weber B: Jane Wright, oncology pioneer, dies at 93. New York Times, March 2, 2013.

ASCO Through the Years: Past Presidents 2013-2014: Clifford A. Hudis, MD

1997-1998: Robert J. Mayer, MD

1977-1978: Vincent T. DeVita, Jr, MD

2012-2013: Sandra M. Swain, MD, FACP

1996-1997: James O. Armitage, MD

1976-1977: James F. Holland, MD

2011-2012: Michael P. Link, MD

1995-1996: John H. Glick, MD

1975-1976: Joseph Bertino, MD

2010-2011: George W. Sledge, Jr, MD

1994-1995: Karen H. Antman, MD

1974-1975: Rose Ruth Ellison, MD

2009-2010: Douglas W. Blayney, MD

1993-1994: George P. Canellos, MD

1973-1974: Bayard Clarkson, MD

2008-2009: Richard Schilsky, MD

1992-1993: Bernard Fisher, MD

1972-1973: Paul P. Carbone, MD

2007-2008: Nancy E. Davidson, MD

1991-1992: Martin D. Abeloff, MD

1971-1972: Kenneth B. Olson, MD

2006-2007: Gabriel N. Hortobagyi, MD

1990-1991: Harvey M. Golomb, MD

1970-1971: Jesse L. Steinfeld, MD

2005-2006: Sandra J. Horning, MD

1989-1990: Robert C. Young, MD

1969-1970: Paul Calabresi, MD

2004-2005: David H. Johnson, MD

1985-1986: John R. Durant, MD

1968-1969: Emil Frei, MD

2003-2004: Margaret A. Tempero, MD

1984-1985: Sydney E. Salmon, MD

1967-1968: George C. Escher, MD

2002-2003: Paul A. Bunn, Jr, MD

1982-1983: Saul A. Rosenberg, MD

1966-1967: Fred J. Ansfield, MD

2001-2002: Larry Norton, MD

1981-1982: John E. Ultmann, MD

1965-1966: Michael J. Brennan, MD

2000-2001: Lawrence H. Einhorn, MD

1980-1981: Emil J. Freireich, MD

1964-1965: Harry F. Bisel, MD

1999-2000: Joseph S. Bailes, MD

1979-1980: Charles G. Moertel, MD

1998-1999: Allen S. Lichter, MD

1978-1979: Albert H. Owens, MD

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Patient’s Corner

Learning to Live in the Moment

I’ve been a pancreatic cancer survivor for 8 years. Whether I live 3 more months or 30 more years, I wouldn’t trade this experience for anything. By Laurie MacCaskill, as told to Jo Cavallo

’ve been health conscious all my life. I have never smoked, I eat a healthy diet, and I have maintained a near-daily exercise routine since I was 20. I’m also steadfast about keeping yearly medical checkups and screenings. So when I felt a sharp, lightning-bolt of pain that went from the top of my head down to my toes and nearly knocked me out, I became alarmed. But the stabbing pain left as quickly as it had come, and the residual pain concentrated in the lower right side of my back was more annoying than debilitating. Still, I knew it wasn’t something I should ignore. I saw several doctors and got a variety of diagnoses. After looking at an x-ray, one doctor said that I had gas and needed an enema. I knew that wasn’t the problem, but I did as I was told. The pain persisted. Another doctor told me I had pulled a muscle exercising and should take a few days off from the gym. I knew that wasn’t true either, but again, I did as I was told and stopped exercising. The pain remained, and now I was also losing a bit of weight. I’m a small person—normally just 105 pounds—so that didn’t sound any immediate alarms. All my tests came back negative. Nothing was wrong, I was assured.

But I know my body, and I knew something was wrong. After a colonoscopy and advanced endoscopy screening, I was given a diagnosis of stage III pancreatic cancer. The news was so terrifying, I told the doctor he had the wrong patient’s file; I couldn’t possibly have pancreatic cancer. As far as I knew, pancreatic cancer is a death sentence.

I would like to think that pancreatic cancer is in my past, but I know that with this disease there are no guarantees. So, I’m living my life with as much enthusiasm and compassion as possible. —Laurie MacCaskill

Near-Death Experience I was prescribed capecitabine but had to have emergency surgery. The surgery was unsuccessful, and a few days later I had a Whipple procedure to remove the head of the pancreas and nearby lymph nodes for biopsy. Because the cancer had spread to the duodenum and several lymph nodes, I was prescribed an aggressive regimen of various combinations of chemotherapy that included bevacizumab (Avastin), fluorouracil, oxaliplatin, cetuximab (Erbitux), paclitaxel, gemcitibine, and nabpaclitaxel (Abraxane). I was on chemotherapy for 3 years, and the experience was daunting. I lost my hair, eyelashes, and eyebrows. There were days I was so fatigued and in pain I couldn’t get out of bed. Despite the grueling treatment, I refused to believe that my life was over.

Giving Back It has been 8 years since my diagnosis, and I would like to think that pancreatic cancer is in my past, but I know that with this disease there are no guarantees. So, I’m living my life with as much enthusiasm and compassion as possible. I became a volunteer for the Pancreatic Cancer Action Network, and I am now Chair of its National Board of Directors. I reach out to other pancreatic cancer survivors and try to provide a support system for them. I think I’m making a difference in their lives. I know they are making a difference in mine.

Living in the Moment When you get a diagnosis of pancreatic cancer, you are filled with fear. Having a supportive husband by my side

and an empathetic oncology team monitoring my progress got me through the worst of that time. Now I appreciate every moment of each day and try not to project too far into the future. I don’t know if I am cured of my cancer, but whether I live only another 3 months or 30 more years, I wouldn’t trade this experience for anything. Having cancer has given me so much more than it could ever take away. n Laurie MacCaskill is Chair of the National Board of Directors of the Pancreatic Cancer Action Network and advocates for increased federal research funding for pancreatic cancer. She and her husband Paul divide their time between Los Angeles and Aspen, Colorado.

