TAP Vol 5 Issue 3 by Harborside Press LLC

Gastrointestinal Cancers 1, 3–5 | ASCO/CAP Guidelines on HER2 Testing

| Pioneers in Oncology

VOLUME 5, ISSUE 3

FEBRUARY 15, 2014

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

ASCO’s Education and Professional Development Services

Gastrointestinal Cancers Symposium

Immunotherapy Duo Improves Survival in Metastatic Pancreatic Cancer By Caroline Helwick

Jamie H. Von Roenn, MD, on Major Changes in Maintenance of Certification and More

verall survival was improved in metastatic pancreatic cancer patients through an innovative immunotherapy strategy in a multicenter study reported at the 2014 Gastrointestinal Cancers Symposium.1 “This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer,” said Dung T. Le, MD, Assistant Professor of Medicine at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore. “This is just a first step, and we believe we’ll be able to take this approach further.”

How the Treatment Works The novel treatment, which may be better tolerated than standard chemotherapy, involves two different anticancer vaccines: GVAX Pancreas followed by CRS-207. GVAX is com-

posed of pancreatic cancer cells that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates the immune system. GVAX is given with lowdose cyclophosphamide to Dung T. Le, MD inhibit regulatory T cells and boost the vaccine’s efficacy. The second vaccine, CRS-207, is live-attenuated Listeria monocytogenes (Lm), which has been genetically modified to be safe for human use while retaining its ability to stimulate an immune response against the protein mesothelin on pancreatic tumor cells. The combination essentially trains the body to recognize and attack pancreatic tumors. In mouse tumor continued on page 4

Health-Care Policy

The Surgeon General’s Report on Tobacco Turns 50: Much Success, Much Work Ahead By Ronald Piana

ast September, Jamie H. Von Roenn, MD, left her position as Professor of Medicine at the Northwestern University Feinberg School of Medicine in Chicago to join ASCO as its Senior Director of Education, Science and Professional Development. In her new position, Dr. Von Roenn will provide strategic vision and operational leadership for the planning, development, implementation, and evaluation of an array of innovative education programs that serve the needs of ASCO members, including the ASCO Annual Meeting, thematic meetings, workshops, and continuing medical education offerings. The ASCO Post talked with Dr. Von Roenn about her goals to expand ASCO’s education programs, the challenges facing oncology care, continued on page 81

Dr. Von Roenn is Senior Director of ASCO’s Education, Science and Professional Development Department.

MORE IN THIS ISSUE

n January 11, 2014, the nation commemorated the 50th anniversary of a document that transformed our public health landscape and has saved millions of lives: Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. This groundbreaking report, which definitively established smoking as the primary cause of lung cancer, became a key publication for those committed to eradi-

cating tobacco-related disease. Although challenged by Big Tobacco and social norms, the Surgeon General’s report fostered a tectonic shift in public health policy, resulting in a dramatic reduction in smoking. Despite considerable success, smoking remains America’s number-one cause of preventable death. In that regard, the Surgeon General’s report is a living document that is still critical to ongoing tobacco cessation initiatives.

The authors of the original Surgeon General’s report would not have foreseen the ability of tobacco companies to hinder efforts to eliminate tobacco smoking in the United States. —Paul Bunn, MD, see page 40

February Is National Cancer Prevention Month

A Time of Change Although the work of Ernst Wynder, MD, and others had brought public awareness to the negative health effects of smoking (see “Paving the Way for the Surgeon General’s Report,” on page 40), it

Oncology Meetings Coverage GI Cancers Symposium �� 1, 3–5 SABCS ��13, 15–16, 18–21 ASH Meeting �� 23–24, 32–33, 36–37 Steven M. Horwitz, MD, on Breast-Implant Associated ALCL ��47 Nancy E. Davidson, MD, on HER2 Testing ��50 Direct From ASCO �� 54–57 Inside the Black Box ��69 In Memoriam: Donald L. Morton, MD �� 112 Geoffrey P. Herzig, MD �� 113

continued on page 38

A Harborside Press® Publication

The ASCO Post | FEBRUARY 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

Samuel Silver, MD, PhD University of Michigan Health System

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

George W. Sledge, MD Indiana University

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

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

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

Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

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 Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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-

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ASCOPost.com | FEBRUARY 15, 2014

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Ramucirumab Plus Paclitaxel Improves Overall Survival After First Progression in Metastatic Gastric Cancer By Caroline Helwick

n the global phase III RAINBOW trial in patients with metastatic gastric cancer, the investigational monoclonal antibody ramucirumab significantly improved both progression-free and overall survival, when added to paclitaxel in second-line therapy, as reported at the 2014 Gastrointestinal Cancers Symposium.1

statistically significant and clinically meaningful overall survival benefit of more than 2 months was observed for ramucirumab plus paclitaxel vs paclitaxel alone.” “This is one of the few trials in gastric cancer that has been significantly positive for all the efficacy parameters,” he added. Ramucirumab is a human IgG1 mono-

This is one of the few trials in gastric cancer that has been significantly positive for all the efficacy parameters. —Hansjochen Wilke, MD

“The primary endpoint of improved overall survival was met,” Hansjochen Wilke, MD, of the Department of Oncology, Kliniken Essen-Mitte in Essen, Germany, reported in a press briefing. “A

clonal antibody that blocks vascular endothelial growth factor receptor 2 (VEGFR-2), and therefore thwarts angiogenesis. Dr. Wilke noted that patients with disease progression after first-line treat-

Ramucirumab Plus Paclitaxel in Gastric Cancer ■■ In a global phase III study, the monoclonal antibody ramucirumab improved overall survival in patients with metastatic gastric cancer who had disease progression after first-line therapy. ■■ Median overall survival was 9.6 months for the combination and 7.4 months for paclitaxel alone, a 19% reduction in risk with ramucirumab on board.

ment usually had a median survival of only about 3 months with best supportive care, and only about one-third of patients in the Western world receive second-line therapy. RAINBOW is the largest clinical trial of second-line therapy in this patient population to date.

RAINBOW Details This randomized, double-blind, placebo-controlled study included 665 patients with metastatic gastroesophageal junction or gastric adenocarcinoma who had disease progression while on or within 4 months after a standard firstline platinum- and fluoropyrimidinebased combination chemotherapy. They

were randomly assigned to receive paclitaxel alone (80 mg/ m2 on days 1, 8, 15) or with ramucirumab (8 mg/ kg IV every 2 weeks) in 4-week cycles until progression or intolerable toxicity. The primary endpoint was overall survival. All efficacy parameters favored the ramucirumab arm. Median overall survival was 9.6 months for the combination and 7.4 months for paclitaxel alone. The hazard ratio was 0.807 (P = .0169)—a 19% reduction in risk of death with ramucirumab plus paclicontinued on page 4

EXPERT POINT OF VIEW

anish Shah, MD, Director of Gastrointestinal Oncology and Associate Professor of Medicine at New York–Presbyterian/Weill Cornell Medical Center in New York, discussed the findings of the RAINBOW trial at the 2014 Gastrointestinal Cancers Symposium. Dr. Shah noted that in this “well sized” study, the addition of ramuricumab to paclitaxel significantly improved overall survival. “The curves split early, at just over 2 months, and stayed separated for over 1 year.”

Outcome Differences in Asian Populations Comparing studies of bevacizu mab (primarily, AVAGAST) and the RAINBOW study of ramucirumab, Dr. Shah noted that outside of the Asian populations, “we see more dramatic benefit with bevacizumab [Avastin] (for overall survival, hazard ratio [HR] = 0.67 outside of Asia vs 0.97 for Asians), and we see a similar hazard ratio outside of Asia in RAINBOW (0.73 outside of Asia vs 0.99 for Asians).” He further pointed out, “For progression-free survival, we see a slight difference distinguishing these two antibodies”:

Hazard ratios were more impressive with ramucirumab, especially in the Asian subset. For AVAGAST, the progression-free survival hazard ratio for Asians was 0.92, whereas for the RAINBOW study, the hazard ratio for progression-free survival

plasma VEGF-A and neuropilin-1, a coreceptor for VEGF receptor signaling. Overall survival was most favorable in patients with high VEGF-A levels (HR = 0.72) and low neuropilin-1 levels (HR = 0.75), compared to low and high

The implications of RAINBOW are that targeting the angiogenesis pathway in gastric and gastroesophageal junction adenocarcinoma is now validated, and ramucirumab plus paclitaxel is a viable, safe, effective treatment option following first-line therapy. —Manish Shah, MD

was 0.63. “This may be an important difference,” he suggested. “Outside of Asia, the hazard ratios for progression free survival are similar in Europe and North American populations for both studies.” Biomarkers are clearly needed, he added. For the VEGF-A inhibitor bevacizumab, potential candidates include

levels, respectively, he indicated. “The implications of RAINBOW are that targeting the angiogenesis pathway in gastric and gastroesophageal junction adenocarcinoma is now validated, and ramucirumab plus paclitaxel is a viable, safe, effective treatment option following first-line therapy,” Dr. Shah concluded.

Disease Biology Whether VEGF receptor-2 inhibition is different from inhibition of VEGF-A remains to be determined, he added. “We have also learned that disease biology is important, as shown by gastric cancer heterogeneity,” Dr. Shah added. “We have shown that the epidemiology of the disease is different across the world, and where the studies are done will affect the types of patients in the various ‘buckets’ of disease subtypes. This may make a difference as we move on with targeted therapies.” The “impressive” fact is that more than 5,000 gastric cancer patients have been treated with targeted therapies within just the last few years, he said, but much remains to be learned— mainly why targeted agents are ineffective in some patients and in some settings. Using biospecimens and advanced molecular analyses, researchers can now turn their focus on how these treatments work, and more importantly, why they sometimes do not. n Disclosure: Dr. Shah reported no potential conflicts of interest.

The ASCO Post | FEBRUARY 15, 2014

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Gastrointestinal Cancers Symposium Immunotherapy Duo continued from page 1

models, Lm/GVAX vaccines are synergistic, and in a phase I study of CRS207, patients with pancreatic ductal adenocarcinoma who had received prior GVAX lived more than 15 months, Dr. Le explained.

Study Details The study randomly assigned 90 pancreatic adenocarcinoma patients 2:1 (51% with two or more prior treatments and 83% with one prior treatment for metastatic disease) to two doses of GVAX followed by four doses of CRS-

and at least one dose of CRS-207. Median overall survival in this population was 9.7 months, vs 4.6 months for GVAX alone, a 47% reduction (P = .0167), she reported. A striking difference was also seen in the subgroup of patients who had had two or more prior chemotherapy regimens. Receipt of combination immunotherapy in the third line or greater led to a median overall survival of 5.7 months, vs 3.7 with GVAX, a 70% reduction in risk that was highly significant (P = .0003). In the per-protocol group (who received at least three doses), median overall survival for this subgroup was 8.3 months vs 4.0 months, respectively, a 68% reduc-

This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. We believe we’ll be able to take this approach further. —Dung T. Le, MD

207, or six doses of GVAX alone, every 3 weeks. (Low-dose cyclophosphamide was always given the day before GVAX.) Courses could be repeated. The primary endpoint was overall survival. At a planned interim analysis, and at a median follow-up of 7.8 months, in the population of patients who received at least one dose of the vaccine, median overall survival was 6.1 months with the combination vs 3.9 months with GVAX alone, a 41% reduction in risk with the combination immunotherapy (P = .0172). The greatest differences were observed in patients who received three total doses, which includes at least two doses of GVAX

tion in risk (P = .0002), she added. There were no responses, but stable disease was observed in 37% of the combination group and 30% of the GVAX-only group. CA19-9 stabilization was observed in 32% receiving the combination, vs 13% of the single-agent group (P = .06). Toxicities included local reactions after GVAX and transient fevers, chills, and lymphopenia after CRS-207 administration. The 1-year survival probability was estimated at 24% for the combination arm and 12% in the GVAX-only arm. “The vaccines appear to be safe and well tolerated,” Dr. Le added. A three-arm study

Immunotherapy for Pancreatic Cancer ■■ Immunotherapy treatment with a combination of two vaccines improved overall survival in metastatic pancreatic adenocarcinoma patients who failed previous therapy. ■■ Patients who received cyclophosphamide/GVAX plus CRS-207 had a median overall survival of 6.1 months, vs 3.9 months for patients receiving only cyclophosphamide/GVAX, a 41% risk reduction (P = .0172). ■■ Patients who had received at least three doses had a median overall survival of 9.7 months after combination immunotherapy, vs 4.6 months for GVAX alone, a 47% risk reduction (P = .0167).

Ramucirumab continued from page 3

taxel. Median progression-free survival was 4.4 months and 2.9 months, respectively, the hazard ratio was 0.635 (P < .0001)—a 36% reduction in risk of tumor progression or death. Median time to progression was 5.5 months and 3.0 months, respectively (P < .0001). The objective response rate with the combination was 28%, vs 16% with

paclitaxel alone (P = .0001), and the disease control rate was 80% and 64%, respectively (P < .0001). “Disease control and response rates are important, because many of our patients are symptomatic,” Dr. Wilke noted. Treatment-emergent adverse events of grade ≥ 3 occurred at a greater frequency in the ramucirumab plus paclitaxel arm (82% vs 63%). Grade ≥ 3 treatment-emergent adverse events oc-

is evaluating the combination compared to CRS-207 alone and to chemotherapy. n Disclosure: Dr. Le reported no potential conflicts of interest.

Reference 1. Le DT, Wang-Gillam A, Picozzi V

Jr, et al: A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results. 2014 Gastrointestinal Cancers Symposium. Abstract 177. Presented January 17, 2014.

EXPERT POINT OF VIEW

ebecca Miksad, MD, MPH, Assistant Professor of Medicine at Harvard Medical School and Attending Physician, Gastrointestinal Medical Oncology, Beth Israel Deaconess Medical Center, Boston, discussed the findings at the symposium and the potential for immunotherapy in pancreatic cancer. Immunotherapy recruits and activates T cells that recognize tumor-specific antigens. Success for this approach in pancreatic cancer has been limited to date, potentially due to the amount of disease burden and tumor immune escape, Dr. Miksad pointed out.

Questions Remain “Researchers at Johns Hopkins have developed a heterologous prime boost approach in an attempt to improve immunotherapy for pancreatic cancer,” she noted. “The phase II survival results are encouraging, and the sequential administration of CRS207 after cyclophosphamide and GVAX appears to be tolerable.” Dr. Miksad commented, “it makes sense from an immune therapy point of view and for the study design” to assess patients after three doses of immune therapy (three doses of cyclophosphamide and GVAX or two doses of cyclophosphamide and GVAX followed by one dose of CRS-207), since “it takes time to develop an appropriate immune response.” But this means “we must still contend with the fact that 30% of patients did not make it to the

curring in more than 10% of patients and at a higher incidence in the ramucirumab plus paclitaxel arm were neutropenia, leukopenia, hypertension, and fatigue. Neutropenia grade 3 (22% vs 16%) and 4 (19% vs 3%) were reported with a higher incidence in the ramucirumab plus paclitaxel arm. “Neutropenia was more frequently reported in the ramucirumab/paclitaxel arm, but the incidence of febrile

Rebecca Miksad, MD, MPH

point of the third dose and, therefore, we were excluded from the perprotocol analysis.” Fortunately, analysis of all subjects who received one dose also demonstrated a benefit for the combination arm, although the survival improvement was smaller. She also questioned the generalizability of the study, which included a “highly selected” population: 40% had undergone surgical resection and 80% received chemotherapy for metastatic disease. Most importantly, the standard of care for first-line treatment of advanced pancreatic cancer has changed since this study was conducted. “The standard of care for first-line treatment of advanced pancreatic cancer has changed since the study was conducted. Will these findings hold for patients exposed to modern combination regimens?” she wondered. “Immunotherapy may offer a treatment alternative for pancreatic cancer, but it’s resource-intensive. We eagerly await the results of the three-arm trial,” she said. n

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

neutropenia was comparable [3.1% vs 2.4%],” Dr. Wilke said. “Adverse events did not lead to a higher discontinuation rate, which was 11% in each arm.” n

Disclosure: Dr. Wilke has received honoraria from Lily.

Reference 1. Wilke H, Van Cutsem E, Oh SC, et al: 2014 Gastrointestinal Cancers Symposium. Abstract LBA7. Presented January 16, 2014.

ASCOPost.com | FEBRUARY 15, 2014

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Maintenance Treatment With Capecitabine and Bevacizumab Is Effective in Metastatic Colorectal Cancer By Caroline Helwick

n patients with metastatic colorectal cancer, maintenance treatment with capecitabine plus bevacizumab (Avastin) after induction treatment with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) significantly delayed disease progression, compared to obser-

Miriam Koopman, MD, PhD

vation, according to the final results of the phase III CAIRO3 trial by the Dutch Colorectal Cancer Group.1 This benefit was evident across all subgroups of patients. The findings were reported at the 2014 Gastrointestinal Cancers Symposium in San Francisco. The investigators also found a nonsignificant benefit in the secondary endpoint of overall survival. Preplanned subgroup analysis showed that this overall survival benefit was restricted to patients with synchronous disease who had their primary

tumor resected and patients with complete or partial response as best response on induction treatment. However, these latter findings require further confirmation. Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B significantly prolonged the time to first disease progression, and also the time from randomization to progression after reintroduction of CAPOX-B (ie, second progression), which was the study’s primary endpoint, according to Miriam Koopman, MD, PhD, of University Medical Center Utrecht in the Netherlands. “Preplanned subgroup analyses showed the benefit of maintenance treatment in all subgroups for the primary endpoint, and an overall survival benefit for maintenance treatment in patients with synchronous disease with resection of the primary tumor, and in patients with a complete or partial response as best response on induction treatment,” she said.

Study Details To help define the optimal duration of chemotherapy and bevacizumab in metastatic colorectal cancer, CAIRO3 evaluated the efficacy of maintenance with capecitabine plus bevacizumab vs

EXPERT POINT OF VIEW

eal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, discussed the CAIRO3 results at the Gastrointestinal Cancers Symposium. He said there are three main lessons from CAIRO3: (1) It is feasible yet challenging to conduct a “window of opportunity” study after induction, as fewer than two patients were accrued per Neal J. Meropol, MD year per center, (2) maintenance treatment clearly will delay progression, and (3) more work is needed to identify patients who may safely receive a treatment holiday.

Time to Jump to the Next Curve Dr. Meropol described the colorectal cancer “S curve,” that shows how survival has steadily increased from the 1980s, with the “tweaking of 5-FU,” to the 1990s, the era of new cytotoxics and antibodies, into the 2000s with further “tweaking” of the same. “We must jump to the next curve,” he emphasized. There are three main ways to get there, he said: through technology (specifically, genomics and big data); through teamwork (specifically, public-private biobanking); and through clinical trials (specifically, new trial models and new infrastructure and regulatory models). n Disclosure: Dr. Meropol has received consulting fees from Precision Therapeutics.

observation in patients who had not had disease progression during induction treatment with CAPOX-B. Of note, patients in whom a radical resection of metastases was planned were also excluded from the study. The 558 patients with previously untreated metastatic colorectal cancer enrolled in CAIRO3 achieved a response or stable disease after six cycles of CAPOXB, then were randomly assigned to continue on maintenance capecitabine plus bevacizumab or to undergo observation. The maintenance regimen was capecitabine at 625 mg/m2 twice daily, given continuously with bevacizumab at 7.5 mg/kg every 3 weeks. Upon first progression, patients in both arms were scheduled to receive CAPOX-B until second progression, which was the primary endpoint. After a median followup of 48 months, CAPOX-B was reintroduced to 61% of the observation arm, compared to 47% of the maintenance arm. The median first episode of disease progression (PFS1) was 4.1 months in the observation arm and 8.5 months in the maintenance arm, a 57% reduction in risk of progression (P < .0001). Median time to second progression (PFS2), the primary endpoint, was 8.5 months vs 11.7 months, respectively, a 33% reduction in risk (P < .0001), Dr. Koopman reported. She emphasized that the time to all endpoints was assessed from randomization and did not include the 4 to 5 months of induction treatment. She also noted that PFS2 was considered equal to PFS1 for patients in whom CAPOX-B was not reintroduced after first progression for any reason. Another endpoint, the time to second progression of disease (TT2PD) included patients who received any treatment after first progression, including CAPOX-B. The clinical relevance of this endpoint was explained by the fact that a substantial number of patients were not able or willing to

CAIRO3 Endpoints PFS1 = first episode of disease progression PFS2 = second episode of disease progression TT2PD = time to second progression of disease

receive reinduction treatment of CAPOXB upon PFS1. Median TT2PD was 11.1 months with observation and 13.9 months with maintenance, a 32% reduction in risk with maintenance (P < .0001). Median overall survival was 18.1 months with observation and 21.6 months with maintenance, which was not a significant difference (hazard ratio = 0.89; P = .22). The drugs administered during metastatic disease were not significantly different between the arms, with about half the patients in each arm receiving a total of four drugs and 12% receiving five. “Quality of life was maintained during maintenance treatment, and was clinically not inferior compared to the quality of life in the observation arm,” Dr. Koopman noted.