The ASCO Post Recognizes

June 1, 2014

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Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY PPAR-δ/β Overexpression Increases Colon Tumorigenesis Although it is known that nuclear receptor peroxisome proliferator-activated receptor-δ/β (PPAR-d) is upregulated in colorectal cancer, the role of PPAR-d in tumorigenesis remains uncertain. In a study reported in Journal of the National Cancer Institute, Zuo and colleagues developed a mouse model of intestinally targeted PPAR-d overexpression to simulate PPAR-d upregulation in human colon cancer. Mice with and without targeted PPAR-d overexpression were tested for azoxymethaneinduced colonic tumorigenesis. It was found that targeted PPAR-d overexpression increased colon tumor incidence from 0 of 10 wild-type littermate mice to 9 of 10 mice in PPAR-d-1 and PPAR-d-2 mouse lines and tumor number from 0.47 in wild-type littermates to 2.15 in PPAR-d-1 mice and from 0.44 in wild-type littermates to 1.91 in PPAR-d-2 mice. PPAR-d overexpression reversed resistance to azoxymethane-induced colon tumorigenesis in C57BL/6 mice. Further, PPAR-d overexpression modulated the expression of a number of novel PPAR-d target genes in normal-appearing mouse colon epithelial cells in a pattern that matched changes in colon tumors. The investigators concluded, “Our finding that PPAR-d upregulation profoundly enhances susceptibility to colonic tumorigenesis should impact the development of strategies of molecularly targeting PPAR-d in cancer and noncancerous diseases.” Zuo X, et al: J Natl Cancer Inst 106(4):dju052, 2014.

NOVEL MECHANISMS Inactivation of E3 Ubiquitin Ligase Cbl-b Allows Natural Killer Cells to Control Metastases New therapeutic approaches to blocking inhibitory pathways of the immune system have raised hopes that such treatments might thwart development of metastases. In a study in Nature, Paolino and colleagues have shown that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity permits natural killer cells to spontaneously reject metastatic tumors.

After TAM tyrosine kinase receptors (Tyro3, Axl, and Mer) were identified as ubiquitylation substrates for Cbl-b, treatment of wild-type NK cells with a novel small-molecule TAM kinase inhibitor was shown to dramati-

cally increase their antimetastatic activity in vivo. In mouse models, oral or intraperitoneal administration of the TAM inhibitor reduced the development of murine mammary cancer and melanoma metastases in a natural

killer cell–dependent manner. The investigators also found that the anticoagulant warfarin exerts antimetastatic activity in mice via Cbl-b/TAM receptors in natural killer cells, providing continued on page 210

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Proceed with confidence

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Lab Notes Ongoing Molecular Research continued from page 209

a molecular mechanism for the reported antitumor and antimetastatic effects of warfarin and other anticoagulants. The investigators concluded, “This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a ‘pill’ that awakens the innate immune system to kill cancer metastases.” Paolino M, et al: Nature 507:508512, 2014.

TUMOR MICROENVIRONMENT IL-15 Deletion Linked to Reduced Local Proliferation of B and T Cells and Poorer Outcome in Colorectal Cancer The tumor microenvironment contains a complex network of cytokines that contribute to the nature of intratumoral immune reactions. In a study reported in Science Translational Medicine, Mlecnik and colleagues assessed chromosomal gains and losses and expression of 59 cytokines and receptors and their functional networks in colorectal cancer. The investigators identified changes in local expression of 13 cytokines. Patients with metastatic disease exhibited increased frequency of deletions of cytokines from chromosome 4. In particular, interleukin (IL)-15 deletion was associated with reduced IL-15 expression, higher risk of tumor recurrence, and reduced patient survival. Decreased IL-15 expression was associated with reduced local proliferation of B and T lymphocytes, and patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. The investigators concluded, “These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL-15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.” Mlecnik B, et al: Sci Transl Med 6:228ra37, 2014.

BIOMARKERS IL-17A Promotes and GMCSF Suppresses Circulating Tumor Cells and Metastasis in Colorectal Cancer In a study of the roles of interleukin (IL)-17A and circulating tumor cells in

colorectal cancer metastasis, Tseng and colleagues measured mesenteric circulating tumor cells according to colorectal cancer stage in patients and assessed the interaction of circulating tumor cells and IL-17A in a mouse model of metastasis. Quantification of circulating tumor cells by EpCAM-positive/CD45-negative immunoselection and flow cytometry showed that mesenteric circulating tumor cell levels were higher in stage II disease than in stages I, III, and IV disease, suggesting that circulating tumor cell count after treatment of the primary tumor in early-stage disease may predict risk of metastasis. After invasion of orthotopic tumors in the mouse model, circulating tumor cells exhibited an increase-then-decrease pattern, with a parallel course exhibited by serum IL17A levels and an opposite course exhibited by granulocyte-macrophage colonystimulating factor (GM-CSF) levels. It was found that ablation of IL-17A and administration of recombinant GM-CSF suppressed the increase in circulating tumor cells and prevented metastasis; further, IL-17A promoted cancer cell motility, matrix digestion, and angiogenesis, whereas GM-CSF resulted in elimination of circulating tumor cells by stimulating host immunity. Measurement of serum IL-17A in colorectal cancer patients showed a correlation with disease-free survival. The investigators concluded, “Our results showed that [circulating tumor cells] and IL-17A could serve as prognostic markers and therapeutic targets for [colorectal cancer] metastasis.” Tseng J-Y, et al: Clin Cancer Res. March 27, 2014 (early release online).

TREATMENT RESISTANCE Epigenetic Reprogramming of HOXC10 Results in Endocrine Resistance in Breast Cancer Resistance to aromatase inhibitors is a major problem in treatment of estrogen receptor (ER)-positive breast cancer. In a study reported in Science Translational Medicine, Pathiraja and colleagues found pervasive DNA hyper- and hypomethylation and enrichment for promoter hypermethylation of developmental genes in two breast cancer cell line models of aromatase inhibitor resistance. Methylation of the homeobox gene HOXC10 occurred in a CpG island shore overlapping a functional ER binding site, resulting in diminished HOXC10 expression. Blocking of ER signaling resulted in reduced HOXC10

repression in both cell lines and breast tumors, but also induced concurrent recruitment of EZH2 and increases in H3K27me3, promoting a transition to increased DNA methylation and silencing of HOXC10. Reduction of HOXC10 in vitro and in xenografts resulted in decreased apoptosis and established antiestrogen resistance. Investigation of paired primary and metastatic breast cancer specimens showed that HOXC10 was reduced in tumors that recurred during aromatase inhibitor treatment. The investigators concluded, “We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas [aromatase inhibitors] induce these genes to cause apoptosis and therapeutic benefit, but long-term [aromatase inhibitor] treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting [aromatase inhibitor]-induced histone and DNA methylation may be beneficial in blocking or delaying [aromatase inhibitor] resistance.” Pathiraja TN, et al: Sci Transl Med 6:229ra41, 2014.

OUTCOME PREDICTORS DNA Repair Pathway Recombination Proficiency Score Correlates With Tumor Sensitivity to Chemotherapy As reported in Science Translational Medicine, Pitroda and colleagues developed a recombination proficiency score that measures the efficiency of DNA repair pathways in the context of cancer therapy aimed at generating DNA damage. The score is based on expression levels of four genes involved in DNA repair pathway preference (Rif1, PARI, RAD51, and Ku80), with high expression of these genes yielding a low score. It was shown that carcinoma cells with low recombination proficiency score exhibit suppression of homologous recombination and frequent DNA copy number alterations, characteristic of the error-prone repair processes that are found in homologous recombination-deficient backgrounds. The scoring system was clinically validated in patients with breast or non– small cell lung carcinomas (NSCLCs); it was shown that low recombinant proficiency score was associated with increased mutagenesis, adverse clinical features, and lower survival rates, indicating that suppression of homologous

recombination contributes to the genomic instability that drives malignant progression. The adverse prognosis associated with low score was improved in NSCLC patients receiving adjuvant platinum-based chemotherapy, indicating that the adverse prognosis is counteracted by suppression of homologous recombination and associated sensitivity to platinum-based treatment. The investigators concluded, “[The recombination proficiency score] may help oncologists select which therapies will be effective for individual patients, thereby enabling more personalized care.” Pitroda SP, et al: Sci Transl Med 6:229ra42, 2014.

NOVEL MECHANISMS New p53-Dependent Gene Cooperates With p53 in Tumor-Suppressor Functions The TP53 tumor-suppressor gene influences genomic stability, apoptosis, autophagy, response to stress, and DNA damage, and identification of new p53target genes could help elucidate mechanisms through which p53 controls cell integrity and response to damage. As reported in Journal of the National Cancer Institute, Polato and colleagues have identified DRAGO (drug-activated gene overexpressed, KIAA0247) as a new p53-responsive gene inducible by treatment with DNA-damaging agents. DRAGO is highly conserved, with ectopic overexpression resulting in suppression of tumor growth and increased cell death. DRAGO−/− mice are viable and have no macroscopic alterations. In p53−/− or p53+/− mice, deletion of both DRAGO alleles significantly accelerated tumor development and reduced lifespan compared with p53−/− or p53+/− mice with wild-type DRAGO alleles. DRAGO mRNA levels were significantly reduced in advanced-stage vs early-stage ovarian tumors, although no mutations were found in several human tumors. It was shown that DRAGO expression is regulated at the transcriptional level by p53 (and p73) and methylation-dependent control and at the post-transcriptional level by miRNAs. The investigators concluded, “DRAGO represents a new p53-dependent gene highly regulated in human cells and whose expression cooperates with p53 in tumor suppressor functions.” n Polato F, et al: J Natl Cancer Inst 106(4):dju053, 2014. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Breaking Bad News Badly Can Add to Upset By Charlotte Bath

hen the prognosis is poor, breaking the bad news badly can exacerbate the distress experienced by cancer patients and their families. A lack of sensitivity to patient and family emotions and not being attuned to how individual patients would prefer to be informed about their prognoses can result in dissatisfaction and misunderstandings, the latter possibly leading to patients continuing to receive treatment that no longer helps them or failing to receive palliative and end-of-life care. Although these findings—along with a six-step protocol known as SPIKES, for delivering bad news to patients with cancer—were reported back in 2000,1 breaking bad news continues to be a challenge for physicians and a cause for discontent among patients.

“Doctors could do a better job in breaking bad news,” announced the headline of a Reuters article2 about a recent German study3 that found only 46.2% of cancer patients reported being completely satisfied with how they had been told about bad news. Patients completed a questionnaire representing the six SPIKES subscales, and researchers concluded, “It could be postulated that the low satisfaction of patients observed in this study reflects the highly significant difference between patients’ preferences and bad-news delivery.”

SPIKES and Its Spinoffs “When the prognosis is poor, oncologists can really struggle with how to phrase the information and how to give hope at the same time as being realistic,” Walter F. Baile, MD, said in an

interview with The ASCO Post. Dr. Baile is Professor of Behavioral Science and Psychiatry and Director of the Interper-

Walter F. Baile, MD

sonal Communication and Relationship Enhancement (I*CARE) program at The University of Texas MD Anderson Cancer Center in Houston, and the lead author of the article in The Oncologist1 describing SPIKES. The most important objectives of

SPIKES are gathering information from the patient, transmitting the medical information, providing support for the patient, and eliciting the patient’s collaboration in developing a treatment strategy for the future. The six steps, according to the SPIKES acronym, are: • Setting up the interview. Prepare yourself for the interview by reviewing any test results and having a plan. Arrange for some privacy, but involve significant others. Sitting down with the patient can relax him or her and show you are not rushing through the discussion. • Perception. Use open-ended questions to assess the patient’s perception of how serious the medical condition is and whether he or she has realistic expectations of treatment. continued on page 212

Don’t Always Expect Questions From Patients About Prognosis

lthough most patients want to know about the potential outcome of their disease and whether treatment is likely to have a significant impact on it, the information needs of patients and how best to fulfill those needs are very variable, Walter F. Baile, MD, told The ASCO Post. Dr. Baile is Professor of Behavioral Science and Psychiatry and Director of the Interpersonal Communication and Relationship Enhancement (I*CARE) program at The University of Texas MD Anderson Cancer Center in Houston. He is also one of originators of the SPIKES six-step strategy for breaking news to patients with cancer (see article above).1

Cues From the Clinician “Sometimes patients and families have information needs but may be afraid to ask because they don’t want to hear bad news. Others may assume that the physician or oncologist is going to tell them everything they need to know,” Dr. Baile noted. Whether or not patients ask questions “often depends on the behavior of the clinician,” Dr. Baile said. “If the clinician has the kind of relationship with the patient that indicates he or she is open to having questions asked, then the patient will pick up on that cue. But if the clinician has a hand on the door knob, or seems harried, that is a cue

that can be interpreted by the patient as ‘I’m too busy.” According to the SPIKES protocol, breaking bad news to patients should be done, whenever possible, in a setting with some privacy, but involving the patient’s significant other, with all seated. “If you sit down, it says, ‘I am available to you.’ If you stand up, it says, ‘I haven’t really got much time to give you.’ I think it is easy to underestimate the nonverbal messages that doctors give to patients about their willingness to answer questions,” Dr. Baile said. One of the recommendations from a recent German study,2 using a variation of the SPIKES protocol, was to consider splitting the delivery of bad news over two visits, which Dr. Baile agreed could be useful. “Many patients, after you use the word cancer or talk about prognosis, may not hear the rest of what you say,” he noted. “So when they come back, there is an opportunity to say, ‘Did you have any questions about our conversation of last week? Is there anything that wasn’t clear to you?’”