Interesting Subgroup Differences The benefit of maintenance was present in all subgroups for the primary endpoint (PFS2), as well as for PFS1 and TT2PD, but some interesting treatment interactions emerged upon deeper analysis. Multivariable analysis for overall survival, with treatment adjusted for a series of potentially confounding factors at baseline, showed significant interactions for treatment (observation vs maintenance) with resection of the primary tumor (yes vs no) and synchronous vs metachronous metastases at baseline (P < .0001 for both continued on page 6

Maintenance Capecitabine/Bevacizumab in Colorectal Cancer ■■ The final results of CAIRO3 validated the benefit of maintenance capecitabine plus bevacizumab after first-line induction chemotherapy in patients with metastatic colorectal cancer. ■■ Times to first and second disease progression were both significantly prolonged in the maintenance arm. ■■ Preplanned subgroup analyses showed that two subsets of patients also experienced an overall survival benefit: those with synchronous metastases whose primary tumor was resected, and patients who achieved a complete or partial response to induction therapy, these findings need confirmation.

The ASCO Post | FEBRUARY 15, 2014

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FDA Update

FDA Accepts New Drug Application for Idelalisib in Refractory Indolent Non-Hodgkin Lymphoma

he U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for idelalisib, a targeted, oral inhibitor of PI3K-delta, for the treatment of refractory indolent non-Hodgkin lymphoma (NHL). The FDA has granted a standard review for the NDA, with

a target review date of September 11, 2014. The application was supported by a single-arm phase II study (Study 10109) evaluating idelalisib in patients

with indolent NHL that is refractory to rituximab (Rituxan) and to alkylating agent–containing chemotherapy. Following the NDA submission for indolent NHL, the FDA granted idelalisib a

Breakthrough Therapy designation for relapsed chronic lymphocytic leukemia (CLL). An NDA for idelalisib for the treatment of CLL was submitted in December 2013. n

Redefine treatment goals with Maintenance Capecitabine/ Bevacizumab continued from page 5

interactions), Dr. Koopman reported. The greatest benefit was observed for the 180 patients with synchronous metastases whose primary tumors were resected. With maintenance, these patients achieved a median overall survival of 25 months, vs 18 months with observation (P < .0001). For the 230 patients with synchronous metastases and no resection of the primary tumor, median overall survival was 16.3 months with observation and 14.9 months with maintenance, she reported. Patients who achieved a complete or partial response on induction treatment before randomization also had very favorable median overall survival with maintenance—24.1 months vs 18.8 months with observation (P < .0001). Given the fact that these subgroup analyses concerned a secondary endpoint, Dr. Koopman stressed that these findings require further confirmation. The main outcome of the CAIRO3 study is that patients with metastatic colorectal cancer receiving induction treatment with CAPOX-B do benefit from maintenance treatment with capecitabine plus bevacizumab. n Disclosure: Dr. Koopman reported an advisory role for Amgen, Bayer, Merck-Serono, and Roche.

Reference 1. Koopman M, Simkens L, May A, et al: Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine plus bevacizumab versus observation after induction treatment with chemotherapy plus bevacizumab in metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract LBA388. Presented January 18, 2014.

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

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

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 | FEBRUARY 15, 2014

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FDA Update

FDA Approves CliniMACS CD34 Reagent System for the Prevention of Graft-vs-Host Disease in AML

he U.S. Food and Drug Administration (FDA) has approved the Miltenyi Biotec’s CliniMACS CD34 Reagent System as a Humanitarian Use Device for the preven-

tion of graft-vs-host disease in patients with acute myeloid leukemia (AML) in first complete remission undergoing allogeneic stem cell transplantation from a matched re-

lated donor. The CliniMACS CD34 Reagent System decreases the risk of developing graft-vs-host disease, a life-threatening complication that

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

can occur following an allogeneic transplant, in which T cells from the donor attack various tissues of the recipient. The FDA-approved continued on page 8

The ASCO Post | FEBRUARY 15, 2014

PAGE 8

FDA Update Graft-vs-Host Disease Prevention Device continued from page 7

device removes donor T cells from the graft prior to transplantation by enriching CD34+ blood stem cells, which go on to repopulate the patient’s immune and blood building systems.

Phase II Trial The FDA approval was based on data from a phase II, single-arm, multicenter study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network, which showed that following intensive myeloablative conditioning, stem cell transplantation from an identi-

cal sibling donor processed using the CliniMACS CD34 Reagent System as the sole means of graft-host-disease prophylaxis leads to a low incidence of chronic graft-vs-host disease (19% at 2 years after transplantation) without negatively affecting relapse, engraftment, overall survival or disease-free survival.

“The low incidence of acute and chronic graft-vs-host disease, in the absence of additional immunosuppression are distinct advantages in using the CliniMACS CD34 Reagent System,” said Robert J. Soiffer, MD, of Dana-Farber Cancer Institute and investigator in the Blood and Marrow Transplant Clinical Trials Network. n

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 | FEBRUARY 15, 2014

PAGE 9

Announcements

Margaret A. Tempero, MD, Named Editor-in-Chief of JNCCN

NCCN – Journal of the National Comprehensive Cancer Network, the journal of the National Comprehensive Cancer Network (NCCN), has named Margaret A. Tempero, MD, as Editor-in-Chief. Dr. Tempero assumed the position of Editor-

in-Chief on February 3, 2014, succeeding Harold J. Burstein, MD, PhD, who served in the position for 5 years. “Dr. Tempero’s highly esteemed career and demonstration of leadership in oncology research and practice, cou-

pled with her expansive knowledge of and experience with professional publications, make her an ideal individual to oversee the operations of JNCCN,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN

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.

Dr. Tempero is Director of the UCSF Pancreas Center, and Professor of Medicine at UCSF Helen Diller Family Comprehensive Cancer Center. Prior to joining the UCSF faculty, Dr. Tempero continued on page 10

The ASCO Post | FEBRUARY 15, 2014

PAGE 10

Announcements New JNCCN Editor-in-Chief continued from page 9

served for 17 years at the Eppley Cancer Center (now called the Fred and Pamela Buffett Cancer Center) at the Nebraska Medical Center, where she was Deputy Director and Professor of Medicine, and served as Chief of Oncology and Hematology at Omaha V.A. Medical Center.

Dr. Tempero is a founding member of the NCCN Board of Directors and has acted as Chairperson of the NCCN Guidelines Panel for Pancreatic Cancer and serves on the JNCCN Editorial Board. She is also a long-time contributor

Margaret A. Tempero, MD

to the NCCN Oncology Research Program and is an active member of the NCCN Continuing Medical Education Advisory Committee. From 2003 to 2004, Dr. Tempero served as President of the American Society of

Clinical Oncology, and she is currently a member of the Board of Directors for the Association of Northern California Oncologists, as well as a member of the Scientific Advisory Board for the Pancreatic Cancer Action Network, and the V Foundation. She served on the Board of Scientific Counselors for the National Cancer Institute from 1998 to 2006. n

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 | FEBRUARY 15, 2014

PAGE 11

Announcements

New Society Launched for Advanced Practitioners in Hematology and Oncology

he Advanced Practitioner Society for Hematology and Oncology (APSHO) announced its launch as a new organization focused on meeting the unique educational and

professional needs of the advanced practitioner in hematology and oncology. The formation of the Society was made public on January 26, 2014, at the

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

First Annual JADPRO LIVE meeting in St. Petersburg, Florida. JADPRO is the Journal of the Advanced Practitioner in Oncology, published by Harborside Press.

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

Tailored to All Advanced Practitioners in Oncology Advanced practitioners, as defined by the Society, include nurse practitiocontinued on page 12

The ASCO Post | FEBRUARY 15, 2014

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Announcements New Society Launched for Advanced Practitioners continued from page 11

ners, physician assistants, clinical nurse specialists, advanced degree nurses, and pharmacists. Nearly all of the attendees at the JADPRO LIVE conference registered to become Charter Members of APSHO. Pamela Hallquist Viale,

RN, MS, CS, ANP, AOCNP®, Editorin-Chief of JADPRO and a Founding Member of APSHO, said “JADPRO has brought the advanced practitioner relevant and practice-changing clinical updates since 2010. With the inception of APSHO, we look forward to doing even more to support the advanced practitioner audience and to provide a level

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®

Sandra E. Kurtin, RN, MS, AOCN®, ANP-C,

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.

Wendy H. Vogel, MSN, FNP, AOCNP®

of educational opportunities targeted to stimulate and add to our clinical and practical knowledge base.” Sandra E. Kurtin, RN, MS, AOCN®, ANP-C, another Founding Member of APSHO, announced that the mission of the Society is “to improve the quality of care for patients with cancer by supporting critical issues in educational, clinical, and professional development for advanced practitioners in oncology.” The Society also will serve to promote collaboration among the oncology team of providers, and to seek continued means for improving the quality of care delivered to patients with cancer. Founding Member Wendy H. Vogel, MSN, FNP, AOCNP®, noted that one of the core values of the Society will be collaboration. “An interdisciplinary team approach to cancer treatment offers the best hope for our patients’ cure, quality of life, and survivorship,” she said.

APSHO’s Peer-Reviewed Journal The Journal of the Advanced Practitioner in Oncology is the official journal of the new Society. Anthony Cutrone, President of Harborside Press, said, “Over the past 5 years of publishing JADPRO, we have had opportunities to meet some incredibly passionate advanced practitioners who are committed to furthering objectives of the advanced practitioner population. The feedback we’ve received has confirmed that the journal is meeting its editorial mission, and we have no doubt that the Society will do the same.” Conor Lynch, Executive Vice-President of Harborside Press, added, “Advanced practitioners in hematology and oncology are a highly committed and necessary part of the health-care team. We are honored to have played a part in initiating this important Society and we look forward to seeing it grow.”

For More Information

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12/13/13

APSHO will be releasing additional information shortly, including a call for members. To register or receive more information, visit APSHO.org or e-mail 1:32 PM the Society at info@APSHO.org. n

ASCOPost.com | FEBRUARY 15, 2014

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San Antonio Breast Cancer Symposium Breast Cancer

SABCS Highlights Include Findings in Triple-Negative Disease, Protective Effects of Exercise, and the Adherence-Copay Link By Alice Goodman and Caroline Helwick

he San Antonio Breast Cancer Symposium brings together specialists from all over the world who focus on management of breast cancer. We have covered many of the important presentations in the pages of The ASCO Post and in our online Evening News. Below are summaries of additional noteworthy meeting highlights. We hope you will find them of interest.

Actionable Genetic Mutations in Triple-Negative Breast Cancer

©ASCO/Todd Buchanan

Mutational analysis of tissue samples of triple-negative breast cancer identified several actionable mutations by genetic sequencing.1 The study included samples from primary tumors and metastatic sites in patients with metastatic triple-negative breast cancer enrolled in a phase II study of carboplatin and paclitaxel as first-line therapy. The investigators obtained 102 unique samples for genomic sequencing; 29 were triplets of germline/primary tumor/metastatic site, and 6 were doublets of normal and primary DNA. Thirty-one metastatic biopsies were obtained from the liver or nonbreast chest wall metastatic disease. The majority (91.4%) of somatic mutations were found in both the primary tumor and the recurrent/metastatic samples. Serial biopsies from the same patient revealed mutational

Kimberly L. Blackwell, MD

changes that occurred only in metastasis in 8.6% of tumors. Specific gene mutations correlated with clinical outcome and suggest therapeutic targets. For example, four genes were associated with poor response to therapy and unfavorable progressionfree survival—WNK1, TP53, JAK1, DCHS2—whereas two genes were associated with more favorable progressionfree survival—ATXN7 and MST1. Four

of these genes were related to microtubule metabolism and will be studied further. Genes that correlated with favorable prognosis or longer disease-free interval included HGF, PLXNA3, CSDE1, and ZNF710. Four genes were associated with overall survival: three with unfavorable survival (TP53, ITSN2, and ADH8A1) and one with improved overall survival (SPHKAP). TP53 was the only mutation that conferred both a worse progressionfree and overall survival. Potential actionable mutations and treatments (in parentheses) currently being studied in breast cancer include the following: TP53 (vaccine, gene therapy, WEE-1 inhibitors, Kevetrin); PARP (PARP inhibitors); ESR (alternative endocrine therapy); JAK1 ( JAK1 inhibitors); and mTOR (mTOR inhibitors). “Further chromosomal rearrangement/loss, mutation activation status, and transcriptional analysis for this tissue set is underway,” said lead author Kimberly L. Blackwell, MD, Professor of Medicine and Assistant Professor in Radiation Oncology at Duke University School of Medicine, Durham, North Carolina. This list is by no means exhaustive, she noted. Other genes with potentially actionable mutations are under study by several groups of investigators.

Protective Effect of Exercise in African American Women Regular vigorous exercise protects against subtypes of aggressive breast cancer, according to a 20-year observational study of more than 44,700 African American women aged 30 years or more called the Black Women’s Health Study.2 Brisk exercise for an average of 3 or more hours a week was associated with a 47% reduced risk of developing estrogen receptor–negative breast cancer compared with exercise for an average of 1 hour per week. “These findings are encouraging. Knowing that exercise may protect against these cancers that disproportionately strike African American women is of great public health importance,” said lead author Lucile AdamsCampbell, PhD, Associate Director of Minority Health and Health Disparities Research at Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC.

San Antonio Breast Cancer Roundup ■■ Mutational analysis of triple-negative breast cancer tissue samples identified several actionable mutations by genetic sequencing. ■■ Physical activity may protect against the development of estrogen receptor–negative breast cancer in African American women, according to a 20-year observational study. ■■ Higher prescription copayment was associated with nonadherence to aromatase inhibitor therapy in a study of more than 13,000 women with early breast cancer.

Estrogen receptor–negative subtypes include HER2-positive and triple-negative breast cancer, both of which are more frequent and have higher death rates in African American women compared with Caucasian women. Estrogen receptor–negative tumors are typically more difficult to treat than estrogen receptor–positive ones. Any level of exercise did not appear to impact the development of estrogen receptor–positive tumors in this study. The authors said that the study was not designed to demonstrate an effect on less aggressive tumors. The authors hope that this study will encourage black women to exercise. “Along with other well known benefits, we now show that exercise can possibly stave off development of potentially lethal breast cancer in African American women,” Dr. Adams-Campbell stated.

Generic Aromatase Inhibitors A large study was conducted to determine the impact of the change from brand name to generic aromatase inhibitors on adherence and discontinuation among breast cancer patients prescribed hormonal therapy.3 Results showed that out-of-pocket costs had an independent and linear association with adherence and discontinuation. Generic aromatase inhibitors were also independently associated with both improved adherence and lower rates of discontinuation. “These findings suggest that breast cancer survival may be improved by increasing access to medications,” said lead author Dawn L. Hershman, MD, MS, Associate Professor of Medicine at Columbia University Medical Center in New York. “Patients, providers, and advocates should be aware of the Cancer Treatment Fairness Act to prohibit higher copayments regardless of benefit category,” she told listeners.

The study was based on the Optum database (25 million members of United Health Care), Medicare (6 million members), and Medicaid (2 million members) and included women with

Dawn L. Hershman, MD, MS

early-stage breast cancer diagnosed between 2001 and 2011 who were older than age 50 and who filled two or more prescriptions for hormonal therapy (tamoxifen, or brand name or generic aromatase inhibitors). Among 13,522 patients, 7,500 did not switch hormonal therapy during the study period while 5,990 switched therapy at some time (72% switched from brand name aromatase inhibitors to generic aromatase inhibitors). Among nonswitchers, 89% had commercial insurance and 84% had no deductible. A multivariate analysis showed that generic aromatase inhibitors had significantly lower rates of discontinuation vs brand name aromatase inhibitors (P = .001). No difference was observed for discontinuations between tamoxifen and brand name aromatase inhibitors. A linear relationship was found between copayment amount and discontinuation, with copayments of $20 or more significantly associated with discontinuation (P < .001). In addition, annual income was associated with adherence, with those at the highest income level (> $100,000 per year) signifcontinued on page 15

Amgen is exploring the expanded potential of biomarker analysis in metastatic colorectal cancer (mCRC)

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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

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San Antonio Breast Cancer Symposium SABCS Highlights continued from page 13

icantly more adherent than those with annual incomes < $40,000 (P = .003).

Occult Metastases Not Clinically Important in Node-Negative Breast Cancer The 10-year follow-up of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 study, which examined outcomes for 5,611 clinically node-negative breast cancer patients randomly assigned to sentinel node dissection or sentinel node dissection plus axillary dissection, was reported in San Antonio by Thomas B. Julian, MD, Senior Surgical Director of NSABP Medical Affairs and Professor of Surgery at Temple University, Allegheny General Hospital, Pittsburgh.4 Occult metastases were found by immunohistochemistry (IHC) in 616 patients (16.4% of the axillary dissection group and 15.3% of the sentinel node–only dissection group). The majority of these metastases (11%) were isolated tumor cells. At 10 years, there continued to be no significant difference between sentinel node dissection and sentinel node plus axillary dissection in terms of overall survival, disease-free survival, distant disease–free survival, or regional control for patients with his-

tologically node-negative disease by strict hematoxylin-and-eosin (H&E) analysis, he reported. Overall survival was approximately 90% per arm, and disease-free survival was about 77%. In an analysis of overall survival according to the presence or absence of occult metastases, the difference between the arms—which was statisti-

10-year rate for those with metastases (HR = 1.32, P = .17). “The impact of occult metastatic nodal disease in this very large cohort of 5,611 patients is clinically nonsignificant,” according to Dr. Julian. “Overall survival, disease-free survival, and local-regional recurrence is not affected by the 15.3% positive occult metastases in the sentinel node resection–only group. Axillary node dissection for occult metastases is of no benefit.”

5-FU Not Beneficial as Adjuvant Therapy

Thomas B. Julian, MD

cally significant at 8-year follow-up— was no longer statistically significant. Overall survival rates were 89% for patients without occult metastases and 85.9% for those with occult metastases, a 3.1% difference (hazard ratio [HR] = 1.26, P = .06). However, the study identified a significant difference in disease-free survival between the groups, with a 4.7% absolute lower 10-year rate for those with occult metastases (HR = 1.25, P = .01). The difference in local-regional recurrence-free interval was not significant, with a 1.4% absolute lower

San Antonio Breast Cancer Symposium Roundup ■■ The presence of occult metastatic nodal disease had minimal impact on survival or local-regional recurrence in 10-year follow-up of the phase III NSABP B-32 trial. ■■ Dose-dense chemotherapy as adjuvant treatment in patients with node-positive breast cancer, improves disease-free and overall survival significantly, but adding 5-FU to epirubicin/cyclophosphamide does not improve clinical outcomes.