‘Perpetual Possibility to Ask Questions’ Frequent reassurances of listeners’ understanding and the “perpetual possibility to ask questions” were also suggested by the German researchers. “Questions are always coming up,” Dr.

Baile said, and clinicians should not to be dismissive of any questions posed by patients since it may leave them feeling foolish for having asked in the first place. “Patients in search of answers may do an Internet research and find an obscure animal study that actually has no relevance for the patient’s outcome. We should not be dismissive of that and bluntly tell them it is an irrelevant study, because that demeans the patient’s quest for being a collaborator in finding answers to questions about the course of their disease,” Dr. Baile stated. “Many patients come with some knowledge from the Internet about their prognosis and treatment. These individuals, I think, are primed to ask questions.” Other patients may be reluctant to ask questions. “If you want to stay patient-centered, you ask patients how much information they want about their disease. That is one of the steps of SPIKES, the invitation piece. Another really important piece that many doctors don’t address is to ask patients what they have been told or what they know. This is important because you can’t begin to give bad news until you know what the patient already knows,” he added. Given the time constraints imposed on physicians, can so much information by imparted in the time al-

lotted? “That’s the biggest complaint,” Dr. Baile said. “However, I can tell you that if you provide information accurately, and you check with the patient and family as to what they’ve understood, in the end it will save you time. If you are upfront with the patient who really wants to know about the likely outcome of the disease, it could save you a lot of grief later on. If you hide that information from a patient, and after the second chemotherapy, when the disease has progressed, the patient says, ‘Well, you didn’t tell me the chemo might not work,’ then you have to pick up a lot of pieces.” Dr. Baile noted, “Some data show that patients consider their oncologist to be, if not the most important, then one of their two most valued sources of support. So what’s support? It is in a large part establishing the ‘connection’ by communicating effectively, acknowledging the patients’ emotions, and answering their questions.” n References 1. Baile WF, Buckman R, Lenzi R, et al: SPIKES—a six-step protocol for delivering bad news: Application to the patient. Oncologist 5:302-311, 2000. 2. Seifart C, Hofmann M, Bar T, et al: Breaking bad news—what patients want and what they get: Evaluating the SPIKES protocol in Germany. Ann Oncol 25:707711, 2014.

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In the News Breaking Bad News continued from page 211

• Invitation. Ask questions to ascertain whether the patient is extending an invitation to provide full and detailed information. A patient not inviting you to tell all may delegate a friend or relative to receive that information.

• Knowledge. Providing information about the patient’s prognosis might be eased by a forewarning that bad news is coming and by being clear, avoiding technical terms if you sense they might confuse the patient. Give information in manageable chunks and check to see if the patient understands. Avoid excessive bluntness.

• Emotions. Address the patient’s emotions with empathic responses. Such responses also allow you to acknowledge your own sadness or other emotions, if they are present. • Strategy and Summary. Presenting treatment options to patients ready to receive them can allay anxiety and

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uncertainty, in addition to establishing shared decision-making and meeting legal mandates. This also provides an opportunity to clear up misunderstandings and “can prevent the documented tendency of patients to overestimate the efficacy or misunderstand the purpose of treatment.”1 Dr. Baile continued, “The fact is, breaking bad news is just one piece [of this process]. The other piece involves finding a way to support the patient and knowing how to respond to difficult questions, such as: ‘How long do I have to live? Am I going to die? If it were you, what would you do.’ So there are these spinoff responsibilities, which I think expand the necessity for a comprehensive training program, not just in the mechanics of using SPIKES, but in preparing for other aspects of giving bad news, including the doctor’s reactions,” Dr. Baile said. “What do you do with patients you have known for a long time when you have to tell them that there is no more effective anticancer treatment, and you get sad and shed a tear, or the patient sees a tear? The focus is really on the interpersonal relationship rather than just the mechanics, because there is a back-and-forth exchange,” he added. “Well, one might say, ‘As you can see, this is tough for me to talk about.’”

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Another acronym, ABCDE, “emphasizes preparing yourself to give bad news,” Dr. Baile said. This includes reviewing lab results ahead of time, “so that you don’t pull them up on the computer in front of the patient and say, ‘Uh-oh’; you need to give yourself the opportunity to rehearse what you are going to say,” he added. ABCDE stands for Advance preparation, Building a relationship, Communicating well, Dealing with emotional reactions, and Empathy, Dr. Baile explained. “In training clinicians to give bad news, another aspect we teach is the concept of amygdala hijacking,” he said. “It is a term coined by Daniel Goleman in his book, Emotional Intelligence: Why It Can Matter More Than IQ,4 and it suggests the doctor needs to be aware of the tendency to try to fix peoples’ emotions with reassurances like, ‘Things are going to be okay,’ or ‘I’ve seen lots of miracles.’” Dr. Baile continued, “Doctors are trained to fix things, but fixing emotions usually doesn’t work, and it

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doesn’t sound genuine to patients. If someone cries, you don’t say, ‘Don’t cry. Everything is going to be okay.’ Better may be, ‘I can see this has really been upsetting for you.’ Goleman talks about how the doctor’s buttons can get pushed by patient emotions and lead them to say things that may not be helpful to patients. Instead letting patients know you are tuned into their feelings reinforces your relationship with them and is experienced as being ‘supportive’.”