The randomized phase III GIM-2 trial found no benefit for adding fluorouracil (5-FU) to standard chemotherapy for early node-positive breast cancer.5 The key finding, according to Francesco Cognetti, MD, a medical oncologist at the Regina Elena National Cancer Institute in Rome, is that “5-FU should be deleted” from anthracycline-taxane combinations in the adjuvant treatment of node-positive disease. It has not been clear whether adding 5-FU to an adjuvant regimen would be of value, and these results put the issue to rest. GIM-2 evaluated 2,091 patients treated with epirubicin and cyclophosphamide, with or without 5-FU, followed by paclitaxel given either every 2 or 3 weeks. After a median follow-up of 7 years, a multivariate analysis showed that the dose-dense arms improved both disease-free and overall survival, but adding 5-FU had no effect on clinical outcomes, regardless of the dosing schedule. The 5-year relapse-free survival rate was 81% in the dose-dense arms and 76% for the standard arms (HR = .78, P < .001). The overall survival rate at 5 years was 94% and 89%, respectively (HR = .69, P = .0001). The accelerated

dosing improved disease-free survival regardless of clinical and pathologic characteristics, Dr. Cognetti reported, making it “the optimal option” for early-stage, node-positive disease. n

Disclosure: Drs. Blackwell, AdamsCampbell, Hershman, and Julian reported no potential conflicts of interest.

References 1. Blackwell KL, Hamilton EP, Marcom PK, et al: Exome sequencing reveals clinically actionable mutations in gthe pathogenesis and metastasis of triple negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S4-03. Presented December 12, 2013. 2. Adams-Campbell L, Palmer JR, Bethea T, et al: Vigorous exercise across the lifespan and reduced risk of estrogen receptor negative breast cancer in African American women. 2013 San Antonio Breast Cancer Symposium. Abstract PD27. Presented December 11, 2013. 3. Hershman D, Tsui J, Meyer JW, et al: The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early stage breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 12, 2013. 4. Julian TB, Anderson SJ, Weaver, et al: 10-yr follow-up results of occult detected sentinel node disease: NSABP B-32. 2013 San Antonio Breast Cancer Symposium. Abstract S2-05. Presented December 11, 2013. 5. Cognetti F, Bruzzi P, De Placido S, et al: Epirubicin and cyclophosphamide followed by paclitaxel versus fluorouracil, epirubicin and cyclophosphamide followed by T, all given every 3 weeks or 2 weeks, in node-positive early breast cancer patients. Final results of the Gruppo Italiano Mammella (GIM)-2 randomized phase III study. 2013 San Antonio Breast Cancer Symposium. Abstract S5-6. Presented December 13, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Manish Shah, MD, on Ramucirumab in Colorectal Cancer see page 3

Andrew D. Zelenetz, MD, PhD, on Maintenance Rituximab in Lymphoma see page 33

Visit The ASCO Post online at ASCOPost.com

Clifford Hudis, MD, on the 50th Anniversary of the Surgeon General’s Report see page 39

The ASCO Post | FEBRUARY 15, 2014

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San Antonio Breast Cancer Symposium Breast Cancer

Postmastectomy Pain Effectively Treated With a Simple Injection By Caroline Helwick

or postmastectomy neuropathic pain, perineural infiltration with a combination of bupivacaine and dexamethasone is a “simple, effective, practice-changing treatment that any surgeon can do,” according to Laura J. Esserman, MD, MBA, Professor of Surgery and Radiology at the University of California, San Francisco, School of Medicine and Director of the Carol Franc Buck Breast Care Center, senior author of the study. The intervention—2-mL injections of an equal ratio of 0.5% bupivacaine and 4 mg/mL of dexamethasone—was described at the 2013 San Antonio Breast Cancer Symposium.1 The study’s first author was Cathy J. Tang, MD, also a surgeon at the University of California, San Francisco.

Study Rationale Some 20% to 68% of breast cancer patients have chronic postoperative breast pain, commonly known as postmastectomy pain syndrome. Usually this is neuropathic in origin and can begin in the immediate postoperative period, but may appear 6 months post-

operatively or later. It often persists beyond the normal healing period, sometimes years. The study’s hypothesis was that T4 and T5 sensory nerves are damaged—cut and cauterized—during surgery, and this is the

the T4 and T5 nerves likely exit the chest wall. We wait half a minute, and then massage it in. Within a minute, the patient has no more pain. For 60% of patients, we never have to inject again.”

This condition affects patients’ daily lives. It can be miserable, and it is much more common than surgeons think. —Laura J. Esserman, MD, MBA

source of the pain. Such trauma can lead to neuroma formation and cause postoperative pain along the specific dermatomes. “We go in and find the maximal point of tenderness, usually at 6 o’clock or 9 o’clock along the intramammary fold,” Dr. Esserman told The ASCO Post. “We take a mixture of bupivacaine and dexamethasone and inject this at the site of the neuroma, where

Managing Postmastectomy Pain ■■ Postmastectomy pain is common and is a huge quality-of-life issue. ■■ It can be simply and effectively treated with injections of bupivacaine and dexamethasone at areas of maximal tenderness.

Outcomes Data Since January 2011, Dr. Esserman and her colleagues have treated and tracked 19 patients who presented with characteristic neuropathic pain and point tenderness located at either the inframammary fold directly inferior to the nipple or laterally along the midaxillary line. Patients were followed from 6 to 25 months. The 19 patients received 29 total injections, and pain resolved in 93% of the injection sites. For 17 patients (59%), only one injection was required. For 10 (34%), pain resolved after multiple injections. In one patient (3.5%), an injection was scheduled but had not occurred yet, and for another

patient (3.5%) who had pain after stereotactic biopsy, the pain did not resolve, possibly because the location of the neuroma was not well targeted. The study also emphasizes the need for careful dissection of the T4 and T5 sensory nerves to avoid cauterizing the nerve along with the accompanying blood vessels, thus avoiding postoperative neuroma formation, which clearly contributes to postmastectomy pain, the authors said. Dr. Esserman said that surgeons and nurses should routinely ask about postoperative focal neuropathic pain, which can also exhibit as the inability to wear a bra or to lie on the affected side. “This condition affects patients’ daily lives. It can be miserable, and it is much more common than surgeons think,” she said. “If you are taking care of a patient and have given her chronic pain, that’s a terrible thing that you have to pay attention to.” n

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

Reference 1. Tang CJ, Elder SE, Lee DJ, et al: 2013 San Antonio Breast Cancer Symposium. Abstract P3-10-03. Presented December 12, 2013.

Addition of Novel Antiangiogenic Agent of No Benefit in Metastatic Breast Cancer By Alice Goodman

amucirumab added to first-line docetaxel failed to improve progression-free survival in patients with metastatic breast cancer in the large, randomized, placebo-controlled ROSE/TRIO-12 trial.1 An interim analysis of overall survival showed no advantage for the addition of

“Thus far, no antiangiogenesis strategy has improved survival in breast cancer. Ramucirumab did not significantly prolong progression-free survival in this trial, and there is no signal that it will prolong overall survival. This was a failed trial,” said lead author John R. Mackey, MD, Professor of Medical Oncology at the University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.

Study Background

John R. Mackey, MD

ramucirumab. This study, presented at the 2013 San Antonio Breast Cancer Symposium, joins a number of other failed antiangiogenesis trials in breast cancer, most of them evaluating bevacizumab (Avastin).

Ramucirumab is a recombinant human monoclonal antibody targeted to vascular epidermal growth factor receptor (VEGFR)-2. This drug has been granted priority review by the U.S. Food and Drug Administration as second-line therapy for advanced gastric cancer based on results of the REGARD trial, a single-agent study.2 Ramucirumab is also being studied as second-line therapy of advanced gastric cancer in combination with paclitaxel in the RAINBOW trial

Ramucirumab in Breast Cancer ■■ Ramucirumab is of no added value to first-line docetaxel chemotherapy in metastatic breast cancer. ■■ Thus far no single trial of an antiangiogenesis agent has shown improved survival in breast cancer. ■■ The only hope for the future of this strategy in breast cancer would be the identification of subgroups that could benefit using a biomarker.

(see page 3).3 Results of phase III trials of ramucirumab in colorectal, hepatocellular, and lung cancer are expected in 2014. ROSE/TRIO-12 was conducted in 25 countries and included 1,144 patients with metastatic breast cancer taking standard-dose docetaxel as first-line therapy. Patients were randomly assigned 2:1 to also receive ramucirumab vs placebo and were treated until disease progression. For the primary endpoint of investigator-assessed progression-free survival, the

addition of ramucirumab failed to make a significant difference. Median progression-free survival was 8.2 months with placebo and 9.5 months with ramucirumab. No advantage in overall survival was observed for ramucirumab at the interim analysis. Final analysis of overall survival is planned in 1 year. No advantage in progression-free or continued on page 18

Another treatment opportunity

NOW AVAILABLE

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) complete remission (CR)/complete remission with incomplete blood count recovery (CRi) in patients who all 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 has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage

• 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

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 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

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

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PAGE 18

San Antonio Breast Cancer Symposium Metastatic Breast Cancer continued from page 16

overall survival was detected in any subgroup analyzed, including those assessed by age, race, performance status, prior taxane treatment, site of metastasis, hormone receptor status, and geographic region, Dr. Mackey said. As expected, more side effects—includ-

ing fatigue, hypertension, bleeding, febrile neutropenia, and stomatitis—were observed in patients assigned to ramucirumab.

Strategy Unsuccessful “Is it time to throw in the towel for the strategy of antiangiogenesis in breast cancer?” asked press conference moderator Peter Ravdin, MD, PhD, a Breast Cancer

Researcher and Biostatistician in San Antonio, Texas. “At the time the trial was designed, we had reason to hope ramucirumab would benefit our patients. I believe that there is a role for antiangiogenesis, if we could find a biomarker,” Dr.

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 peripheral neuropathy after the first dose reduction to 2 mg/m2:

Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 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 Sulfate Injection must be done in a biological safety cabinet or by established pharmacy safety procedures for the preparation of

Peter Ravdin, MD, PhD

Mackey responded. Thus far, efforts at finding a biomarker for antiangiogenesis strategies have been unsuccessful. “There are hints that certain markers might predict the benefit of antiangiogenesis, but these markers

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 Charcot-MarieTooth 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.

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San Antonio Breast Cancer Symposium have not yet been included in analysis of studies. Drugs with no overall benefit may be of benefit in a particular subset of patients. It is still a work in progress to identify subsets that will benefit,” said Dr. Ravdin, who noted that the diversity of breast cancer is well recognized. n Disclosure: Drs. Mackey and Ravdin reported no potential conflicts of interest.

References 1. Mackey JR, Ramos-Vasquez M, Lipatov O, et al: Primary results of ROSE/TRIO-12, a randomized, placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-04. Pre-

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.

sented December 13, 2013. 2. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastrooesophageal junction adenocarcinoma (REGARD). Lancet 383:31-39, 2014. 3. Wilke H, Van Cutsem E, Oh SC, et al: RAINBOW: A global, phase III, randomized, double-blind trial of ramu-

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 non-leukemia 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.

cirumab and paclitaxel versus placebo and paclitaxel in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression of first-line platinum and fluoropyrimidine-containing combination therapy. 2014 Gastrointestinal Cancers Symposium. Abstract LBA7. Presented January 16, 2014.

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San Antonio Breast Cancer Symposium Breast Cancer

Switching Chemotherapy Based on Elevated Circulating Tumor Cells Does Not Change Outcome in Metastatic Breast Cancer By Alice Goodman

levated circulating tumor cells were prognostic for survival but did not pan out as a marker for switching after one cycle of chemotherapy

in patients with metastatic breast cancer. The phase III Southwest Oncology Group (SWOG) S0500 clinical trial, presented at the 2013 San

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 post-implantation 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 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.

Antonio Breast Cancer Symposium, showed that switching chemotherapy after one cycle based on elevated circulating tumor cell levels did not

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]. 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. Distributed by: Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Talon Therapeutics, Inc., 11500 South Eastern Ave., Suite 240, Henderson, NV 89052 ©2013 Talon Therapeutics, Inc. Marqibo® is a registered trademark of Talon Therapeutics, Inc. All rights reserved. October 2013. Printed in the USA. 0125-080400 SPPIRX.com

Jeffrey B. Smerage, MD, PhD

improve progression-free survival or overall survival in women with metastatic breast cancer.1 “We concluded that [circulating tumor cells] are not a good marker to help decide whether to switch chemotherapies early after only one cycle of initial therapy,” said Jeffrey B. Smerage, MD, PhD, Clinical Associate Professor in Medical Oncology at the University of Michigan Comprehensive Cancer Center, Ann Arbor. “Our hope was that switching would increase the chances of having an effective therapy and decrease exposure to toxicity from less effective therapies, and that early switching based on [circulating tumor cells] would improve survival and time to progression,” he continued. “Most important, we have validated the hypothesis that the group of patients with elevated [circulating tumor cells] at baseline and 21 days after starting the first chemotherapy

Circulating Tumor Cells in Metastatic Breast Cancer ■■ Elevated circulating tumor cell levels were prognostic for survival in the SWOG S0500 clinical trial in patients with metastatic breast cancer. ■■ Switching to another chemotherapy based on elevated circulating tumor cells at day 21 after one cycle of chemotherapy did not improve survival compared to remaining on the same chemotherapy. ■■ Further studies are needed to characterize circulating tumor cells and select therapy based on molecular characteristics.

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PAGE 21

San Antonio Breast Cancer Symposium has a worse prognosis with regard to [progression-free and overall survival], while low baseline levels signal a very good prognosis,” he told listeners.

Study Design SWOG S0500 recruited 624 patients with measurable metastatic disease between 2006 and 2012. Circulating tumor cells were captured and enumerated using the CellSearch System, one of several platforms designed for this purpose, and the only one that is U.S. Food and Drug Administration–approved for determining prognosis and monitoring therapy. Of the 595 patients eligible for the trial, 276 had low circulating tumor cells at baseline and went on Arm A continuing on their initial chemotherapy. Among 319 patients with elevated circulating tumor cells at baseline, 286 had a circulating tumor cell result at day 21 after the first cycle

tients with low circulating tumor cell levels at baseline. Elevated circulating tumor cells at baseline that drop below the threshold after one cycle of chemotherapy were associated with median overall survival of 23 months (arm B). Patients with elevated circulating tumor cells after one cycle of chemotherapy (arms C1 and C2) had the worst prognosis. “Although chemotherapy may be effective in some patients [with elevated circulating tumor cells], it does not have a prolonged effect. Our results suggest that this patient population needs more effective treatment options beyond chemotherapy,” he commented. “Early consideration of clinical trial participation would be appropriate.” At the time the study was initiated, the technology only allowed enumeration of circulating tumor cells. “Now we can do more with molecular profiling of [circulating tumor cells], and we hope this will lead to the ability to

These smaller studies may help us identify patients who will benefit from hormonal therapy, as well as to select the next therapy for nonresponders. —Jeffrey B. Smerage, MD, PhD

of chemotherapy. Of these, 163 had decreased levels of circulating tumor cells at day 21 and were continued on their initial chemotherapy (arm B); 123 patients with elevated circulating tumor cells at day 21 were randomly assigned to arm C1 and continued initial chemotherapy (n = 64) or were randomly assigned to arm C2 and had a switch in chemotherapy (n = 59 patients). Dr. Smerage noted that the study was not designed to compare chemotherapies.

Key Results Median overall survival was 12 months for both randomized arms (maintaining therapy and switching therapy based on circulating tumor cell levels). Median progression-free survival was 3.5 months for the maintain-therapy arm and 4.6 months for the switchtherapy arm, which was not statistically significant. Low baseline circulating tumor cell levels (defined as < 5 cells/7.5 mL) were associated with a very good prognosis, with median overall survival of 35 months in arm A (pa-

predict appropriate treatment strategies for patients that simply counting cells does not allow us to do,” Dr. Smerage said. Ongoing circulating tumor cell studies at the University of Michigan include a three-center study of HER2 cells and circulating tumor cells to predict which patients have high-risk disease without requiring more biopsies. Another study will test estrogen signaling in circulating tumor cells prior to initiation of hormonal therapy and then on treatment to determine if these markers predict better outcomes. “These smaller studies may help us identify patients who will benefit from hormonal therapy, as well as to select the next therapy for nonresponders. Once we have positive results in smaller studies, we will move to larger ones,” Dr. Smerage told listeners. n

EXPERT POINT OF VIEW

ellSearch can be ordered to enumerate circulating tumor cells, but this test is not recommended in the National Comprehensive Cancer Network guidelines, said Peter Ravdin, MD, PhD, a Breast Cancer Researcher and Biostatistician in San Antonio, Texas, and moderator of the press conference where Southwest Oncology Group (SWOG) S0500 results were discussed.

[Circulating tumor cells] cannot be used as a new marker to determine if patients who are failing on one chemotherapy should be switched to another chemotherapy. —Peter Ravdin, MD, PhD

“The study shows that at this time, [circulating tumor cells] cannot be used as a new marker to determine if patients who are failing on one chemotherapy should be switched to another chemotherapy,” Dr. Ravdin said. “Although this study was negative, intuitively the concept of using elevated [circulating tumor cells] to decide when to switch therapy should work. The study had enormous heterogeneity and was not designed to compare the effectiveness of chemotherapies. Physicians had the choice of front-line therapy and then they switched to another therapy based on circulating tumor cell level. Perhaps if the trial had a cleaner design using specific chemotherapies, the results would have been different,” Dr. Ravdin commented. “We hope elevated [circulating tumor cells] will be useful in the future. We need uniform and effective second-line therapies. Then we would expect switching early based on [circulating tumor cells], before symptoms develop, would have enormous benefit,” he stated. n Disclosure: Dr. Ravdin reported no potential conflicts of interest.

therapy for metastatic breast cancer patients who have elevated circulating tumor cell (CTC) levels at first follow-up

assessment. 2013 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 13, 2014.

Disclosure: Dr. Smerage has received research funding from Genomic Health.

Reference 1. Smerage JB, Barlow WE, Hortobagyi GN, et al: SWOG S0500: A randomized phase III trial to test the strategy of changing therapy versus maintaining

San Antonio Breast Cancer Symposium: C Kent Osborne, MD, presented the William L. McGuire Memorial Lecture award to Monica Morrow, MD, FACS. Dr. Morrow is Chief, Breast Service, Department of Surgery, and Anne Burnett Windfohr Chair of Clinical Oncology, at Memorial Sloan Kettering Cancer Center in New York. Dr. Morrow delivered the William l. McGuire Memorial Lecture on “Local Therapy in the Molecular Era: Relevant or Relic?” Photo Courtesy © SABCS/Todd Buchanan 2013.

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PAGE 23

ASH Annual Meeting Hematology

ASH Studies Refine Myeloma Treatment and Show Promise for New Agents By Caroline Helwick

ultiple myeloma researchers moved the field forward at the 2013 American Society of Hematology (ASH) Annual Meeting, presenting evaluations of treatment schedules and reports of encouraging activity with compounds in development.

Alternating vs Sequential Regimens In 231 newly diagnosed elderly patients, Spanish investigators evaluated sequential vs alternating use of VMP (bortezomib [Velcade], melphalan, and prednisone) and Rd (lenalidomide [Revlimid] plus low-dose dexamethasone) in the GEM2010MAS65 trial.1 The sequential treatment scheme was nine consecutive cycles of VMP followed by nine consecutive cycles of Rd. Patients treated with the alternating

“After nine induction cycles, the alternating scheme is superior in efficacy, especially in terms of stringent complete responses and complete responses, as compared with the sequential scheme, and with no more additional toxicity,” she concluded. “The benefit of these combinations seems to be consistent in different risk groups, especially in patients with high-risk cytogenetic abnormalities.” She suggested evaluat-

Novel Approaches to Multiple Myeloma ■■ Bortezomib/melphalan/prednisone (VMP) and lenalidomide/ dexamethasone (Rd) might best be used on an alternating schedule, rather than sequentially. ■■ In a community-based population, triplet alkylating combinations did not lead to improved progression-free survival or overall survival over doublet therapy. ■■ Promising activity was reported for ixazomib citrate (MLN9708), panobinostat, and filanesib (ARRY-520).

ing the final benefit of these two approaches as incorporated into a total therapeutic approach in the elderly.

Doublets as Good as Triplets Maria-Victoria Mateos, MD, PhD

scheme either started with one cycle of VMP and alternated with one cycle of Rd, or started with one cycle of Rd and alternated with one cycle of VMP, each for up to 18 cycles. After 9 months of treatment, response rates were higher for the alternating scheme (93% vs 89% with sequential treatment), and the proportion of patients achieving a very good partial response or greater was 78% vs 56%, respectively (P = .004). At 20 months, the alternating group also had numerical improvements in progression-free survival (84% vs 80%) and overall survival (92% vs 88%), but the differences were not statistically significant, according to Maria-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca, Spain. The study also established the benefit of achieving a stringent complete response or complete response. In this group, progression-free survival was 96% in the alternating arm and 92% in the sequential arm, which was significantly better than those with less than a very good partial response, whose progression-free survival rates at 20 months were 78% and 62%, respectively.

months, progression-free survival was 22 months, 27 months, and 24 months, respectively, and overall survival was 80%, 81%, and 84%. None of the differences were statistically significant, Dr. Palumbo reported. MPR was associated with significantly more neutropenia (P < .0001), thrombocytopenia (P < .003), and anemia (P < .0001), and required significantly more dose reductions (P <

In a community-based population, triplet alkylating combinations did not lead to improved progression-free survival or overall survival benefits over doublet therapy, Antonio Palumbo, MD, of the University of Torino in Italy reported at the ASH meeting. The study compared Rd (lenalidomide plus low-dose dexamethasone, n = 211) vs the alkylating-based regimens MPR (melphalan, prednisone,

Antonio Palumbo, MD

lenalidomide, n = 210) and CPR (cyclophosphamide, prednisone, lenalidomide, n = 220) in elderly, transplantineligible, newly diagnosed myeloma patients. After a median of nine cycles, all patients received maintenance lenalidomide until disease progression. A partial response or better was achieved by 74% of the Rd group, 73% of the MPR group, and 72% of the CPR group. At a median follow-up of 26

.0001) than the other regimens. Differences in subsets of patients led Dr. Palumbo to conclude that CPR may be a good regimen for fit patients, Rd may be good for unfit patients, and a lower-dose regimen of lenalidomide at 15 mg plus dexamethasone at 10 mg may be best for frail patients.

Ixazomib Citrate In newly diagnosed patients, the oral proteasome inhibitor ixazomib citrate (formerly known as MLN9708) combined with lenalidomide and dexamethasone, led to high response rates and increased depth of response with extended treatment duration, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, reported at the meeting.3 “To date, this is the first all-oral combination of a proteasome inhibitor with an immunomodulatory drug under investigation in this setting, and the data strongly support the feasibility and activity of this combination in newly diagnosed patients,” Dr. Richardson said. Ixazomib was given twice weekly

Paul G. Richardson, MD

with lenalidomide/dexamethasone to 71 treatment-naive patients, mostly at a dose of 3.0 mg. Patients received up to 16 cycles of the triplet. The overall response rate was 94%, and the rate of complete response plus very good partial response was 76%. A stringent complete response was reached in 75% of complete responders. Responses appeared to deepen over the course of treatment, with 93% of patients responding after 4 cycles (at least a very good partial response in 61%) and 95% responding after both 8 and 16 cycles (at least a very good partial response in 71%). Drug-related serious adverse events were seen in 28% of patients, grade 3 drug-related adverse events were reported in 58%, and there were no grade 4 events. The investigators concluded, “These data suggest that twice-weekly oral ixazomib plus [lenalidomide/dexamethasone] is feasible and active in patients with newly diagnosed [multiple myeloma]. However, rates of rash, [peripheral neuropathy], and dose reductions appear higher than in the parallel study using weekly ixazomib, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase III trials.”

Panobinostat Trials Dr. Richardson also presented an updated analysis of the phase II PANORAMA 2 trial of the oral histone deacetylase inhibitor panobinostat paired with bortezomib and dexamethasone in 55 patients with relapsed and bortezomib-refractory disease.4 Patients showing clinical benefit by eight cycles continued on treatment. The median duration of exposure was about 5 months. The objective response rate was 35% (with very good partial responses in 5.5%), and the clinical benefit rate was 53%, with a median duration of response of 6 months. High-risk cytogenetics did not negatively impact response rates; in this subset, the response rate was 42.9% and the clinical benefit rate was 71.4%. For all patients, median progression-free survival was 5.4 months and median overall survival was 17.5 months. “These results, and those from the recently completed phase III trial of panobinostat, bortezomib, and dexacontinued on page 24

The ASCO Post | FEBRUARY 15, 2014

PAGE 24

ASH Annual Meeting Panobinostat Trials continued from page 23

methasone in relapsed/refractory myeloma (PANORAMA 1), will better elucidate the role of this combination,” he said. “In particular, the announcement at the meeting that the PANORAMA 1 trial had met its primary endpoint with a highly significant improvement in progression-free survival is especially encouraging, and we await further results from this study with great interest.” Another multicenter dose-finding phase II study evaluated panobinostat in combination with the proteasome inhibitor carfilzomib (Kyprolis) in 44 patients with relapsed/refractory myeloma.5 Median progression-free survival was 6.8 months, the 12-month progression-free survival rate was 41%, the 12-month overall survival rate was 85%, overall response rate was 64%, and clinical benefit rate was 76%. “The combination of panobinostat and carfilzomib is feasible and effective in the relapsed or relapsed/refractory population, and prior exposure to pro-

Jesus G. Berdeja, MD

teasome inhibitors or [immunomodulatory drugs] does not seem to affect the response rate or overall survival of patients on this combination,” according to Jesus G. Berdeja, MD, of Sarah Cannon Research Institute, Nashville.

Other Emerging Agents Several monoclonal antibodies are in various stages of development in my-

eloma. One that targets CD38, daratumumab, is considered promising and received Breakthrough Therapy designation from the U.S. Food and Drug Administration in 2013. Torben Plesner, MD, of Vejle Hospital in Denmark, presented data on 11 patients who relapsed after at least two prior lines of therapy.6 Eight achieved at

Torben Plesner, MD

least a partial response after treatment with daratumumab (up to 16 mg/kg), in combination with lenalidomide and dexamethasone, including complete responses in three and very good partial responses in two. No patients had disease progression, and the treatment was well tolerated. Thus, the previously reported finding of single-agent activity and tolerability of daratumumab for relapsed or relapsed/refractory myeloma (ASH 2012) has now been extended to the combination of daratumumab with lenalidomide and dexamethasone. A new class of agents that target the kinesin spindle protein is also being tested in myeloma. One such kinesin spindle protein inhibitor is filanesib (ARRY-520). Mature data from a phase II trial of this agent in 87 heavily pretreated patients (median, 6 prior therapies) found response rates to be 16% for the single agent, and 15% for filanesib plus dexamethasone, which was administered to patients who were dual-refractory to both bortezomib and lenalidomide, reported Jonathan Kaufman, MD, of Emory University’s

Jonathan Kaufman, MD

Winship Cancer Insitute, Atlanta.7 In addition, the retrospective use of AAG (acute phase protein alpha1-acidic glycoprotein) levels as a biomarker improved predictive outcomes. In patients with low AAG levels, the response rate was 24% for single-agent filanesib and 19% for filanesib plus dexamethasone in dual-refractory patients. The median overall survival in AAG-low patients receiving the single agent was 23.3 months, and was 11 months in dual-refractory patients with low AAG levels, compared to 4.5 months and 2.9 months, respectively, for patients with high AAG levels in these treatment arms. n Disclosure: Dr. Mateos has received honoraria from Janssen, Onyx, Millennium, Novartis, and Celgene. Dr. Palumbo is a consultant for and has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium, and Onyx. Dr. Richardson is an advisor for Millennium, the Takeda Oncology Company, Celgene, and Johnson & Johnson. Dr. Berdeja reported no potential conflicts of interest. Dr. Plesner has been a consultant for Genmab and a member of advisory committees for Janssen and Celgene. Dr. Kaufman has been a consultant for Onyx, Novartis, Janssen, and Millennium, and has received research funding from Celgene, Novartis, and Merck.

References 1. Mateos M-V, Martinez-Lopez J, Hernandez M, et al: Comparison of sequential vs. alternating administration of bortezomib, melphalan and prednisone and lenalidomide plus dexamethasone in elderly patients with newly diagnosed multiple myeloma patients: GEM2010MAS65 Trial.

2013 ASH Annual Meeting. Abstract 403. Presented December 9, 2013. 2. Palumbo A, Magarotto V, Bringhen S, et al: A randomized phase 3 trial of melphalan-lenalidomide-prednisone (MPR) or cyhclophosphamide-prednisone-lenalidomide (CPR) vs lenalidomide plus dexamethasone (Rd) in elderly newly diagnosed multiple myeloma patients. 2013 ASH Annual Meeting. Abstract 536. Presented December 9, 2013. 3. Richardson PG, Hofmeister C, Rosenbaum C, et al: Twice-weekly oral MLN9708 (ixazomib citrate), an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma: Final phase 1 results and phase 2 data. 2013 ASH Annual Meeting. Abstract 535. Presented December 9, 2013 4. Richardson PG, Schlossman R, Alsina M, et al: Time to event analyses in PANORAMA 2: A phase 2 study of panobinostat, bortezomib, and dexamethasone in patients with relapsed and bortezomibrefractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 1970. Presented December 7, 2013. 5. Berdeja J, Savona M, Mace J, et al: A single-arm, open-label, multicenter phase I/ II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapse/refractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 1937. Presented December 7, 2013. 6. Plesner T, Arkenau T, Lokhorst H, et al: Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 1986. Presented December 7, 2013. 7. Lonial S, Shah JJ, Zonder J, et al: Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma patients with low α-1 acid glycoprotein levels: Results from a phase 2 study. 2013 ASH Annual Meeting. Abstract 285. Presented December 9, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Steven M. Horwitz, MD, on Breast Implant– Associated ALCL see page 47

Nancy E. Davidson, MD, on ASCO/CAP Guidelines on HER2 Testing see page 50

Visit The ASCO Post online at ASCOPost.com

Richard Boxer, MD, FACS, and William J. Aronson, MD, on Telomerase Activity in Prostate Cancer see page 61

In postmenopausal women with advanced HR+, HER2-negative breast cancer,

When your patients need MORE...

There is a treatment regimen that has more than doubled median PFS after failure of a nonsteroidal aromatase inhibitor1

Abbreviations: HR+, hormone receptor-positive; PFS, progression-free survival.

AFINITOR plus exemestane Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

55%

HR=0.45 [95% CI, 0.38-0.54]

reduction in risk of progression or death1

Log-rank P value: <0.0001

PFS curves began to diverge

at 6 weeks

(the first tumor assessment) 1,2

PFS Probability (%)

Median PFS

7.8 months

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

0 0

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2.

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 •

Median PFS was 11.0 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information) Noninfectious Pneumonitis: •

•

• •

•

For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose

MORE THAN DOUBLES MEDIAN PFS

over exemestane alone1

Proven PFS benefit across all preplanned patient subgroups1,2 Median PFS Across Preplanned Patient Subgroups2 AFINITOR plus exemestane

Placebo plus exemestane

Median PFS (months) 8.3 6.8

2.9 4.0

8.1 6.8

3.9 2.8

6.8 9.9

2.8 4.2

8.3 6.9

4.1 2.8

12.9 6.9

5.3 2.8

8.2 7.0

3.2 3.5

8.1 6.9 8.2

4.4 3.0 3.0

8.1 7.0

2.8 4.1

8.1 6.9

3.3 2.8

11.5 6.7 6.9

4.4 3.5 2.6

Subgroups (n) All (724)

Age <65 (449) ≥65 (275) Sensitivity to prior hormonal therapy YES (610) NO (114) Presence of visceral metastasis YES (406) NO (318) Baseline ECOG PS 0 (435) 1 or 2 (274) Bone-only lesions at baseline YES (151) NO (573) Prior chemotherapy YES (493) NO (231) No. of prior therapies used in the adjuvant setting or to treat advanced disease 1 (118) 2 (217) ≥3 (389) Prior hormonal therapya YES (398) NO (326) Progesterone receptor status Positive (523) Negative (184) No. of organs involved 1 (219) 2 (232) ≥3 (271)

Excluding anastrozole and letrozole.

Favors placebo plus exemestane

Favors AFINITOR plus exemestane

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Hazard Ratio

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.

Prescribe AFINITOR plus exemestane upon first progression on letrozole or anastrozole therapy1 Important Safety Information) Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR •

Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment •

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: •

Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed If symptoms are moderate, patients should be managed with dose interruption until symptoms improve The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose

In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed •

Renal Failure: •

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR

Geriatric Patients:

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended •

Vaccinations:

• The use of live vaccines and close contact with In the randomized advanced hormone those who have received live vaccines should receptor-positive, HER2-negative breast cancer be avoided during treatment with AFINITOR study, the incidence of deaths due to any cause within 28 days of the last AFINITOR Embryo-Fetal Toxicity: • dose was 6% in patients ≥65 years of age • Fetal harm can occur if AFINITOR is compared to 2% in patients <65 years of age administered to a pregnant woman. Women of • Adverse reactions leading to permanent childbearing potential should be advised to use discontinuation occurred in 33% of patients a highly effective method of contraception • ≥65 years of age compared with 17% in while using AFINITOR and for up to 8 weeks patients <65 years of age after ending treatment • • Careful monitoring and appropriate Adverse Reactions: dose adjustments for adverse reactions • The most common adverse reactions (incidence are recommended ≥30%) were stomatitis (67%), infections Laboratory Tests and Monitoring: (50%), rash (39%), fatigue (36%), diarrhea • (33%), and decreased appetite (30%) Elevations of serum creatinine, proteinuria, • glucose, lipids, and triglycerides, and • The most common grade 3/4 adverse reactions reductions of hemoglobin, lymphocytes, (incidence ≥2%) were stomatitis (8%), infections Infections: neutrophils, and platelets, have been reported (5%), hyperglycemia (5%), fatigue (4%), dyspnea • AFINITOR has immunosuppressive properties • Renal function (including measurement of blood (4%), pneumonitis (4%), and diarrhea (2%) and may predispose patients to bacterial, urea nitrogen, urinary protein, or serum Laboratory Abnormalities: fungal, viral, or protozoal infections (including creatinine), blood glucose, lipids, and • The most common laboratory abnormalities those with opportunistic pathogens). Localized hematologic parameters should be evaluated (incidence ≥50%) were hypercholesterolemia and systemic infections, including pneumonia, prior to treatment and periodically thereafter (70%), hyperglycemia (69%), increased aspartate mycobacterial infections, other bacterial • When possible, optimal glucose and lipid transaminase (AST) concentrations (69%), anemia infections, invasive fungal infections such as control should be achieved before starting a (68%), leukopenia (58%), thrombocytopenia aspergillosis or candidiasis, and viral patient on AFINITOR (54%), lymphopenia (54%), increased alanine infections, including reactivation of hepatitis B transaminase (ALT) concentrations (51%), and Drug-Drug Interactions: virus, have occurred hypertriglyceridemia (50%) • Avoid coadministration with strong CYP3A4 • Some of these infections have been severe (eg, • The most common grade 3/4 laboratory inhibitors (eg, ketoconazole, itraconazole, leading to respiratory or hepatic failure) or fatal abnormalities (incidence ≥3%) were clarithromycin, atazanavir, nefazodone, • Physicians and patients should be aware of the lymphopenia (12%), hyperglycemia (9%), saquinavir, telithromycin, ritonavir, indinavir, increased risk of infection with AFINITOR anemia (7%), decreased potassium (4%), nelfinavir, voriconazole) • Treatment of preexisting invasive fungal increased AST (4%), increased ALT (4%), • Use caution and reduce the AFINITOR dose to infections should be completed prior to and thrombocytopenia (3%) 2.5 mg daily if coadministration with a starting treatment moderate CYP3A4 and/or PgP inhibitor is • Be vigilant for signs and symptoms of infection Please see Brief Summary of Prescribing required (eg, amprenavir, fosamprenavir, and institute appropriate treatment promptly; Information on adjacent pages. aprepitant, erythromycin, fluconazole, interruption or discontinuation of AFINITOR verapamil, diltiazem) To learn more, please visit should be considered • Avoid coadministration with strong CYP3A4 www.AFINITOR.com. • Discontinue AFINITOR if invasive systemic inducers (eg, phenytoin, carbamazepine, fungal infection is diagnosed and institute rifampin, rifabutin, rifapentine, phenobarbital); appropriate antifungal treatment References: 1. AFINITOR [prescribing information]. East Hanover, however, if coadministration is required, NJ: Novartis Pharmaceuticals Corp; 2012. 2. Data on file. AFINITOR Oral Ulceration: CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals increase the AFINITOR dose from 10 mg daily Corp; March 2012. • Mouth ulcers, stomatitis, and oral mucositis have up to 20 mg daily, using 5-mg increments occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients •

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

•

8/13

AFB-1066531

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

T:14”

B:14.25”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 Pneumonitisd 19 4 0.2 0.4 0 0 Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median duration of treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

T:14”

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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

The ASCO Post | FEBRUARY 15, 2014

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ASH Annual Meeting Hematology

Novel Agents Show Activity in Non-Hodgkin Lymphoma By Caroline Helwick

I3K-mediated activation of downstream effectors allows tumors to escape from negative growth control, and this action may be checked with PI3K inhibitors. At the 2013 American Society of Hematology (ASH) Annual Meeting, researchers reported results in patients with relapsed or refractory lymphoma treated with two novel PI3K inhibitors and a first-in-class Bcl2-targeted “DNA interference” (DNAi) molecule.

phoma (50%), and diffuse large B-cell lymphoma (13%). “The overall response rate was 40% to 45% in indolent lymphoma and 70% in mantle cell lymphoma, which is quite high. But what was most striking was the somewhat unexplained fact that of four patients with peripheral T-cell lymphoma, two achieved a complete (unconfirmed) response as assessed by the

Compared to other compounds— such as a [Bruton’s tyrosine kinase] inhibitor or other PI3K inhibitors— [copanilisib produces] a much quicker response than we are used to seeing.

Copanilisib in Relapsed/ Refractory Lymphoma BAY 80-6946, now known as copanilisib, is an intravenously administered compound that has significant activity against alpha and delta isoforms of PI3K; the delta isoform has a role in B-cell signaling, development, and survival. Martin Dreyling, MD, of the Klinikum der Universität München in Munich, Germany, reported single-agent activity for BAY 80-6946 in 67 relapsed or refractory lymphoma patients.1 The population included 33 patients with indolent disease (follicular lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma) and 34 with aggressive lymphomas (diffuse large Bcell lymphoma, mantle cell lymphoma, transformed indolent lymphoma, T-cell lymphoma, mediastinal B-cell lymphoma, follicular lymphoma subtype G3b). They had been administered a median of three prior chemotherapy lines. Patients received copanilisib as an intravenous 1-hour infusion given weekly for 3 out of 4 weeks, starting with a dose of 0.8 mg/kg and with a maximum dose of 65 mg.

—Martin Dreyling, MD

investigator,” Dr. Dreyling said. “There were high-quality responses in diffuse large B-cell, mantle cell, and follicular lymphomas, and chronic lymphocytic leukemia as well.” He described one patient with mantle cell lymphoma who reported the elimination of symptoms after only 1 week of treatment. Radiologic imaging showed a very good partial response and almost complete disappearance of a large pleural effusion. “Compared to other compounds— such as a [Bruton’s tyrosine kinase] inhibitor or other PI3K inhibitors—this is a much quicker response than we are used to seeing,” he commented. Gastrointestinal toxicity was “minor

Novel Agents in Lymphoma ■■ BAY 80-6946, or copanilisib, produced responses in 40% of relapsed/ refractory indolent lymphoma patients and in 70% of patients with mantle cell lymphoma. ■■ SAR 245409 produced responses in 44% of relapsed/refractory follicular lymphoma patients. ■■ PNT2258 produced clinical benefit in 9 of 11 patients with various subtypes of non-Hodgkin lymphoma.