Understanding and Recall Dr. Baile advises physicians to make sure that patients understand the information delivered. “Just saying, ‘Did you understand’ is not enough. Better to say, ‘When you go home, tell me what you are going to tell your loved ones.’ That way, you will be sure that the information got across.” Understanding does not guarantee, however, that patients will have accurate recall. “That’s why having a trusted significant other with the patient, whether it be a relative or partner, is so important, because that person can take notes,” Dr. Baile pointed out. In some cases, patients may signal that they don’t want to know all the details, but delegate that responsibility to significant others. In fact, this is quite common in non–AngloSaxon cultures. “It is not unethical or inappropriate to not tell patients if they don’t want to

know,” Dr. Baile said. In order to ensure patient understanding, sending a follow-up letter summarizing the findings discussed “is a strategy that increases patient satisfaction.” Having patients audiotape conversations with their physicians has been shown to be helpful in returning information, Dr. Baile said, although in his experience audiotaping doesn’t happen very often. “I don’t think most oncologists would have a problem with that,” Dr. Baile said, and knowing that they are being taped actually may encourage physicians to be more clear in their explanations to patients. “Sometimes doctors get nervous when patients audiotape things because they are concerned that they may be liable for something. But as far as I know, there has never been a lawsuit based on that,” Dr. Baile said.

Practice and Role Playing The 2000 article outlining SPIKES cited an informal study conducted at the 1998 ASCO Annual Meeting, which found that approximately 74% of those responding indicated they had to break bad news to patients at least 5 times per month, and some did so more than 20 times per month. Less than 50% of respondents, however, said they had any training in the techniques of dealing with patient’s emotions, and for most of those who did, it consisted of sitting in with a practicing clinician. Becoming a good communicator

Can Empathy Really Be Taught?

n an op-ed article in The New York Times (February 27, 2014) about the challenges of designing training courses to help physicians communicate more effectively with patients about important topics such as end-of-life care, Timothy D. Gilligan, MD, and Mikkael A. Sekeres, MD, of the Cleveland Clinic wrote, “as we devote more time to teaching students and doctors effective communication techniques, we risk muting their authentic human voices, and instead of learning to connect they apply rote tools and scripts.” They also warned that communication courses using what they called “a script for empathy” run the risk of contrived responses. “Having physicians sound like customer service representatives is not the goal,” they wrote. Walter F. Baile, MD, one of the originators of a six-step strategy that uses simulation and role-playing to train physicians how to break bad news to patients with cancer, told The ASCO Post that he was aware of that concern. “I think you have to be genuine,” Dr. Baile said. “If you can reverse physicians into the role of the patient and have them experience what it is like to get bad news, and then reverse them back into their own role, then you’ve created an insight into what makes sense with the patient that is different from just giving them a script and saying, ‘Say these words,’” he said. “Most people can put themselves in the shoes of someone else. They just need to be encouraged and helped to do it.” Dr. Baile is Professor of Behavioral Science and Psychiatry and Director of the Interpersonal Communication and Relationship Enhancement (I*CARE) program at The University of Texas MD Anderson Cancer Center in Houston. n

does not just happen or result from watching others do it, according to Dr. Baile. “It is clearly a skill set that needs to be practiced. Most of the data show that if you don’t teach these kinds of skills in a way that clinicians can actually practice, with opportunities to try out different strategies, then it doesn’t stick,” he said. “It is like any other skill. If you are trying to teach someone how to do a bone marrow aspiration, you don’t tell them to read an article and then go try it on a patient.” Teaching how to deliver bad news and deal with the questions that follow is best accomplished using roleplays—simulations of situations that present challenges when individuals interact, Dr. Baile explained. The purpose of practice and role-playing “is to practice verbal skils and create empathy for the patient. Empathy for what the other person is thinking and feeling is the gateway to effective communication skills,” he said. “Tuning in to how the patient is feeling is very important,” he continued. “If you step into someone else’s shoes and you have a good facilitator who can immerse you in the role of that other person, then you can get a sense of what it is like to be given bad news and use that insight to guide your own communication. Part of the teaching is to also let learners hear their own words in the role of the patient. I think it is crucial in bringing them to the realization of what works [when having to break bad news] and will aid in their adopting appropriate behaviors.”

Increasing Use of Simulation A survey conducted 8 or 9 years ago found that simulation and practice weren’t being widely used to teach how to break bad news, but that is changing, according to Dr. Baile. Communication skills constitute one of the six competencies required by the Accreditation Council for Graduate Medical Education, which strongly encourages the use of simulation methods and recognizes that physicians “need to prepare for difficult conversations and practice them in order to acquire the necessary skills,” he said. “Here at MD Anderson we spend 12 hours a year with first-year medical oncology fellows, teaching them how to give bad news and how to respond to difficult questions. We use advanced role-play techniques called ‘action methods,’ and create enactments called stereodramas,” Dr. Baile continued. He and a colleague at MD Anderson, Daniel E. Epner, MD, described that

program in articles recently published in Academic Medicine and Simulation in Healthcare.5,6 As part of the expanding interest in communication skills as a core competency, he noted that the Cleveland

Daniel E. Epner, MD

Clinic has dedicated itself to training every one of its staff and faculty in communication skills. “I have been working with their Institute for Healthcare Communication in training their fellows, staff, and faculty using simulation methods,” Dr. Baile noted. He also conducts such programs at other centers here and abroad, and at the time of the interview with The ASCO Post was preparing for a trip to conduct a 2-day workshop for five palliative care teams in Rome. The National Cancer Institute and ASCO have run several training courses on these topics, and modules about breaking bad news to patients are available at several online sites, including ASCO University (university.asco.org) and the I*CARE website at MD Anderson (mdanderson.org/ICARE.) n

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

References 1. Baile WF, Buckman R, Lenzi R, et al: SPIKES—a six-step protocol for delivering bad news: Application to the patient. Oncologist 5:302-311, 2000. 2. Seaman AM: Doctors could do a better job of breaking bad news: Study. Reuters, February 28, 2014. 3. Seifart C, Hofmann M, Bär T, et al: Breaking bad news—what patients want and what they get: Evaluating the SPIKES protocol in Germany. Ann Oncol 25:707711, 2014. 4. Goleman D: Emotional Intelligence: Why It Can Matter More Than IQ. New York, Bantam Books, 1995. 5. Epner DE, Baile WF: Difficult conversations: Teaching medical oncology trainees communication skills one hour at a time. Academic Medicine 89:578584, 2014. 6. Baile WF, Blatner A: Teaching communication skills: Using action methods to enhance role-play in problem-based learning. Simul Healthc. March 7, 2014 (early release online).