“The preliminary efficacy results are encouraging,” Dr. Dreyling reported. After a median of three treatment cycles, significant activity (objective responses, including many complete responses), was observed in follicular lymphoma (40%), chronic lymphocytic leukemia (43%), mantle cell lymphoma (71%), peripheral T-cell lym-

tor, so you get metabolic side effects, but they were manageable with conventional therapy,” Dr. Dreyling noted. “The most meaningful number is how many patients stopped therapy due to adverse events not associated with disease progression, and this was 19%.” He added that opportunistic infections do not appear to be a problem. Further studies of copanilisib are on-

and self-limiting” and hematologic toxicity was also “minor,” he noted. Diarrhea (all grades) was reported by 36% of patients, but was grade 3 or higher in only 3%. Similarly, nausea occurred in 28%, but was grade 3 or higher in 2%. Hyperglycemia occurred in 58% and hypertension in 57%. “This is a nonspecific PI3K inhibi-

going or planned in both indolent and aggressive non-Hodgkin lymphoma.

SAR 245409 in Follicular Lymphoma SAR 245409 is a potent oral paninhibitor of PI3K that also inhibits mTORC1 and mTORC2; mTOR is involved in dysregulated signaling. The multicenter phase II ARD12130 study evaluated the efficacy of SAR 245409 in 28 follicular lymphoma patients who had received a median of three prior regimens.2 Patients received 50 mg of SAR 245409 twice daily, continuously in 28-day cycles. “Single-agent SAR 245409 exhibited clinical activity in patients with relapsed or refractory follicular lymphoma,” reported Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston. In 27 efficacy-evaluable patients, the response rate was 44%, including complete responses in 15%, meeting the study’s prespecified endpoint to expand to stage 2, namely an objective response rate ≥ 25%. All but four patients had a reduction in targeted lesions; in more than half the patients, the reduction exceeded 50%. Progression-free survival > 24 weeks was observed in 52%. Eight patients (29%) remain on SAR 245409, and 20 (71%) discontinued treatment, primarily because of disease progression (39%) or adverse events (21%). Altogether 57% of patients experienced a serious adverse event. The most common toxicity was diarrhea,

seen in about 45% of patients; but grade 3 was observed in only two patients (7%). Other adverse events of grade 3 or higher included pneumonia in three patients (11%) and acute renal failure in two patients (7%). With regard to adverse events “of special interest,” she said that rash was observed in 14 (50%) patients, which was at least grade 3 in 2 (7%). Liver toxicities were observed in 4 (14%), including 2 (7%) of grade 3 or higher. These toxicities were not surprising since, according to Dr. Brown, transaminitis is relatively common with targeted kinase inhibitors. Hyperglycemia events and increases in blood glucose occurred in five patients (18%), two cases (7%) of which were ≥ grade 3.

Targeting Bcl2 With PNT2258 The rationale for targeting Bcl2 is that it plays a role in lymphomagenesis, it is involved in chemotherapy resistance, and its disruption leads to cell death. The PNT2258 DNAi molecule targets the noncoding, nontranscribed regulatory region of the Bcl2 gene. A study reported at the ASH meeting enrolled 12 patients with follicular, diffuse large B-cell, mantle cell, and chronic lymphocytic leukemia/small lymphocytic lymphomas.3 Patients received PNT2258 at 120 mg/m2 intravenously on days 1 to 5 every 21 days for six cycles. Those who appeared to benefit had the option of continuing on a maintenance schedule on days 1 and 2 of a 28-day cycle. Senior author Ayad Al-Katib, MD, FACP, of Van Elslander Cancer Center in Grosse Pointe, Michigan, reported,

Ayad Al-Katib, MD, FACP

“PNT2258 exhibited antitumor effects in patients with relapsed/refractory nonHodgkin lymphoma.” In 11 evaluable patients, clinical benefit was observed in 9, including complete responses in 2 and a partial response in 1. The follicular lymphoma patients experienced progression-free survival times of 200 to 250 days, which is ongoing in some patients. continued on page 33

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ASH Annual Meeting Hematology

ASH Studies Confirm Benefit of Rituximab Maintenance in Follicular Lymphoma By Caroline Helwick

indings from two major studies presented at the 2013 American Society of Hematology Annual Meeting not only confirm the benefit of rituximab (Rituxan) maintenance in follicular lymphoma, but also indicate that the longer the maintenance

The study enrolled 270 patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma (all grades) and treated them with four weekly doses of rituximab at 375 mg/m². A total of 124 patients were chemotherapy-naive. The 165 patients achieving a complete or partial response to this induction regimen were randomly assigned to receive rituximab at 375 mg/m² as either short-term maintenance (four

administrations every 2 months) or long-term maintenance (every 2 months for a maximum of 5 years or until disease progression or unacceptable toxicity). The primary endpoint was event-free survival from the time of randomization. Events included disease progression or relapse, unacceptable toxicity, death from any cause, initiation of nonprotocol or concomitant steroids or radiotherapy, or secondary malignancy.

Primary Endpoint Not Met The primary endpoint, event-free survival, was not met with long-term maintenance rituximab. Median eventfree survival was 3.4 years after shortterm maintenance and 5.3 years with long-term maintenance, which under the prespecified log-rank test was not a statistically significant difference (P = .14), Dr. Taverna reported. “We observed an imbalance in early continued on page 37

EXPERT POINT OF VIEW Christian J. Taverna, MD

period, the greater the impact on progression-free survival. However, overall survival differences have still not emerged, even after 6 years of follow-up.

Longer Maintenance Doubles Remission Time In a study designed to determine the optimal duration of rituximab maintenance in patients with follicular lymphoma, median progression-free survival doubled when treatment was continued to a maximum of 5 years, and this benefit of prolonged maintenance occurred “without increased undue toxicity,” said Christian J. Taverna, MD, of Kantonsspital in Munsterlingen, Switzerland.1 “Rituximab maintenance has been shown to be effective in patients with follicular lymphoma, but the optimal duration of maintenance therapy remains unknown,” he said. The randomized phase III SAKK 35/03 trial, therefore, was initiated in 2004 to determine if maintenance with rituximab every 2 months for 5 years or until relapse or progression, unacceptable toxicity, or death would be superior to maintenance every 2 months for four treatments.

Novel Agents continued from page 32

“Patients tolerated the administration of the drug, and we saw no tumor lysis syndrome or major organ system toxicity. Patients maintained their baseline performance status while on the study,” he said. “Our results support further clinical development of PNT2258, and we feel that the DNAi strategy warrants

ndrew D. Zelenetz, MD, PhD, Chair of the Non-Hodgkin Lymphoma Guideline Panel of the National Comprehensive Cancer Network (NCCN) and former Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York, put the latest maintenance trials into perspective for The ASCO Post. “There are two ways to interpret the data. Both studies support the evidence of a prolongation in progression-free survival with maintenance rituximab (Rituxan). The SAKK trial did not meet its primary endpoint, but when investigators corrected for early failures that had nothing to do with maintenance, it did meet the endpoint of an improvement in progression-free survival. In PRIMA, this was very highly significant,” he noted.

we cannot improve survival—that’s not true, we can,” Dr. Zelenetz said. In the current maintenance trials, overall survival was not improved. Dr. Zelenetz emphasized the mature data from PRIMA—6 years of follow-up—and the overlapping of the survival curves between the maintenance and observation arms. “There’s absolutely no difference, and no trend. There’s nothing to suggest the curves were separating, even with follow-up at 6 years,” he said. He concluded that if overall survival is the most important hard endpoint for this disease, maintenance does not improve that. The reason for that is the fact that retreatment at progression is very effective, he maintained.

Most Important Endpoint

He also pointed out that the NCCN states, because of the lack of a survival advantage, maintenance rituximab is not the standard of care, despite the fact that some lymphoma specialists do consider it virtually mandatory. “I think the position is much more nuanced,” he added. “Mainte-

“There are those who argue that an improvement in progression-free survival is important, but most of us believe that the most important endpoint in follicular lymphoma is making patients live longer. We proved we can do this by adding rituximab to chemotherapy, so to those who say

further exploration as a cancer therapy,” he said. n Disclosure: Dr. Dreyling has been a scientific advisor for Bayer. Dr. Brown has been a consultant for Sanofi-Aventis, Gilead, Celgene, and Pharmacyclics. Dr. Al-Katib has received research funding from ProNAi Therapeutics.

References 1. Dreyling M, Morschhauser F, Bron

Maintenance an Option, Not a Mandate

D, et al: Preliminary results of a phase II study of single agent Bay 80-6946, a novel PI3K inhibitor, in patients with relapsed/ refractory, indolent or aggressive lymphoma. 2013 ASH Annual Meeting. Abstract 87. Presented December 8, 2013. 2. Brown JR, Hamadani M, Arnason J, et al: SAR 245409 monotherapy in relapsed/refractory follicular lymphoma: Preliminary results from the phase II

nance should be an option. I tend to try to find the middle ground. I tell patients why it might be right for them, or why it might not be right.” While there are some exceptions,

Andrew D. Zelenetz, MD, PhD

Dr. Zelenetz usually recommends observation to patients. He estimates that about 30% of his patients opt for maintenance therapy—for example, those who have a compelling reason to delay the time to next treatment, such as mothers with school-age children. “It needs to be a case-bycase discussion between the physician and patient,” he said. “For some, it’s a legitimate option.” n Disclaimer: Dr. Zelenetz is advisory board of and receives support from Genentech/Roche a consultant for Hospira, Dr. Laboratories, and Celgene.

on the research and is Reddy’s

ARD12130 study. 2013 ASH Annual Meeting. Abstract 86. Presented December 8, 2013. 3. Harb W, Lakhani N, Logsdon A, et al: The BCL2 targeted deoxyribonucleic acid inhibitor PNT2258 is active in patients with relapsed or refractory nonHodgkin’s lymphoma. 2013 ASH Annual Meeting. Abstract 88. Presented December 8, 2013.

Take a bite out of G-CSF acquisition costs*

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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.

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» 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.

The ASCO Post | FEBRUARY 15, 2014

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ASH Annual Meeting Hematology

Ibrutinib Induces Prompt and Durable Responses in Some Lymphomas By Caroline Helwick

he Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) is changing the landscape of treatment in chronic lymphocytic leukemia. New research with the drug in lym-

phoma, presented at the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans, indicates it may be of benefit in this malignancy, as well.

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 nonUS-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. 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

Findings in Waldenstrom’s Macroglobulinemia In a multicenter phase II study of 63 patients with relapsed or refractory Waldenstrom’s macroglobulin-

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: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

emia, treatment with ibrutinib led to rapid reductions in serum immunoglobulin M (IgM) levels and improvements in hematocrit levels. “Responses were durable, with 87% of patients continuing on treatment at a median of nine cycles,” said Steven Treon, MD, PhD, Director of the Bing Center for Waldenstrom’s Research and attending physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.1 Patients received ibrutinib at 420 mg/d for up to 2 years. At baseline, mean serum IgM level was 3,610 mg/ dL and mean hemoglobin level was 10.5 mg/dL. The overall response rate was 83%, with major responses observed in 64% of patients. Following treatment, serum IgM fell to 1,260 mg/dL (P = 1.46088−17) and hemoglobin improved to 13.4 mg/dL (P = 9.0366−19). “You see profound drops in IgM,” he noted. Among 31 patients with extramedullary disease for whom scans were available, 67.7% had an improvement in adenopathy and 20% had an improvement in splenomegaly; 25.8% and 80%, respectively, were stabilized. “By far, this was a very well-tolerated therapy,” Dr. Treon said. The most common grade 2 or higher adverse events were thrombocytopenia (n = 10) and neutropenia (n = 12), mostly occurring in heavily pretreated patients. Most bleeding events were seen in patients taking fish oil supplements.

Genetic Driver Identified Dr. Treon and his colleagues initiated the study after laboratory research revealed the high prevalence of the MYD88 L265P gene in Waldenstrom’s macroglobulinemia, triggering activation of Bruton’s tyrosine kinase in Waldenstrom’s macroglobulinemia cells. “Later, through deactivation of [Bruton’s tyrosine kinase], ibrutinib was found to abolish binding of MYD88 to [Bruton’s tyrosine kinase] in L256P-expressing [Waldenstrom’s macroglobulinemia] cells,” he said. Ibrutinib can selectively kill tumor cells of L265P-mutant cell lines, relative to wild-type controls. They also looked at mutations in

ASCOPost.com | FEBRUARY 15, 2014

PAGE 37

ASH Annual Meeting a chemokine receptor called CXCR4, which are present in about 30% of Waldenstrom’s macroglobulinemia patients. These mutations reduce the ability of ibrutinib to kill Waldenstrom’s macroglobulinemia cells, but based on in vitro lab work, this obstacle may be reversible by inhibitors of CXCR4, he noted. Patients with WHIM syndrome, (a rare immunodeficiency disorder with symptoms manifesting as Hypogammaglobulinemia, Warts, Infections, and Myelokathexix), and the CXCR4 mutation were significantly less likely to respond to ibrutinib (30%) than were patients with

Follicular Lymphoma continued from page 33

events,” he said, chiefly an unexplained difference in disease progression and relapse during the first 8 months after randomization (3 in the short-term arm vs 10 in the long-term arm), when treatment in both arms was the same. “This led to an early crossing of the event-free survival curves at 18 months,” he said, indicating this was responsible for the negative outcome. In the short-term rituximab arm, three events occurred in the first 8 months, all disease progressions or relapses. In the long-term arm, 14 events occurred, including 1 death, 10 disease progressions or relapses, 2 secondary malignancies, and 1 unacceptable toxicity. Nevertheless, progression-free survival, a secondary endpoint, was significantly improved with longer maintenance—from 3.5 years in the short-term arm to 7.4 years in the longterm arm (hazard ratio [HR] = 0.63; P = .04). Overall survival and response rates were similar in the two arms. Importantly, in a retrospectively defined analysis of only patients at risk after 8 months from randomization, median event-free survival was significantly prolonged with longer maintenance: 7.1 years compared with 2.9 years (P = .004), Dr. Taverna reported. At least one adverse event was experienced by 50% of patients in the shortterm cohort and 76% in the long-term cohort. Maintenance was stopped due to unacceptable toxicity in three patients receiving long-term maintenance. Other adverse effects included, respectively, six and eight subsequent cancers and one and seven infections grade 3 and higher. “There is no explanation for this difference in early events, when treatment in both arms was the same,” Dr.

wild-type CXCR4 (80%, P = .0065), whereas the MYD88 L265P mutation had no significant impact on response. “The IgM reductions are far more impressive in individuals who have wild-type CXCR4 status. The degree of gain in hemoglobin is also more impressive in individuals with wildtype CXCR4,” Dr. Treon noted. Better responses to ibrutinib were associated with lymphocytosis.

Active in Diffuse Large B-Cell Lymphoma In a phase Ib study in 22 treatment-naive diffuse large B-cell lymTaverna concluded. “Otherwise, outcomes were significantly better with long-term maintenance rituximab, including a doubling in median progression-free survival without an increase in toxicity.”

PRIMA Confirms Maintenance Benefit Gilles Andre Salles, MD, PhD, of the Université Claude Bernard in Lyon, France, presented updated 6-year follow-up of the phase III PRIMA study of 2-year rituximab maintenance after immunochemotherapy, showing a 43% reduction in progression and a 38% reduction in time to next treatment, but no improvement in overall survival.

Role of Ibrutinib in Lymphoma Treatment ■■ Ibrutinib led to impressive responses in patients with Waldenstrom’s macroglobulinemia, along with reductions in serum IgM levels and improvements in hemoglobin levels. The effect was most pronounced in patients with wild-type CXCR4 status. ■■ Ibrutinib plus R-CHOP led to a 100% response rate (91% complete responses) in treatment-naive diffuse large B-cell lymphoma patients in a phase Ib single-center study.

phoma patients, 100% of subjects responded to the combination of ibrutinib at 560 mg/d plus standard R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone), given

“The durability of rituximab maintenance benefit for progression-free survival and time to next treatment is consistent across patients with different Follicular Lymphoma International Prognostic Index (FLIPI) scores, chemotherapy induction regimens, and response to chemotherapy induction,” Dr. Salles reported. PRIMA enrolled 1,217 patients treated with various rituximab-based induction regimens, then randomly assigned 1,018 to observation or rituximab maintenance. At 3 years, in the initial analysis, progression-free survival rates (from the time of randomization) were 75% for maintenance vs 58% for observation (hazard ratio [HR] = 0.55; P < .0001).

continued on page 38

Rituximab Maintenance in Follicular Lymphoma ■■ In the Swiss SAKK 35/03 trial, up to 5 years of rituximab maintenance doubled progression-free survival compared with 8 months of maintenance, from 3.5 years to 7.4 years (P = .04). The primary endpoint (event-free survival), however, was not met, being 3.4 years with short-term maintenance vs 5.3 years with long-term maintenance (P = .14). ■■ With a median 6 years of follow-up, the PRIMA trial demonstrated a persistent benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression-free survival (59.2% and 42.7%, P < .0001).

The updated analysis, with a median follow-up of 6 years, found progression-free survival rates to be 59.2% and 42.7%, respectively (HR = 0.57; P < .0001). At 70 months, subsequent treatment was required by 63.5% vs 51.0%, respectively (HR = 0.625; P < .0001), Dr. Salles reported. Overall survival was “excellent,” he said, at 88.7% and 87.4%, respectively (HR = 1.027; P = .885).

Subgroup Analyses Gilles Andre Salles, MD, PhD

for six cycles. Complete responses were observed in 91% and partial responses in 9%, according to Anas Younes, MD, Chief of the Lymphoma Service at Memorial

Benefit for maintenance was observed after either induction regimen: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP). “However, [the benefit associated with] R-CHOP may be a little more significant,” he suggested, citing a progression-free survival rate of 62.9% with maintenance vs 44.5% with observation (HR = 0.538; P < .0001). By FLIPI score, FLIPI-low patients had the best outcomes, with a 76% progression-free survival rate vs 60% with observation (HR = 0.596; P = .0052), but all FLIPI groups benefited from maintenance over observation. Two years of maintenance was beneficial regardless of response status after induction, with hazard ratios of 0.520

for complete responders, 0.635 for unconfirmed complete responders, and 0.449 for partial responders. Response to second-line treatment was 79% in the observation group and 76% in the maintenance group, and rates of histologic transformation were also similar, about 20% per arm. “Rituximab maintenance did not lead to the selection of more aggressive clones in these patients,” Dr. Salles said. About half of all deaths were associated with lymphoma progression in each arm. n

Disclosure: Dr. Taverna reported no potential conflicts of interest. Dr. Salles is a consultant for and has received honoraria and research funding from Roche.

References 1. Taverna CJ, Martinelli G, Hitz F, et al: Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: Results of the randomized phase III trial SAKK 35/03. 2013 ASH Annual Meeting. Abstract 508. Presented December 9, 2013. 2. Salles GA, Seymour JF, Feugier P, et al: Updated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy. 2013 ASH Annual Meeting. Abstract 509. Presented December 9, 2013.

The ASCO Post | FEBRUARY 15, 2014

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Health-Care Policy Surgeon General’s Report continued from page 1

was a 1962 report by the Royal College of Physicians in Britain that clearly showed cigarette smoking caused lung cancer. Shortly after that report’s release, Luther Leonidas Terry, MD, appointed by President John F. Kennedy as the country’s ninth Surgeon General, established and chaired the Surgeon General’s Advisory Committee on Smoking and Health. Pouring over the biomedical literature, the committee analyzed more than 7,000 articles related to smoking and disease. On January 11, 1964, after exhaustive work, Dr. Terry released the Surgeon General’s report, concluding that cigarette smoking caused lung cancer and was therefore a serious health hazard that needed remedial action. The reaction to Dr. Terry’s report was swift. For several days after its release, the report provided headlines for newspapers and lead stories on television news programs across the country. Moreover, the national attention helped galvanize the antismoking dialogue of policymakers on Capitol Hill. Soon after, the U.S. Congress adopted the Federal Cigarette Labeling and Advertising Act of 1965 and the Public Health Cigarette Smoking Act of 1969.

Ibrutinib in Lymphoma continued from page 37

Sloan-Kettering Cancer Center, New York.2 Serious adverse events were reported in 12 patients, most commonly febrile neutropenia (17%). A phase III trial of R-CHOP plus ibrutinib is ongoing in a select group of patients with de novo, treatment-naive non–germinal-center B-cell–like diffuse large B-cell lymphoma. Disclosure: Dr. Treon has served as a consultant for and received honoraria and research funding from Pharmacyclics and Janssen. Dr. Younes has received honoraria from Pharmacyclics, Janssen, Seattle Genetics, Millennium, and Incyte.

In short, these laws required health warnings on cigarette packages, banned cigarette advertising in broadcast media, and called for an annual report on the health consequences of smoking. For historical perspective, in the early 1960s, more than 50% of U.S. men smoked cigarettes, and of 535 members of Congress, 521 were men. Therefore, although legislators would tend to be better educated and have higher incomes (see Trends in Smoking, below), a large percentage of those who initiated these antismoking acts were likely smokers themselves. The enormous publicity generated by the Surgeon General’s report had an unparalleled impact on public health, ending a 6-decade pattern of nearly uninterrupted U.S. cigarette consumption. Despite the addictive nature of tobacco and the formidable economic forces promoting its use, smoking rates have declined annually since 1964; adult smoking prevalence in the 1960s was about 42%, and has since fallen to about 18%. The success of the Surgeon General’s report earned the “recognition of tobacco use as a health hazard” a spot on the Centers for Disease Control and Prevention’s (CDC’s) list of 10 great public health achievements of the 20th century. References 1. Treon SP, Tripsas CK, Yang G, et al: A prospective multicenter study of the Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstrom’s macroglobulinemia. 2013 ASH Annual Meeting. Abstract 251. Presented December 9, 2013. 2. Younes A, Flinn I, Berdeja J, et al: Combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): Updated results from a phase 1b study in treatment-naïve patients with CD20positive B-cell non-Hodgkin’s lymphoma. 2013 ASH Annual Meeting. Abstract 852. Presented December 10, 2013.

Trends in Smoking The first major shifts in national smoking habits were instigated by two factors unrelated to industry’s intentions to influence tobacco use: World War I and the Great Depression. In preWWI America, smoking cigarettes was considered effeminate; most men opted for manlier cigars or pipes. However, cigars and pipes were unwieldy on the battlefields, so cigarettes were supplied in soldier’s rations. When the addicted men returned from the war, cigarette smoking rapidly escalated. Several years later, the Great Depression had a dampening effect on smoking prevalence. The reason was simple economics: jobless people couldn’t afford the habit. These two grand examples of behavior modification demonstrate how events can shape public health. The Surgeon General’s report accelerated research into contemporary social behavior trends that affect smoking, which provides a powerful tool for creating targeted cessation programs. For instance, a 2008 National Cancer Institute report confirmed that exposure to actors smoking in the movies promotes adolescent smoking initiation; other studies found that viewing celebrities smoking is a catalyst for between one-third and onehalf of adolescents starting to smoke.

Studies have also established a strong corollary in how education levels affect smoking trends. The National Health Interview Survey revealed that about 25% of adults with a high school education (or less) smoke, whereas only 7% of those with a postgraduate education light up,1 showing a much-needed cessation effort in our less educated populations. Age is another factor in smoking habits. The same poll found that smoking among young adults is far more prevalent than in older people, with 24% of 18- to 24-year olds smoking, compared with less than 9% of adults 65 or older.1 While epidemiologic studies have multiple factors that affect their results, they give a broad understanding of the socioeconomic elements driving increased smoking in certain populations, which is key to creating effective antismoking programs.

Economics of Tobacco The CDC estimates that since 1964, tobacco use in the United States is responsible for more than 20 million deaths. It impossible to separate economics from the devastating health consequences of tobacco use illustrated by CDC’s shocking mortality data. In a statement commemorating the 50th anniversary of the Surgeon

EXPERT POINT OF VIEW

“I

brutininb appears to be the most promising drug we have seen in Waldenstrom’s macroglobulinemia and will likely significantly change the therapeutic landscape,” according to Bruce Cheson, MD, Deputy Chief, Hematology-Oncology and Head of Hematology Research at Georgetown Lombardi Cancer Center in Washington, DC. “The situation in [diffuse large B-cell lymphoma] is a bit more complicated,” he noted. “Ibrutinib has Bruce Cheson, MD activity in one subtype of the disease—activated Bcell–type—but minimal activity in the other [non–germinal-center B-cell–type]. Even in the former, there are different mutations that respond more favorably than others. Certainly, not all [diffuse large B-cell lymphomas] are created equal. This clearly pushes the case for personalized therapeutic strategies.” n Disclosure: Dr. Cheson reported no potential conflicts of interest.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | FEBRUARY 15, 2014

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Health-Care Policy

General’s report, ASCO President Clifford Hudis, MD, said, “Unfortunately, tobacco still kills more than 440,000 Americans each year and costs our economy close to $193 billion annually. [Editor’s note: Since this statement was released, the 2014 Surgeon General’s report has estimated the annual number of American deaths attributable to smoking and sec-

Clifford Hudis, MD

ondhand smoke to be about 480,000, and related costs to the U.S. economy to be more than $170 billion.] We must continue to be vigilant in our fight against this deadly addiction. Our efforts to fight the largest preventable cause of death and disability cannot cease or diminish.” The effort to thwart the tobacco addiction that Dr. Hudis and ASCO call for would not only

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

save hundreds of thousands of American lives each year, it would reallocate billions of dollars toward valuable research and drug development. One stark example of the economics of tobacco is taxation. For example, New York has the nation’s highest per-pack tax of $4.35. The Empire State has seen its smoking rates among adults drop to 16%. By contrast, Missouri has the lowest per-pack tax of $0.17—and 24% of Missouri adults smoke. Other factors besides cost contribute to the difference in smoking prevalence between states. However, studies show that higher perpack costs reduces cigarette consumption in two of the heaviest smoking groups: low income and youth. continued on page 40

Highlights of the American Lung Association’s State of Tobacco Control 2014 ■■ A state-by-state update on the progress of antismoking initiatives. States are graded on four metrics: tobacco prevention, smoke-free air, cigarette tax, and cessation coverage. For example, Kentucky received 4 F’s, while New York received grades of, F, A, A, and F, respectively. ■■ Major parts of the Patient Protection and Affordable Care Act include new insurance options and incentives that cover quit-smoking treatments as a preventive care service. ■■ The new Surgeon General’s Report on Smoking & Health: 50th Anniversary, 1964–2014 documents the progress that has been made on reducing tobacco use over the past 50 years, and provides an update on the health effects of tobacco use. ■■ The U.S. Food and Drug Administration launches its public education campaign, aimed at preventing priority populations from starting to use tobacco products. n

Visit www.stateoftobaccocontrol.org for more from the American Lung Association report.

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Health-Care Policy Surgeon General’s Report continued from page 39

But efforts to thwart tobacco addiction also have had a long-standing economic nemesis: Big Tobacco. Well before the Surgeon General’s report in 1964, the tobacco industry waged an unending lobbying and public relations campaign to simultaneously promote cigarettes and block any potentially effective antismoking initiative. The most well known of the industry’s efforts was the infamous 1954 “Frank Statement to Cigarette Smokers” published in more than 400 national newspapers, in which Big Tobacco used phony science to purposely deceive the public about the health risks of smoking. Years later, the release of millions of pages of secret documents exposed Big Tobacco’s big lie, laying the groundwork for class actions such as the landmark 1998 Master Settlement Agreement between the states and the tobacco industry. The monies from the class-action settlements were earmarked for tobacco prevention. Although the changing tides of culture, politics, and economics have challenged our efforts to curb smoking, the Surgeon General’s report demonstrated that well directed antismoking programs do reduce the rate of smoking. A recent report in JAMA concluded that

Perspective on the Politics of Tobacco

he tobacco industry has always been a major player in congressional races, especially in Southern tobacco-growing states. Moreover, the industry is notoriously bipartisan in their political donations, and members of both parties have returned the favor by voting for tobacco interests. “The 2014 Surgeon General’s report provides irrefutable evidence that elected officials hold the key to ending death and disease caused by tobacco use,” Harold P. Wimmer, American Lung Association National President and CEO, stressed in a public statement. However, Paul Bunn, MD, Chair, Lung Cancer Research at the University of Colorado, Denver, gave this sobering assessment to The ASCO

between 1964 and 2012, tobacco control was estimated to have saved 8 million premature tobacco-related deaths.2 Despite vast progress, lung cancer remains America’s number-one cause of preventable death. Therefore, the unequivocal call for action generated by the

Post: “It is likely that the authors of the original Surgeon General’s report would not have foreseen the ability of tobacco companies to hinder efforts to eliminate tobacco smoking in the

Paul Bunn, MD

United States and Big Tobacco’s huge success in promoting smoking in underdeveloped nations. The American public can only view this as additional evidence that the Congress can be Surgeon General’s report in 1964 is as powerful today as it was 50 years ago. n Disclosure: Drs. Hudis and Bunn reported no potential conflicts of interest.

References 1. Agaku IT, King BA, Dube SR: Cur-

easily bought by private monies, and that these monies are more important to them than the public health of our citizens or the millions of citizens around the world who will die 10 to 20 years earlier due to their tobacco addiction.” Speaking with The ASCO Post, Clifford A. Hudis, MD, also commented that American Big Tobacco has had great success at exporting this problem globally. “They successfully challenge labeling and restrictions around the world, sometimes under the guise of the free trade agreements our country signs with others,” he noted. n Disclaimer: This commentary represents the views of those individuals interviewed and may not necessarily reflect the views of The ASCO Post or ASCO.

rent cigarette smoking among adults— United States, 2005-2012. MMWR Morb Mortal Wkly Rep 63:29-34, 2014. 2. Holford TR, Meza R, Warner KE, et al: Tobacco control and the reduction in smoking-related premature deaths in the United States, 1964-2012. JAMA 311:164-171, 2014.

Paving the Way for the Surgeon General’s Report

he connection between smoking and lung cancer is universally accepted as scientific fact, and those who choose to smoke are painfully aware of the risk it poses for addiction and subsequent cancer. However, to fully appreciate the significance of the Surgeon General’s report, one must turn back to a period when cigarette smoking was aggressively promoted and ingrained into our social fabric. In 1964, when the Surgeon General’s report was issued, some 46% of American adults smoked cigarettes; they were cheap and easy to buy. Seductive ads featuring celebrities were ubiquitous, even popping up during popular children’s TV shows, such as The Flintstones. Imagine the challenge of trying to convince half the country that their enjoyable, publically accepted behavior was, in fact, a road to suffering and premature death. It’s worth noting that the causal relationship between cigarettes and disease was on the medical radar long before the 1964 Surgeon General’s report. From the opening of the 20th century,

when cigarettes attained social status, a growing number of critics warned of the dangers of smoking. However, opposition to smoking would gain little ground until a medical student named Ernst Wynder became convinced that smoking caused lung cancer.

Dogged Researchers Ernst L. Wynder, MD, was born in 1922 in Herford, Germany, to Jewish parents who fled to New Jersey in 1938 to escape Nazi persecution. A precocious student, he whipped through high school and entered Washington University in St. Louis to study medicine. During a summer internship at New York University, Dr. Wynder’s interest in lung cancer was first aroused when he attended an autopsy of a twopack-a-day smoker who had died of lung cancer. Seeing a plausible a connection between cigarettes and lung cancer, he began collecting case histories of lung cancer victims in New York and St. Louis. Dr. Wynder’s dogged research caught the attention of well-known

thoracic surgeon Evarts Graham, MD, a heavy smoker himself. Despite Dr. Graham’s initial skepticism, he granted access to his extensive case histories and agreed to sponsor the young medical student. Their relationship culminated in a seminal Ernst L. Wynder, MD Evarts Graham, MD JAMA paper in 1950: “Tobacco Smoking as a Possible Etiologic was later declared a landmark research Factor in Bronchiogenic Carcinoma: A paper in 1985 and 1992. It had preceded the Surgeon General’s report Study of 684 Proven Cases.”1 by 14 years, serving as a launching pad Landmark Paper for the national smoking cessation iniThis wasn’t the first study to link tiative. Dr. Wynder devoted his entire smoking to cancer, but its sophisti- career to the study and prevention of cated design and meticulous findings cancer, publishing more than 770 artigarnered attention and signaled a need cles on worldwide cancer epidemiolofor more research. Equally important, gy as it related to tobacco use. He died it began a sea change in the medical on July 14, 1999, at the age of 77. n culture, persuading doctors—many of whom smoked—of the health risks Reference 1. Wynder EL, Graham E: Tobacco associated with cigarettes. Dr. Graham kicked the habit in 1952, but owing to smoking as a possible etiologic factor his many years of smoking, he died of in bronchiogenic carcinoma: A study of 684 proven cases. JAMA 143:329-336, lung cancer in 1957. Dr. Wynder’s JAMA publication 1950.

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Journal Spotlight Hematology

Breast Implant–Associated Anaplastic Large Cell Lymphoma Shows Better Outcome in Cases With No Distinct Tumor Mass By Matthew Stenger

nly recently described, breast implant–associated anaplastic large cell lymphoma usually presents as an effusion-associated fibrous capsule surrounding the implant and less frequently as a mass. Little is known about the natural history and long-term outcomes of such disease. In a study reported in the Journal of Clinical On-

among 15 patients with known stage of breast cancer at time of implantation, 5 had stage I disease and 6 had carcinoma in situ. Type of implant in 51 patients was silicone in 23 and saline in 28. The surface of the implant was reported in only 21 patients; all were textured implants. Presentation was characterized by

[P]atients without a mass may benefit from a conservative therapeutic approach, perhaps removal of the implant with capsulectomy alone, whereas patients with a tumor mass may need removal of the implants and systemic therapy that still needs to be defined. —Roberto N. Miranda, MD, and colleagues

cology, Roberto N. Miranda, MD, Associate Professor in the Department of Hematopathology at The University of Texas MD Anderson Cancer Center, and colleagues assessed disease characteristics, treatment, and outcomes in 60 cases.1 They found that outcomes are better in women with effusion confined by the fibrous capsule, whereas disease presenting as a mass has a more aggressive clinical course.

Study Details The investigators reviewed the literature for all published reports of implant-associated anaplastic large cell lymphoma between 1997 and 2012. Corresponding authors for the published reports were contacted to obtain information on patient follow-up. The 60 women had a median age of 52 years (range, 28–87 years). Median time from implantation to diagnosis (n = 59) was 9 years (range, 1–32 years). Location of the implant in 58 patients was the right breast in 37, the left in 20, and both in 1. Implantation was for cosmetic purposes in 34 patients and for reconstructive surgery for breast cancer in 26;

effusion in 42 patients and by a distinct mass in 18, usually with associated effusion. Investigation for axillary lymphadenopathy in 29 patients was positive in 10, pathologic evaluation of lymph nodes in 8 patients showed lymphoma in 4, and 2 patients had positive nodes based on clinical or radiologic assessment. Among 59 patients with staging data at presentation, 49 (83%) had stage I, 6 (10%) had stage II, and 4 (7%) had stage IV disease. In the 42 patients with tumor confined to the fibrous capsule, lymphoma cells were present as small clusters in the effusion or lining the capsule, without growth as a distinct mass. In 18 patients with mass presentation, a distinct mass of tumor cells within or beyond the capsule was found, with lymphoma cells in confluent sheets or loose clusters associated with a variable amount

of necrosis or sclerosis. All tumors were strongly positive for CD30 and had a Tcell immunophenotype; all 57 tumors tested for ALK were negative.

Treatments Capsulectomy and implant removal was performed in 56 (93%) of the 60 patients, with mastectomy also performed in 5 and axillary lymph node dissection in 5. Among patients for whom information was available, adjuvant chemotherapy was received by 39 (71%) of 55 patients and local radiation was received by 31 (55%) of 56, with 26 (47%) receiving both, and 13 receiving chemotherapy and no radiation. Among the patients receiving no chemotherapy, 12 opted for watchful waiting after implant removal and 6 received radiation alone. Autologous stem cell transplantation was performed in 8 patients. Of 31 patients with identified chemotherapy regimens, all received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOPlike regimens; of 28 who received a known number of cycles, 22 received 6.

Survival Outcomes Follow-up ranged from 0.1 to 14 years (median, 2 years; mean, 3.1 years). Median overall survival was 12 years for all patients, including 12 years in those with mass and not reached in those without mass (P = .051). The 3-year and 5-year overall survival rates were both 97% in those without mass and 92% in those with mass, including 100% vs 82% (P = .0308) and 100% vs 75% (P = .0308) in those without vs with mass. Median progression-free survival was not reached in those without mass vs 1.8 years in those with mass (P = .005). Among the 42 patients without mass, 39 (93%) had complete remis-

Anaplastic Large Cell Lymphoma Linked to Breast Implants ■■ Disease characterized by effusion in fibrous capsule was associated with better disease-free survival than disease characterized by a distinct mass. ■■ The more aggressive course of disease characterized by mass suggests the need for systemic adjuvant therapy in addition to implant removal.

sion at last-follow-up; 6 (14%) had disease relapse, with 2 having persistent disease at last follow-up, 1 dying of unrelated causes at 7 years after relapse, and 3 having complete remission at last follow-up. Among the 18 with mass, 13 (72%) had complete remission at last follow-up; 9 (50%) had relapse, with 3 dying, 2 having persistent disease at last follow-up, and 4 having complete remission at last-follow-up. There was no significant difference in overall survival (P = .44) or progression-free survival (P = .28) between patients receiving vs not receiving chemotherapy. Follow-up ranged from 0.1 to 10 years in the 16 patients not receiving chemotherapy (median, 1.5 years) and in the 12 undergoing watchful waiting (median, 1 year). There were no significant associations of survival with age, side of lymphoma, reason for implant, implant type, or time from implant to lymphoma. The investigators concluded: These data suggest that there are two patient subsets. Most patients who present with an effusion around the implant, without a tumor mass, achieve complete remission and excellent disease-free survival. A smaller subset of patients presents with a tumor mass associated with the fibrous capsule and are more likely to have clinically aggressive disease. We suggest that patients without a mass may benefit from a conservative therapeutic approach, perhaps removal of the implant with capsulectomy alone, whereas patients with a tumor mass may need removal of the implants and systemic therapy that still needs to be defined.

They noted that the median 2-year follow-up in this patent population is short and that it will prove valuable to continue follow-up of the cohort. n

Disclosure: The study was supported in part by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Miranda RN, Aladily TN, Prince HM, et al: Breast implant-associated anaplastic large-cell lymphoma: Long-term follow-up of 60 patients. J Clin Oncol 32:114-120, 2013.

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Journal Spotlight

Longer-Term Follow-up of Breast Implant–Associated Anaplastic Large Cell Lymphoma: More Certainty About Certain Uncertainties By Steven M. Horwitz, MD

hen what is now called breast implant–associated anaplastic large cell lymphoma was first recognized and initially described, a number of uncertainties prevailed—mainly, was the association with breast implants real, and was this a true lymphoma? Through the significant efforts of those who tracked down, collected, and reviewed these cases, a more clear-cut understanding was achieved. It appears that there is a real association. Breast implant–associated anaplastic large cell lymphoma was not being reported in people with systemic lymphomas who just happened to have breast implants, and the association was specific to this histology. Moreover, a characteristic clinical presentation emerged with anaplastic large cell lymphoma confined to a seroma and/ or the capsule that surrounded the implant. In a few telling cases, clonal rearrangements of T-cell receptors and other clonal cytogenetic abnormalities were found. It is now generally accepted that this is a rare but real phenomenon.