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In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Genitourinary Toxicity More Likely With Stereotactic Body Radiotherapy Than With IntensityModulated Radiotherapy A retrospective analysis of patients with prostate cancer receiving primary treatment with either stereotactic body radiation therapy or intensity-modulated radiation therapy found that those receiving stereotactic body radiotherapy had greater rates of genitourinary toxicity during 2-year follow-up. “The increased [genitourinary] toxicity was present at all time points and indicated an increase in both acute and later toxicity. This increase was largely associated with a higher rate of urethritis, urethral strictures, urinary incontinence, and obstruction among patients receiving [stereotactic body radiotherapy],” James B. Yu, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues reported in the Journal of Clinical Oncology. Stereotactic body radiotherapy “is an innovative and aggressively marketed form of radiation therapy that is disseminating into national practice for the treatment of prostate cancer,” the authors wrote. The higher doses of radiation per treatment with stereotactic body radiotherapy can mean a shorter overall course of treatment, making it less expensive but more toxic, and the study was designed to compare both treatment costs and toxicity outcomes. Using a national sample of Medicare beneficiaries age ≥ 66 years who received stereotactic body radiotherapy or intensity-modulated radiotherapy as primary treatment for prostate cancer from 2008 to 2011, the researchers identified 1,335 stereotactic body radiotherapy patients and 2,670 intensitymodulated radiotherapy patients. Each stereotactic body radiotherapy patient was matched to two intensity-modulated radiotherapy patients with similar follow-up (6, 12, or 24 months).

Key Findings “In the 6 months after treatment initiation, 15.6% of [stereotactic body radiotherapy] vs 12.6% of [intensitymodulated radiotherapy] patients experienced [genitourinary] toxicity [odds ratio (OR) = 1.29; 95% confidence interval (CI) = 1.05–1.53; P = .009]. At 24 months after treatment initiation, 43.9% of [stereotactic body radiotherapy] vs 36.3% of [intensity-modulated radiotherapy] patients had [genitourinary] toxic-

ity [OR = 1.38; 95% CI = 1.12–1.63; P = .001],” the researchers reported. Patients receiving stereotactic body radiotherapy also had increased gastrointestinal toxicity at 6 months, with 5.8% having had a Medicare claim indicative of gastrointestinal toxicity vs 4.1% of intensity-modulated radiotherapy patients. But there was no difference in gastrointestinal toxicity in stereotactic body radiotherapy vs intensity-modulated radiotherapy patients at 12 or 24 months. There were no differences in any other toxicities at any of the study time points. Mean treatment costs were $13,645 for stereotactic body radiotherapy and $21,023 for intensity-modulated radiotherapy, the researchers reported. For the two subcategories of complications (diagnostic procedures to investigate incontinence or obstruction, urethritis, urethral strictures, and bladder outlet obstructions), the mean cost was $145 for stereotactic body radiotherapy and $69 for intensity-modulated radiotherapy. For nonradiation cancerrelated care, the mean costs were $2,963 in the year following stereotactic body radiotherapy and $1,978 for the year following intensity-modulated radiotherapy. The researchers remarked: Despite our finding of increased toxicity, it is still possible that [stereotactic body radiotherapy] may be preferable to [intensity-modulated radiotherapy] for both insurers and patients. Given that a late risk of fistula is a concern for [stereotactic body radiotherapy], it is important to note that we found no statistically significant difference in the incidence of fistulas between [intensity-modulated radiotherapy] and [stereotactic body radiotherapy] at any time point. First, [stereotactic body radiotherapy] is a more convenient treatment given its shorter treatment length. Second, we found that despite an increased cost of complications and medical care, [stereotactic body radiotherapy] was still less expensive than [intensity-modulated radiotherapy] overall. Third, [stereotactic body radiotherapy] may be more effective than [intensity-modulated radiotherapy] in terms of cancer cure and so may be preferable in the long-term when accounting for the morbidity of cancer recurrence.

investigators also noted that stereotactic body radiotherapy technique may have improved since the years the patients in the study were treated (2008–2011), and a learning curve for stereotactic body radiotherapy may mean that direct clinical experience improved outcomes. “Regardless, as radiation therapy techniques improve, and as practitioners become more experienced with [stereotactic body radiotherapy], the comparison between [stereotactic body radiotherapy] and [intensity-modulated radiotherapy] is a moving target,” the authors noted. “It is important to recognize that Yu et al generate a testable hypothesis and not proof of causation because these results are nonrandomized and there are several patient and treatment factors that could have influenced the results,” Anthony V. D’Amico, MD, PhD, of Brigham and Women’s Hospital and Dana Farber Cancer Institute in Boston, wrote in an accompanying editorial. Dr. D’Amico added that “despite the potential limitations of the study by Yu et al, including the lack of adjustment for important patient and treatment factors in the model and the inability to assess the grade of the [genitourinary] complications, the results of the current study should raise our awareness that the potential for an increase in clinically significant [genitourinary] toxicity with [stereotactic body radiotherapy] as compared with [intensity-modulated radiotherapy] exists.” He also recommended that until the results of a Swedish randomized controlled trial evaluating the relative efficacy and toxicity of intensity-modu-

lated radiotherapy vs an accelerated radiation treatment regimen are available, accelerated radiation therapy regimens using cyberknife or stereotactic body radiotherapy to treat prostate cancer “should only be performed in the setting of well-designed clinical trials.” Yu JB, et al: J Clin Oncol 32:11951201, 2014. D’Amico AV: J Clin Oncol 32:11831185, 2014.