New Questions Arise We have become more certain of the “what,” and the “why” largely remains a mystery, but the primary uncertainty became “what to do about it?” Although breast implant–associated anaplastic large cell lymphoma was histologically similar to the systemic disease, there was a sense from the early reports that this was not the same entity as aggressive systemic anaplastic large cell lymphoma. Rather, breast implant–associated anaplastic large cell lymphoma seemed to be more of an indolent or even locally reactive process. It was almost certain that this was underreported, as the degree of paDr. Horwitz is Associate Attending, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York.

thology review necessary to diagnose anaplastic large cell lymphoma was not routine for implant removal or capsulectomy occurring after cosmetic surgery. Yet, very few patients had locally disseminated or advancedstage disease, and fewer deaths were noted than one would expect if aggressive lymphomas were not being diagnosed or treated promptly. In

of the condition by excluding cases in which the lymphoma “was confined to skin, patients with breast tumors not adjacent to the fibrous capsule around an implant, or patients who had concomitant systemic disease at time of presentation.” The inclusion of longer follow-up and the addition of 12 patients (20% of all the cases) who were treated with

Despite some remaining uncertainties around our understanding of breast implant– associated anaplastic large cell lymphoma, the study by Miranda et al provides useful guidance on approaching and managing what is surely to be an increasingly diagnosed condition. —Steven M. Horwitz, MD

addition, some women reported seromas present for years prior to diagnosis without progression. Despite this sense of indolence, one could not be certain of this conclusion. Many reports were sparse in terms of details, and follow-up on case reports was short or nonexistent. In addition, most of those diagnosed had received chemotherapy, often with radiation, raising the possibility that it was effective therapy as opposed to indolent biology that has led to a favorable prognosis.

Some Clarification The enlightening study by Miranda and colleagues published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post provides significantly more detail and longer follow-up on the reported cases, clarifying some of the clinical uncertainties.1 The investigators provided an important refinement of the definition

implant and capsule removal only allow us to see how conservatively managed patients fared. Of the 42 patients with localized disease confined to the capsule, none died of lymphoma, 1 died of unrelated causes, and 93% were in complete remission at last follow-up. Moreover, there was no apparent advantage to chemotherapy, with equally excellent results in those observed post-surgery or receiving radiation alone. These favorable outcomes lend support to what was previously more of a “gut feeling” that breast implant–associated anaplastic large cell lymphoma is clinically more akin to primary cutaneous anaplastic large cell lymphoma, for which local therapy is the standard and a good prognosis prevails for almost all patients, without the need for chemotherapy.

Persistent Uncertainties Other uncertainties persist. Follow-up remains short at a median of

only 2 years. Median progressionfree survival and overall survival are excellent at not reached and 12 years, respectively. However the majority of patients are censored at 2 years or less of follow-up, leaving these curves potentially unstable. And a good prognosis is not guaranteed, since relapses have been seen, including in 14% of those with localized disease. The main prognostic factor seems to be the presence of a mass within or through the capsule, conferring a moderately worse progression-free and overall survival. If any patients need more aggressive therapy, and this remains unclear, it may be those with tumor masses. The authors highlight this distinction and suggest that those without a mass be diagnosed as having a lymphoproliferative disorder associated with a breast implant, while the term “anaplastic large cell lymphoma” could be reserved for patients with a tumor mass or advanced-stage disease. However, it is not certain how reliably one can make this distinction with masses as small as 5 mm included in this group. It is possible that there are two biologically different processes, but it is also possible that those with a mass or with nodal disease have merely progressed to more-advanced disease of the same process. Despite some remaining uncertainties around our understanding of breast implant–associated anaplastic large cell lymphoma, the study by Miranda et al provides useful guidance on approaching and managing what is surely to be an increasingly diagnosed condition. n

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

Reference 1. Miranda RN, Aladily TN, Prince HM, et al: Breast implant-associated anaplastic large-cell lymphoma: Long-term follow-up of 60 patients. J Clin Oncol 32:114-120, 2014.

NOW ENROLLING A Phase 3 Trial for Newly Diagnosed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target 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 x 2, then monthly

1:1 Randomization

Diagnosis/Resection Chemoradiation EGFRvIII-positive glioblastoma

Temozolomide 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 x 2, then monthly

N=~440

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles KLH=keyhole limpet hemocyanin.

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)

ECOG PS=Eastern Cooperative Oncology Group Performance Status.

For more information visit glioblastomastudy.com and http://www.clinicaltrials.gov/show/NCT01480479 or e-mail info@celldextherapeutics.com. 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. ©2013 Celldex Therapeutics, Inc.

6/13

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Journal Spotlight Breast Cancer

ASCO and College of American Pathologists Guideline Update: Recommendations for HER2 Testing in Breast Cancer By Matthew Stenger

he American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) recently convened an Update Committee to conduct a systematic literature review and update recommendations for optimal HER2 testing. In particular, the Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations and has been published jointly by invitation and consent in both the Journal of Clinical Oncology1 and the Archives of Pathology & Laboratory Medicine.2 In brief, the Update Committee recommends that HER2 status be determined in all patients with invasive breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2 status as positive when, in examining an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells, there is evidence of protein overexpression (by IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (on revised criteria) on IHC or ISH, reflex testing should be performed using the alternative assay. Repeat testing should be considered if results appear discordant with other histopathologic findings. Testing laboratories should demonstrate high concordance with a validated HER2 test. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Committee urges providers and health systems to cooperate in following the updated guidelines to ensure the highest quality testing. The following summarizes key recommendations for oncologists and pathologists.

Recommendations for Oncologists • HER2 testing should be requested for every primary invasive breast cancer (and for metastatic sites for stage IV disease) to guide the decision regarding HER2-targeted

therapy. This includes patients who previously tested HER2-negative in a primary tumor who present with disease recurrence with clinical behavior suggestive of HER2-positive or triple-negative disease. • HER2-targeted therapy should be recommended if the HER2 test result is positive, if there is no apparent histopathologic discordance with HER2 testing, and if clinically appropriate. In the case of any outcomes of HER2 testing, additional testing should be discussed if the pathologist or oncologist observes an apparent histopathologic discordance after testing. • The decision regarding HER2targeted should be delayed if the initial HER2 test is equivocal. Reflex testing should be performed on the same specimen using the

Recommendations for Pathologists • At least one tumor sample from all patients with breast cancer (earlystage or metastatic disease) should be tested for either HER2 protein expression (IHC assay) or HER2 gene expression (ISH assay) using a validated HER2 test. • In the United States, the ASCO/ CAP Guidelines recommend use of an assay that has received FDA approval, although a CLIA-certified laboratory may use a laboratorydeveloped test; the analytic performance of the laboratory-developed test must be prospectively validated in the same clinical laboratory that will perform it and the test must have documented analytic validity. Bright-field ISH assays must be initially validated by compar-

The Update Committee recommends that HER2 status be determined in all patients with invasive breast cancer on the basis of one or more HER2 test results. alternative test or on an alternative specimen. • HER2-targeted therapy must not be recommended if the HER2 test result is negative and if there is no apparent histopathologic discordance with HER2 testing. • The decision on HER2-targeted therapy should be delayed if HER2 status cannot be confirmed as positive or negative after separate HER2 tests. The oncologist should confer with the pathologist regarding the need for additional HER2 testing on the same or another tumor specimen. • If HER2 testing is ultimately deemed to be equivocal, even after reflex testing with an alternative assay, HER2-targeted therapy may be considered. The feasibility of testing another tumor specimen to definitively establish HER2 status should also be considered. The clinical decision to consider HER2-targeted therapy should be individualized on the basis of patient status (comorbidities, prognosis, etc) and patient preferences after discussing available clinical evidence.

ing them with an FDA-approved fluorescence in situ hybridization (FISH) assay. • The HER2 test result must be reported as positive if it is: (a) IHC 3+ positive; or (b) ISH positive using either a single-probe ISH or dual-probe ISH. Recommendations regarding positive, equivocal, and negative results all assume that there is no apparent histopathologic discordance observed by the pathologist. • The HER2 test result must be reported as equivocal and a reflex test ordered on the same specimen (unless there are concerns about the specimen) using the alternative test if the result is: (a) IHC 2+ equivocal; or (b) ISH equivocal using single-probe ISH or dual-probe ISH. Some rare breast cancers (eg, gland-forming tumors, micropapillary carcinomas) show IHC 1+ staining that is intense but incomplete (basolateral or U shaped) and are found to be HER2 amplified. The pathologist should consider reporting these specimens as equivocal and request reflex testing using

the alternative test. • The HER2 test result must be reported as negative if a single test (or all tests) performed in a tumor specimen show: (a) IHC 1+ negative or IHC 0 negative results; or (b) ISHnegative results using single-probe ISH or dual-probe ISH. • The HER2 test result must be reported as indeterminate if technical issues prevent one or both of IHC and ISH from being reported as positive, negative, or equivocal. Another specimen should be requested for testing and a comment should be included in the pathology report documenting intended action. • Bright-field ISH should be interpreted based on a comparison between patterns in normal breast and tumor cells, because artifactual patterns may occur that are difficult to interpret. If the tumor cell pattern is neither normal nor clearly amplified, the test should be submitted for expert opinion. • Any specimen used for HER2 testing should undergo the fixation process quickly (time to fixative within 1 hour) and be fixed in 10% neutral buffered formalin for 6 to 72 hours; routine processing and staining or probing should be performed according to standardized analytically validated protocols. • The testing laboratory should conform to standards of CAP accreditation or an equivalent accreditation authority, including initial test validation, ongoing internal quality assurance, ongoing external proficiency testing, and routine periodic performance monitoring. • If an apparent histopathologic discordance is observed in any testing situation, the pathologist should consider ordering additional HER2 testing and conferring with the oncologist and should document the decision-making process and results in the pathology report. The pathologist may also pursue additional HER2 testing without conferring with the oncologist. • Although categories of HER2 status on IHC or ISH not covered by the guidelines can be created, they are uncommon in practice and should be considered IHC equivocal or continued on page 50

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Journal Spotlight HER2 Testing continued from page 49

ISH equivocal if encountered. n Disclosure: For full disclosures of the guideline authors, visit jco.ascopubs.org or www.arachivesofpathology.org.

References 1. Wolff AC, Hammond MEH, Hicks DG, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American

Pathologists Clinical Practice Guideline Update. J Clin Oncol 31:3997-4013, 2013. 2. Wolff AC, Hammond MEH, Hicks DG, et al: Recommendations for human epidermal growth factor recep-

tor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. Arch Pathol Lab Med. October 7, 2013 (early release online).

HER2 Testing: The Next Chapter By Nancy E. Davidson, MD

ate last year, the American Society of Clinical Oncology and College of American Pathologists published a comprehensive update of guidelines for HER2 testing,1 the first such update since their initial landmark publication in 2007.2 This new report, summarized in this issue of The ASCO Post, provides the opportunity to take stock of progress in anti-HER2–directed therapy and testing over the past 6 years. One might ask what is new and why an update of the guidelines is needed now. Over the past few years, much has been learned about the HER2 signaling pathways in breast cancer, and three additional anti-HER2 drugs—lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtansine (Kadcyla)—have joined trastuzumab (Herceptin) on the market in the United States. The importance of well-defined predictive markers matched to targeted therapeutics is increasingly understood, and the need to perform and interpret such predictive assays correctly is also clearly recognized.

pathologist in the testing process and correctly place the patient in the center of the discussion. Of course, these will not be the last words on this subject because of the rapid pace of discovery in this field. Indeed, these guidelines presage areas that we will need to follow. For example, breathtaking progress is being made in the realm of multigene testing through transcriptional profiling. The 2013 HER2 testing guidelines recommended against the use of these assays as a means to select for or against anti-HER2 therapy for now, but it seems likely that RNA-based, multiplex assays will ultimately emerge as part of our testing repertoire. Even more intriguing is the question of whether next-generation sequencing

The need to develop and validate reproducible and reliable assays that can inform a clinical decision for the patient should not be forgotten in our rush to embrace these new technologies.

Numerous Strengths The strengths of the new guidelines are numerous. First, they strongly recommend that testing be performed on any invasive primary breast cancer derived from a patient for whom systemic therapy is under consideration. Second, they provide very specific guidelines about how such testing should be done and interpreted, focusing on the commonly used immunohistochemistry and in situ hybridization assays to detect protein expression and DNA amplification, respectively. Third, they clearly tie the use of antiHER2-targeted agents to knowledge about HER2 status of the tumor— gone are the days of empiric use of a targeted therapy like trastuzumab. Finally, the guidelines highlight the important partnership between oncologist and Dr. Davidson is Hillman Professor of Oncology, and Director, University of Pittsburgh Cancer Institute and UPMC Cancer Center.

in Oesterreich and Davidson).4 These ESR1 gene mutations appear to be extremely rare in primary breast cancers, but are detected in a subset of metastases that emerge in women who have received adjuvant endocrine therapy. This finding emphasizes the dynamic nature of breast cancer, a disease with the potential for a long natural history and the opportunity for multiple interventions that might alter the tumor. The substantial challenges of tumor heterogeneity are also highlighted, including intratumor heterogeneity, heterogeneity between metastases, and heterogeneity over time. Little is known at present about how HER2 status evolves over time and under the pressure of serial HER2-targeted agents

—Nancy E. Davidson, MD

approaches will soon inform the use of anti-HER2 therapies, given the report of rare mutations in the HER2 (ERBB2) gene.3 The need to develop and validate reproducible and reliable assays that can inform a clinical decision for the patient should not be forgotten in our rush to embrace these new technologies.

Emerging Challenges These guidelines also foreshadow the emerging need for serial assessment of a predictive marker with their recommendation that biopsy of a metastatic site to reestablish HER2 status be considered in women with stage IV disease. One of the unexpected discoveries of 2013 was the documentation of mutations in another critical gene in breast cancer, ESR1, which encodes the estrogen receptor–alpha protein (reviewed

with variable mechanisms of action; even less is known about how (or even if) we need to evaluate this serially in the individual patient to inform our clinical recommendations. What else might we hope for in the next version of these guidelines? The search for markers of sensitivity or resistance to anti-HER2 therapies beyond HER2 expression by immunohistochemistry or gene copy number by in situ hybridization has been surprisingly unhelpful thus far. We can hope that such markers will soon become apparent and that suitable assays for their testing and guidelines for their use will be established.

Ongoing Trials Finally, even though the paradigm of positive HER2 testing driving the

selection of anti-HER2 targeted therapy seems well established, we should not forget the provocative finding from the first adjuvant trastuzumab trials that benefit from trastuzumab was observed in a handful of women with tumors with “normal” HER2 expression.5 This observation is now being prospectively explored in a randomized trial of trastuzumab vs no trastuzumab in women who would not normally be candidates for antiHER2 therapy based on conventional testing and current clinical recommendations (NCT01275677). The results from this trial, along with the many ongoing trials of second-generation anti-HER2–targeted therapies in the adjuvant, neoadjuvant, and metastatic settings, will provide a fertile ground for refinement of our understanding, evaluation, and implementation of HER2 testing and targeting in the future. n

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

References 1. Wolff AC, Hammond ME, Hicks DG, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997-4013, 2013. 2. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007. 3. Bose R, Kavuri SM, Searleman AC, et al: HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224-237, 2013. 4. Oesterreich S, Davidson NE: The search for ESR1 mutations in breast cancer. Nature Genet 45:1415-1416, 2013. 5. Paik S, Kim C, Wolmark N: HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409-1411, 2008.

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The ASCO Post | FEBRUARY 15, 2014

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Announcements

University of Pittsburgh Researchers Awarded More than $1 Million by NIH to Study New Treatments for Pancreatic Cancer Patients

he National Institutes of Health (NIH) has awarded a 5-year grant of more than $1.5 million to Herbert J. Zeh III, MD, and Michael

T. Lotze, MD, at the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, to study a novel treatment for pancre-

atic ductal adenocarcinoma. Drs. Zeh and Lotze hypothesize that the cancer progresses and is difficult to treat because of a biological

pathway called autophagy, a form of programmed cell survival that tumor cells use to avoid apoptosis, or cell death. “It is our hope that blocking

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ASCOPost.com | FEBRUARY 15, 2014

PAGE 53

Announcements

Herbert J. Zeh III, MD

Michael T. Lotze, MD

autophagy, a new approach to treating cancer, will improve the efficacy of chemotherapy for pancreatic cancer patients,” said Dr. Lotze, Professor of Surgery, Immunology and Bioengineering, and Assistant Vice Chancellor, University of Pittsburgh Schools

of the Health Sciences. “Our goal with this award is to improve the quality of life for patients with pancreatic cancer,” said Dr. Zeh, Associate Professor of Surgery and Chief of the Division of Gastrointestinal Surgical Oncology at UPCI and UPMC Cancer Center. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

Contact

The ASCO Post

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

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

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

The ASCO Post | FEBRUARY 15, 2014

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Direct From ASCO

Serving the Underserved: Dr. Gina Villani and ASCO’s Health Disparities Committee Work to Minimize Cancer Care Gaps

t has been a little over a decade since the Institute of Medicine landmark report Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care found overwhelming evidence of racial disparities in the U.S. health-care system. Since then, ASCO has been dedicated to minimizing these disparities in cancer care through its Health Disparities Committee, which works to develop programmatic and policy solutions to address these issues and improve outcomes for all populations. ASCO Connection spoke with Gina Villani, MD, MPH, Chair-Elect of ASCO’s Health Disparities Committee and CEO and Medical Director of the Ralph Lauren Center for Cancer Care and Prevention in New York, a community oncology outpatient facility. As Dr. Villani discusses in this article, disparities in cancer care still very much exist. Following are her experiences with serving the underserved and how she believes the field of oncology can further improve its outreach to these patients.

One Building, Two Levels of Care When Dr. Villani started out in oncology working at a hospital in

Disparities in Cancer Care Educational Partners ■■ American Nurse Practitioner Foundation ■■ American Pharmacists Association ■■ American Society of Clinical Oncology ■■ American Society of Pediatric Hematology Oncology ■■ American Society of Radiation Oncology ■■ Association of Oncology Social Work ■■ Association of Physician Assistants in Oncology ■■ Commission on Cancer, American College of Surgeons ■■ Interstate Postgraduate Medical Association ■■ LIVESTRONG Foundation ■■ Oncology Nursing Society ■■ Society of Gynecologic Oncology ■■ Society of Surgical Oncology

New York, she had her own practice and office hours in what she called a “beautiful suite” on one floor and ran a fellows clinic on another. The differences she saw in the behavior toward patients between these two floors was astonishing and not something she’d soon forget. “It was like I was in a different place,” Dr. Villani said. “The clinic pa-

“It’s a struggle to make ends meet because you’re providing a service and barely getting paid for it,” Dr. Villani explained. “We’re providing enhanced services, too. We have a food pantry, and people are leaving here with bags of groceries. We give them MetroCards. It’s what we have to do to build trust and get them to come back.” In her brief tenure, Dr. Villani has

I think the Center has made a difference. I have seen, on a case‑by‑case basis, many women who waited so long to get their breast cancer treated, and we convinced them to get treatment. —Gina Villani, MD, MPH

tients would come to the same area to get their chemotherapy as our private practice patients, and they were treated completely differently. I thought, ‘Wait a minute, I’m in the same building and there are two levels of care depending on what your insurance is. I don’t like this.’” This experience motivated Dr. Villani to get a Master’s degree in public health and dedicate her professional life to working in underserved areas. As CEO of the Ralph Lauren Center, Dr. Villani spent the last 18 months helping to bring the Center back from the brink of financial ruin. “The Center was in so much financial trouble that if someone didn’t come and turn it around it was going to close down,” she explained. “And I thought, ‘There is no way this Center can close because it’s done so much good for disparities in New York.’ I had to come try to help it.”

The Ralph Lauren Center for Cancer Care and Prevention Located in the Harlem neighborhood of New York, the majority of patients seen at the Ralph Lauren Center are black or from Hispanic and Asian backgrounds with multiple comorbidities, including diabetes, obesity, and substance abuse. Eighty-five percent are Medicaid- or Medicaid-managed patients. The other 15% are uninsured or think they are; the Center is usually able to help half of that 15% obtain health insurance coverage.

reduced the Center’s $2.5 million deficit by $1.4 million. She has also conducted outreach to primary care doctors in the area, educating them on how to best handle uninsured patients with cancer. “Primary care is well organized until a patient is diagnosed with cancer,” Dr. Villani said. “The doctor often tells these patients to just go to the hospital. But maybe that’s not the best way to do it. Maybe patients get a bit lost when they go to the hospital. Maybe they aren’t getting timely treatment and have a hard time navigating the system.”