Tadalafil Did Not Prevent Erectile Dysfunction Among Men Receiving Radiotherapy Daily use of tadalafil (Cialus) did not improve erectile function compared to placebo or prevent erectile dysfunction among men undergoing radiotherapy for prostate cancer, according to results of a stratified, placebo-controlled, double-blind, parallelgroup study with 1:1 randomization at 76 community-based tertiary medical sites in the United States and Canada. “These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients,” Thomas M. Pisansky, MD, of Mayo Clinic, Rochester, Minnesota, and coauthors wrote in the Journal of the American Medical Association. Patients with clinical stage II (T1bT2b, N0, M0) prostate adenocarcinoma and intact erectile function were assigned 5 mg of tadalafil daily or placebo for 24 weeks, starting within 7 days after the initiation of external radiotherapy (63%) or brachytherapy (37%). All participants were ≥ 18 years old with a Gleason score < 7 and a serum prostate-specific antigen

Study Limitations Among the study limitations listed were inability to detect milder toxicities that did not require medical intervention and lack of toxicity grading and treatment-related information such as actual radiation doses and fields. The

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S U B M I T A N A B ST R AC T TO THE INAUGURAL

PALLIATIVE CARE IN ONCOLOGY SYMPOSIUM OCTOBER 24-25, 2014 The Westin Boston Waterfront Boston, Massachusetts

pallonc.org Abstract Submission Deadline: July 1 at 11:59 PM (EDT) Cosponsored by

TARG E T I NG

C A NC E R

C A RE

Multinational Association of Supportive Care in Cancer

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In the Literature Emerging Clinical Data continued from page 215

(PSA) level < 20 ng/mL, or a Gleason score ≥ 7 and a PSA < 15 ng/mL. “The primary end point was to determine whether tadalafil maintained spontaneous erections between weeks 28 and 30 after the start of radiotherapy, which was 4 to 6 weeks after tadalafil was stopped,” the investigators explained. “Among 221 evaluable participants, 80 [79%; 95% CI = 70%–88%] assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 [74%; 95% CI = 63%–85%] assigned to receive placebo (P = .49)—an absolute difference of 5% (95% CI = −9% to 19%). A significant difference was also not observed at 1 year [72%; 95% CI = 60%–84% vs 71%; 95% CI = 59%–84%; P = .93],” the investigators reported. “Tadalafil was not associated with significantly improved overall sexual function or satisfaction,” the authors added, and the “partners of men assigned tadalafil noted no significant effect on sexual satisfaction.” Grade 1 to 2 adverse effects attributed to treatment (tadalafil or radiotherapy) were reported by 65 patients (59%) in the tadalafil group and 56 patients (52%) in the placebo group. Severe or life-threatening adverse events were observed in 3% of patients in the tadalafil group and 1% in the placebo group. The U.S. Food and Drug Administration approved prescribing 2.5 or 5 mg of tadalafil daily, the authors noted. They added: Selection of 5 mg of tadalafil once daily in this study was well supported by its efficacy profile, its performance relative to other phosphodiesterase-5 inhibitor medications, and its pharmacological properties and mechanism of action. Despite the soundness of preliminary investigations, we found no benefit to tadalafil as an [erectile dysfunction] prevention agent after radiotherapy, with not even the slightest suggestion in this regard.

Pisansky TM, et al: JAMA 311:13001307, 2014.

BREAST CANCER Adjuvant Chemotherapy Accelerates Pace of Physiologic Aging in Women Treated for Breast Cancer “Adjuvant chemotherapy for breast cancer is gerontogenic,” accelerating the pace of physiologic aging, according to an analysis of blood and clinical data from 33 women with stage I to III breast cancer. “We have shown that cytotoxic chemotherapy potently induces the

expression of markers of cellular senescence in the hematologic compartment in vivo, comparable with the effects of 10 to 15 years of chronologic aging in independent cohorts of healthy donors,” Hanna K. Sanoff, MD, of the University of North Carolina School of Medicine at Chapel Hill, and colleagues concluded in the study report published in the Journal of the National Cancer Institute. “Cellular senescence is triggered by the activation of tumor-suppressor mechanisms in response to varied cellular stresses such as oncogene activation, tissue injury, telomere dysfunction, and persistent DNA damage,” the researchers explained. The authors previously showed p16INK4a is a marker of accelerated molecular age in peripheral blood T lymphocytes associated with smoking, physical inactivity, and chronic human immunodeficiency virus infection. Blood and clinical data were prospectively obtained from women before, immediately after, 3 months after, and 12 months after neoadjuvant or adjuvant anthracycline-based chemotherapy. The median age of the women was 49. “The women had few comorbid conditions, although nearly half were obese,” the investigators noted. Most women received adjuvant doxorubicin and cyclophosphamide, usually in a dose-dense fashion, and a taxane. Analyzing the blood for markers of cellular senescence, the researchers observed increased expression of the senescence markers p16INK4a and ARF in peripheral blood T lymphocytes immediately after chemotherapy, and these remained elevated for at least a year after treatment. The median increase in log2p16INK4a represented “a 75% increase equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16INK4a and ARF was associated with dose-dense therapy and hematological toxicity,” the authors stated. “Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy,” the authors continued. Telomere length, previously identified as a marker of cellular senescence, was not affected by chemotherapy.

Persistent Effect An independent cross-sectional cohort of 176 long-term breast cancer survivors confirmed the effect of chemotherapy on p16INK4a expression comparable with 10.4 years of chronologic aging. “Because patients in this cohort were a median 3.4 years from the completion of chemotherapy (some up

to 18 years from treatment), these results suggest that the sharp increase in p16INK4a expression observed after chemotherapy persists for at least several years, if not indefinitely, after chemotherapy exposure,” the authors stated. The investigators noted: Adjuvant anthracycline-based chemotherapy unequivocally saves lives, markedly decreasing the relative risk of breast cancer recurrence by 27% and death by 21%. Therefore, we believe the finding of durable, age-promoting effects of anthracyclines and alkylating agents must be weighed against these established benefits with regard to relapse risk. The ability to serially measure markers of molecular age in patients may provide a means to identify beneficial adjuvant approaches that are less ‘pro-aging.’

The researchers are currently enrolling in two prospective trials, “one evaluating whether changing PBTL p16INK4a expression is a biomarker of acute toxicity of various chemotherapy regimens (LCCC1027, NCT01305954); and a second focused exclusively on older patients evaluating the combination of a validated geriatric assessment and PBTL p16INK4a for prediction of treatment-related toxicity and change in function (NCT01472094).” Sanoff HK, et al: J Natl Cancer Inst 106(4):dju057, 2014.

ORAL CHEMOTHERAPY Food and Drug Interactions Could Reduce Effectiveness of Oral Chemotherapy Oral chemotherapy agents are associated with drug and food interactions that can significantly reduce the effectiveness of oral chemotherapy and possibly result in harm to patients, according to a study in the Journal of Oncology Practice. It is important therefore, according to the study’s authors, to evaluate patients’ diet and concurrent medications and provide education, monitoring, and, if necessary, alternative recommendations. A team of pharmacists led by Eve M. Segal, PharmD, of Froedtert and the Medical College of Wisconsin in Milwaukee, systematically reviewed 58 oral chemotherapeutics using U.S. Food and Drug Administration–approved product labeling, primary literature, and tertiary databases. “Our study of drug interactions revealed that the addition of an oral chemotherapeutic to an anticoagulant may have unpredictable effects on the international normalization ratio (INR),” the pharma-

cists reported. “Approximately 16 of the oral chemotherapeutics affected the absorption of coumarin-derived anticoagulants, and prolongation of the QTc interval was remarkable in 14 agents.” Acid suppression medications, such as proton-pump inhibitors, were found to affect absorption rates for nine oral chemotherapeutic agents. Warnings to avoid proton-pump inhibitors were included on the package inserts for dasatinib (Sprycel), erlotinib (Tarceva), and ponatinib (Iclusig). “Manufacturers of several other oral chemotherapeutics recommend that avoidance of [proton-pump inhibitors] be considered,” the authors added. Bosutinib (Bosulif) and nilotinib (Tasigna) “have demonstrated increased absorption with concomitant [proton-pump inhibitor] therapy,” the authors noted. In addition, “[proton-pump inhibitors] interact with methotrexate, resulting in a delayed elimination, and therefore have the potential to cause methotrexate toxicity.” Because “acid suppression with [protonpump inhibitors] is a drawn-out process,” they noted, timing doses to avoid a drug interaction can be “a futile exercise.” Many drug-food interactions were noted. ”For nine drugs, ingestion with food was recommended, whereas 20 required that they be taken on an empty stomach. The fat content of a patient’s meal was noted as important in the total absorption of four of those medications advised to be taken on an empty stomach. Three drugs were noted to have interactions with calcium-containing foods or supplements, and nine drugs had pH-dependent absorption. Four of the oral chemotherapeutics noted significant quantities of lactose in the pills as inactive ingredients.” In addition, clinically significant or moderate interactions with grapefruit were noted for 19 drugs. “Food interactions can be difficult to manage for patients receiving oral chemotherapy because of the lifestyle changes they might require, even if changes apply only to daily regimens, one meal a day, or time of day medication is taken. Changes in lifestyle can adversely affect the likelihood of adherence,” the pharmacists stated. “It is imperative that health care providers monitor patients for potential food-drug and drug-drug interactions to avoid a loss in efficacy or increased risk of toxicity from oral chemotherapy,” the researchers concluded. n Segal, EM, et al: J Oncol Pract. April 22, 2014 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Guidelines

ASCO Issues Two New Guidelines on Treating Patients With Advanced, HER2-Positive Breast Cancer

SCO recently issued two clinical practice guidelines on treating women with advanced, HER2-positive breast cancer. The first guideline lists the appropriate systemic therapies for women newly diagnosed with advanced disease and those whose early-stage disease progressed to advanced cancer. The second guideline provides recommendations for treating brain metastases in women with HER2-positive advanced breast cancer. Watch future issues of The ASCO Post for a comprehensive report on these new guidelines. See pages 1, 45, 48, 49, 50, and 54 in this issue for more on newly released ASCO guidelines.

survival benefit in this setting. • Second-line therapy: ado-trastuzu mab emtansine (Kadcyla), formerly known as T-DM1 • Third-line line therapy and beyond: treatment depends on what patients have received in the first- and secondline settings. Options may include ado-trastuzu mab emtansine, hormonal therapy or chemotherapy with trastuzumab and in some cases with lapatinib, the combination of trastuzumab and lapatinib, or a pertuzu mab-based regimen if the patient had not previously received pertuzumab.

Systemic Therapy for Advanced, HER2-Positive Breast Cancer

ASCO has released a clinical practice guideline providing consensusbased recommendations for use of local and systemic therapies in patients with HER2-positive breast cancer that has spread to the brain.

ASCO’s new guideline provides evidence-based recommendations for using systemic targeted therapies in treating advanced (inoperable locally advanced and metastatic), HER2-positive breast cancer. The recommendations will help standardize care and maximize the potential benefit from HER2-targeted therapies.

Key Recommendations • First-line therapy: combination of chemotherapy, trastuzumab (Herceptin) and pertuzumab (Perjeta). For select patients, such as those with contraindications and/or slow-growing hormone receptor–positive cancer, hormonal therapy administered with or without either trastuzumab or lapatinib (Tykerb) may be substituted for a chemotherapy-based HER2-targeted regimen because it may have fewer side effects. However, hormonal therapy is not appropriate for all patients with advanced, hormone receptor–positive breast cancer and it has not been associated with a

Consensus Recommendations for Treating Brain Metastases

Key Recommendations • For patients with favorable prognosis for survival, surgery and/or radiotherapy are recommended, depending on the size and number of metastases, resectability, and symptoms. • For patients with a poor prognosis for survival, options include surgery, whole-brain radiation therapy, and systemic therapies with some evidence of activity in the setting of brain metastases, such as lapatinib and capecitabine. • Additional options include best supportive care, enrollment in a clinical trial, and/or palliative care. n The guideline, Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline, was published in the Journal of Clinical Oncology, May 5, 2014.

The ASCO Post

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

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information. WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

AVASTIN® (bevacizumab) 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

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AVASTIN® (bevacizumab) 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

AVASTIN® (bevacizumab) In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo Preferred terma (n = 304) Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

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

Adverse events were encoded using MedDRA, Version 10.1.

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

AVASTIN® (bevacizumab) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. 17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. • To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. • Of increased risk of wound healing complications during and following Avastin. • Of increased risk of an arterial thromboembolic event. • Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin. • Of the increased risk for ovarian failure following Avastin treatment.

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

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Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

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

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

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Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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

AVASTIN® (bevacizumab) 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Confronting a common threat across approved indications Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

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

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

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

AVA0000488404

Printed in USA.

(12/13)

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,* the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC *Avastin is not approved for use in combination with irinotecan or any other combination regimens. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. March 2013.