Building Trust This outreach has tripled the number of patients the Center sees, but has not negatively affected the care the Center provides. Unlike most facilities in the Manhattan area, the Center guarantees a next-day appointment for anyone who calls and says they have a cancer diagnosis. The patient may not be able to have a full medical assessment during that appointment, but they are able to tour the facility and meet with a nurse navigator who will ultimately guide them through the entire treatment process. With a 40% no-show rate across the board with these patients, getting them in as soon as possible is extremely important to building trust in the system. And because the system has failed so many of these patients, building trust can be challenging.

“I think in medicine in general, we are very quick to blame the patient, especially in this population,” Dr. Villani said. “There is a level of distrust, and there is a reason for that distrust. I once worked in a place where the minute you walked in the door, the first person you saw was a uniformed security officer who was never very nice. You walk through the hospital, and it’s not clean and it’s not inviting, and then you meet a doctor who doesn’t spend time and doesn’t treat you nicely. Are you really looking to go back to that?”

Forging Ahead One of the first action items Dr. Villani had when she became CEO of the Center was to conduct a “secret shopper” experiment. She wanted to see how long it took a Medicaid-managed patient with stage IV lung cancer to be seen at one of the area hospitals. “I had one of our employees pose as the son of this patient and call 10 different hospitals in Manhattan and the Bronx, looking for an appointment for a medical oncologist for his father with lung cancer,” she explained. “We recorded how many times he got transferred on the phone, what it took to get to a person, what was the wait time, when was that appointment being made, and where was his father going to be seen. We set up a grid of these 10 different hospitals, and what we found was really scary. Our longest wait time was 53 days. And the next one was 35 days. Among these 10 hospitals, the best we could do—and that was our outlier—was to see the patient in a week.” The problem, Dr. Villani believes, is in the reimbursements. “I think the truth of the matter is if you’re going to have a patient reimburse you $300 vs $40, you’re going to get those $300 people in first. It’s just reality,” she said. “I think the Center has made a difference,” Dr. Villani said. “I have seen, on a case-by-case basis, many women who waited so long to get their breast cancer treated, and we convinced them to get treatment. We have many stories of people who didn’t have the right treatment, and we’ve tried to fix that. These patients are so nice and so grateful and have had so many hard knocks in life. What keeps me going are these nice, grateful people. They have a lot of humility. continued on page 56

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Direct From ASCO

ASCO Turns Attention to Community Researchers With Community Research Forum

he implementation of clinical trials and quality research programs by community-based investigators and research staff is one of the most effective weapons available in the fight against cancer. The ASCO Community Research Forum was designed in support of this mission and to aid these professionals in navigating and overcoming the challenges that are unique to community-based research. “The Community Research Forum is a group that has been established to think critically about the problems and challenges to doing clinical cancer research in the community setting, identify those problems, and, with the support of ASCO staff, help to solve those problems,” said Nicholas J. Robert, MD, Chair of the Community Research Forum subcommittee and a medical oncologist with Virginia Cancer Specialists, Fairfax, Virginia.

Identifying and Solving Problems The idea for the Community Research Forum was conceived in the ASCO Board of Directors’ Clinical Trials Strategic Plan of 2010, which defined ASCO’s role in supporting clinical investigators and increasing their participation in cancer clinical trials. In response, ASCO’s Cancer Research Committee convened a Subcommittee in December 2010 to implement the Community Research Forum as a solution-oriented venue for community research sites.

The Community Research Forum’s objectives include convening community-based research to identify challenges to conducting research, developing solution-oriented projects to address these challenges, and helping shape ASCO programs and policies to better support members engaged in community research.

feels can provide solutions to common issues. In the 2 years since its inception, the Forum has already developed and is testing two helpful new tools. The first tool developed by the Forum is the ASCO Clinical Research Quality Assessment Tool. Expected to be available in spring 2014, this tool is designed to help community-based re-

We hope that the more problems we can solve, the more patients can be treated on these important clinical trials. —Nicholas J. Robert, MD

A major part of that mission is completed each year with an annual meeting used to discuss known problems and propose solutions to common challenges. The Community Research Forum has held two annual meetings to date with its next planned for fall 2014. The meeting is held at ASCO headquarters and is open to anyone doing research in the community setting, including physician investigators and research staff.

Valuable Assessment Tools Based on the information coming out of each annual meeting, the Community Research Forum Subcommittee selects topic areas and projects that it

search sites exceed the minimum standards of conducting clinical research. It provides an overview of ASCO recommendations for the important components of an internal quality assessment program and a checklist to help sites conduct an assessment of whether their program includes these important components. “This tool is something that researchers can use to see if their program measures up, to identify any deficiencies,” Dr. Robert said. “This will allow us to really raise the bar in terms of quality programs doing community research.” The second tool in development is the ASCO Clinical Trial Workload

Assessment Tool, which has been designed to help research sites assess staff workload, based on the complexity of research protocols and the number of patients assigned to staff. This tool is expected to be available in summer 2014. “At a community cancer center the amount of funding to support research is limited, so it is important to know that you have the right amount of people, that is enough, but not too many,” Dr. Robert said. “This tool has real practical value and speaks to the needs of those doing community research.” This tool is currently being tested in about 50 community-based programs to determine its utility and to collect data on clinical trial workload benchmarks for community-based research programs. Findings from the project, expected in early 2014, will help to further shape the tool before it is made available to the public. “So far we have been able to pick two areas and have had success in terms of identifying solutions,” Dr. Robert said. “We hope that the more problems we can solve, the more patients can be treated on these important clinical trials.” To find out more about the Community Research Forum, visit ASCO online at www.asco.org/practiceresearch /community-research-forum or contact Eden Mesfin at eden.mesfin@ asco.org or Patricia Hurley at patricia .hurley@asco.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

Conquer Cancer Foundation Launches New Planned Giving Website

n November of 2013, the Conquer Cancer Foundation partnered with the Stelter Company—one of the leaders of planned giving resources in the nonprofit community—to launch a new planned giving portal on the Foundation’s website. The planned giving portal focuses on the variety of ways individuals can benefit the people and causes they love through charitable giving. It also introduces planning strategies that fit financial goals at each stage of life. It is continuously updated with relevant planned giving articles and the most current planned giving information. There are almost as many variations on ways to make a planned gift as there are needs to be met. Visitors

are welcome to explore the website to discover new ways to make a gift that also take into consideration their personal circumstances, philanthropic

priorities, and the needs of their heirs. Dozens of brochures are available for download as is a 23-page comprehensive estate planning kit. Whether you have a comprehensive estate plan or are just getting started, the planned

giving portal has information for everyone. Planned gifts are an excellent way to help propel the mission of the Conquer Cancer Foundation. When you include a planned gift to the Conquer Cancer Foundation in your overall estate and financial plans, you are helping provide the resources necessary to conquer cancer worldwide by funding breakthrough research and sharing cutting-edge information. The Foundation has designed the website to help you organize your future plans and find a charitable giving option that fits your comprehensive financial and charitable goals.

After you have had a chance to use the online planning tools, please contact the Foundation. The Planned Giving team would be happy to work with you and your advisors to help create a world free from the fear of cancer. Visit the new planned giving portal by going to the Conquer Cancer Foundation’s website at www .c o n q u e r c a n c e r f o u n d a t i o n .o r g /plannedgiving. To discuss your planned giving options with the Foundation’s Planned Giving team, contact plannedgiving @conquercancerfoundation.org or call (571) 483-1700. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | FEBRUARY 15, 2014

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Direct From ASCO Serving the Underserved continued from page 54

ASCO’s Health Disparities Efforts

ASCO is committed to educating its membership about disparities in cancer care. For example, ASCO is working on a series of patient education videos about common barriers to

receiving quality cancer care, as well as how to navigate these challenges. The videos, funded by the LIVESTRONG Foundation, will be available soon on Cancer.Net. Furthermore, ASCO University® has partnered with the LIVESTRONG Foundation and 11 other organizations to create an eLearning Series comprised of three

courses focusing on disparities in cancer care. (see sidebar on page 54 for the full list of partnering organizations). The courses are: • Disparities in Cancer Care: Take Action!—which includes an overview of perspectives from a care provider, an institution providing care, and a patient ASCO POST

• Cultural Competence for Oncology Practice—which examines three different patients with similar clinical issues, but from diverse backgrounds • Disparities in Cancer Care: Do You Know…?—a multiple-choice self-assessment that allows participants to assess their knowledge and understanding of issues relating to disparities in cancer care These eLearning courses, funded by the LIVESTRONG Foundation, include audio commentary, slides, and links to references and resources. Visit university.asco.org/disparities for more information. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Serving the Underserved: Dr. Gina Villani and ASCO’s Health Disparities Committee Work to Minimize Cancer Care Gaps.” ASCO Connection, January 2013: p. 30. All rights reserved.

The Latest From the 2014 Genitourinary Symposium

elp your patients catch up on the latest research on genitourinary cancers—direct them to www.cancer .net/gusymposium for summaries of what the latest research means for patient care and a podcast with an ASCO expert explaining the importance of this research. They can also look for coverage of the symposium on www.cancer.net/ blog. n © 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date

For more information, please call 800-843-8197 or visit www.GILOTRIF.com

ASCO 50th Annual Meeting May 30 - June 3, 2014 McCormick Place Chicago, Illinois

(11/13)

GF591301PROF-B

ASCOPost.com | FEBRUARY 15, 2014

PAGE 57

Direct From ASCO

Charting the Successes: CancerProgress.Net Chronicles More Than 50 Years of ASCO and Progress Against Cancer

n this historic year, as ASCO proudly commemorates its 50th anniversary and decades of evolutionary change and growth, it also celebrates the significant progress that has been made against cancer throughout history. ASCO’s anniversary website, CancerProgress.Net, chronicles these achievements and more. In honor of the Society’s anniversary, the site features stories about ASCO’s evolution, an upgraded timeline of advances in cancer, aggregated news and views on ASCO’s anniversary and progress, social media features, and an opportunity to vote on the most significant milestones in the field.

timeline, and the story of progress is shared by the timeline editors in their video interviews. In his video interview about changes in the detection and treatment of prostate cancer, Derek Raghavan, MD, PhD, FASCO, editor of the Pros-

veloped a whole series of techniques and better drugs that allow patients to go to work, to actually deal with their cancer and their cancer treatment but in much better physical shape.” Dr. Raghavan also recalled that “many of the chemotherapy drugs that

We’ve developed techniques and better drugs that allow patients to go to work, to actually deal with their cancer and their cancer treatment but in much better physical shape. —Derek Raghavan, MD, PhD, FASCO

Cancer Progress Timeline A key feature of the site, the interactive Cancer Progress Timeline developed under the guidance of an editorial board of 21 of the nation’s leading oncologists, has been updated with a fresh look and is now accessible on all mobile devices. Advances in nearly 20 types of cancers are represented on the

tate Cancer Timeline, cited several major advances. “I’ve been treating cancer for more than 30 years.… When I started, one of the hardest things was to find the balance for people who had advanced cancer and were in pain,” said Dr. Raghavan. “Now, we’ve de-

we used to give really made patients incredibly sick. With the new medications that we have now, those drugs can be administered to patients and still have them going out to play sports or go to work. In addition to having better antinausea treatments, which we’ve de-

veloped, many of the drugs have been refined to make them less toxic.” Tour ASCO’s anniversary website, CancerProgress.Net, to navigate the timeline advances, hear from other editors about milestones in cancer research, and vote on the top cancer advances over the past 5 decades. Also, follow ASCO on ASCO Connection, Twitter, and Facebook to join the conversation about progress. n © 2014. American Society of Clinical Oncology. All rights reserved.

It’s Time to Reignite Our Nation’s Commitment to Cancer Research

s 2014 rolls in, ASCO is calling for a renewed commitment to federal funding of cancer research. In a letter sent to House and Senate Appropriations leaders, ASCO urged Congress to use spending levels in the recently passed budget to set the highest possible funding level for the National Institutes of Health The nation’s investment in cancer research has made it possible for people with cancer to live longer and with a better quality of life. Today, nearly 13 million Americans are considered cancer survivors. And yet this year cancer is expected to claim the lives of 580,000 Americans, making it the second leading cause of death in the United States. In a Guest Commentary on ASCO Connection, ASCO Chief Medical Offi ASCO, cer Richard L. Schilsky, MD, F noted that although ASCO’s recently

issued report on Clinical Cancer Advances (http://cancerprogress.net/ clinical-cancer-advances-2013) highlights dozens of research breakthroughs reported in 2013, due to the flat federal

Richard L. Schilsky, MD, FASCO

funding for biomedical research, progress against cancer is in real jeopardy of stalling just when the opportunities and need are greatest.1 The NIH budget has been flat for more than a decade and is 23% lower today than in 2003, when adjusted for inflation. Scan the QR code at left to share this new full-color graphic with your social

networks—and elected representatives—to help ASCO communicate how federal funding for biomedical research is vital to our nation’s health and our economy. Contact your Members of Congress directly about the need for a greater national investment in cancer research through ASCO’s ACT Network at www.capwiz.com/asco/issues/ alert/?alertid=62933636. n

Reference 1. Schilsky R: Funding cuts threaten future progress against cancer. ASCO Connection. Available at connection . a s c o. o r g / C o m m e n t a r y / A r t i c l e / id/3740/Funding-Cuts-Threaten-FutureProgress-Against-Cancer.aspx. Accessed January 23, 2014.

Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19:1008-1016. ÂŠ2013 Amgen Inc. All rights reserved. 11/13 74385-R2-V7

Fight it ONCOLYTIC IMMUNOTHERAPY

Cancer cell

is an innovative area of research that uses a modified virus designed to help T cells find and fight cancer cells as part of a hypothesized systemic, tumor-specific immune response.1

Learn more at: www.oncolyticimmunotherapy.com

Amgen. Leading the way in the study of Oncolytic Immunotherapy.

The ASCO Post | FEBRUARY 15, 2014

PAGE 60

Journal Spotlight Risk Factors

Long-Term Follow-up Indicates Increased Telomere Length With Lifestyle Change in Men With Low-Risk Prostate Cancer By Matthew Stenger

hort telomere length in peripheral blood mononuclear cells is associated with aging and age-related diseases such as cancer, stroke, vascular dementia, cardiovascular disease, obesity, osteoporosis, and diabetes. Telomere attrition is considered a potential mechanism in triggering the chromosomal rearrangement observed in prostate cancer, with variable telomere length in prostate cancer cells and short telomere length in prostate cancer-associated stromal cells being associated with increased risk of metastasis or death from prostate cancer. Dean Ornish, MD, of the University of California San Francisco and Preventive Medicine Research Institute in Sausalito, and colleagues previously reported an association between 3 months of comprehensive lifestyle changes and increased telomerase activity in peripheral blood mononuclear cells in a small pilot study in men with low-risk prostate cancer.1 In a long-term follow-up reported in The Lancet Oncology, Ornish and colleagues found increases in relative telomere length after 5 years in patients in the lifestyle intervention group.2 This is the first controlled study showing that an intervention may increase telomere length.

Lifestyle Intervention The lifestyle intervention consisted of the following: a diet high in whole foods, plant-based protein, fruits, vegetables, unrefined grains, and legumes, and low in fat (approximately 10% of calories) and refined carbohydrates, with takehome meals being provided to patients for the first 3 months of the intervention; moderate aerobic exercise (eg, walking 30 minutes per day on 6 days per week); stress management (eg, gentle yogabased stretching, breathing, meditation, imagery, and progressive relaxation for 60 minutes daily); and increased social support (eg, 60-minute support group sessions once per week). At each weekly support session, pa-

on their own for two 4-hour meetings per month for the duration of the study. A physician or nurse was on site during meetings, and patients could request that other clinical staff attend or be available by telephone at these times.

Change in Telomere Length There were no significant differences at baseline between the intervention group and the control group in age, weight, body mass index, or blood pressure. Median lifestyle adherence scores at baseline were 0.58 (interquartile range [IQR] = 0.31– 0.79) in the intervention group and 0.60 (IQR = 0.32–0.72) in the control group. At 5 years, relative telomere length increased from baseline by a median of

Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of follow-up, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding. —Dean Ornish, MD, and colleagues

Study Details The follow-up study compared 10 lifestyle intervention group patients and 25 controls with biopsy-proven low-risk prostate cancer who had chosen to undergo active surveillance. Men in the intervention group followed a program of comprehensive lifestyle changes and men in the control group underwent active surveillance alone. Blood samples were taken at 5 years to determine relative telomere length and telomerase activity and values were analyzed according to degree of lifestyle changes. Lifestyle index scores were calculated to reflect mean percentage of adherence to the initial lifestyle intervention, with a score of 1.0 indicating 100% adherence.

tients performed 1 hour of moderate exercise supervised by an exercise physiologist and 1 hour of stress-management techniques supervised by a certified stress-management specialist and attended a 1-hour support group led by a clinical psychologist and a 1-hour lecture during dinner, generally from a dietitian, registered nurse, or physician. All members of the intervention staff were available to answer patient questions and to provide counseling at the weekly support sessions. Spouses and partners were encouraged to attend support sessions but were not required to do so. After the first 3 months, meetings were not mandatory, but intervention group patients could continue to meet

Lifestyle, Telomere Length, and Prostate Cancer ■■ At 5 years, relative telomere length increased in the lifestyle intervention group and decreased in the control group. ■■ Changes in telomere length were associated with degree of adherence to lifestyle changes. ■■ Telomerase activity was not associated with degree of adherence to lifestyle changes.

0.06 telomere to single-copy gene ratio (T/S) units (IQR = 0.05–0.11) in the lifestyle intervention group and decreased by a median of 0.03 T/S units (IQR = –0.05 to 0.03; P = .03). Relative telomere length decreased in 16 (64%) of 25 control patients and in 3 (30%) of 10 intervention patients. That said, there was a 10% average increase in telomere length in the lifestyle intervention group but a 3% average shortening in telomere length in the control group. Three patients in the intervention group received conventional treatment during the study, with two undergoing brachytherapy (at 17 and 24 months after enrollment) and one having hormonal treatment (at 25 months). Two control group patients received conventional treatment during the study, with one having radical prostatectomy (at 15 months) and one undergoing brachytherapy (at 39 months). In analysis excluding these five patients, the increase in relative telomere length in the intervention group was slightly smaller (0.05 T/S units) but remained significant compared with the control group (P = .05).

Association of Adherence and Telomere Length Median changes in lifestyle adherence scores changes were 0.22 (IQR = 0.13–0.36) in the intervention group vs –0.06 (IQR = –0.17 to 0.08) in the control group. The median lifestyle score change for the three intervention group patients in whom relative telomere length decreased was 0.13 units (IQR = 0.03–0.34), compared with 0.29 units (IQR = 0.21–0.56) for those whose relative telomere length increased. When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length on multivariate analysis adjusting for age and length of followup; for each percentage point increase in lifestyle adherence score, T/S units increased by 0.07 (P = .005). Age at the end of the study was also significantly associated with relative telomere length; for each year increase in age, T/S units decreased by 0.005 (P = .007).

Telomerase Activity At 5 years, telomerase activity had decreased from baseline by a median of 0.25 (IQR = 2.25 to 2.23) units in the intervention group and by a median of 1.08 (IQR –3.25 to 1.86) units in the control group (P = .64). Telomerase activity was not associated with adherence to lifestyle changes (relative risk = 0.93, P = .57). The investigators concluded, “Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of followup, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding.” n

Disclosure: The study was funded by the U.S. Department of Defense, National Institutes of Health/National Cancer Institute, and others. For full disclosures of the study authors, visit www.thelancet.com.

References 1. Ornish D, Lin J, Daubenmier J, et al: Increased telomerase activity and comprehensive lifestyle changes: A pilot study. Lancet Oncol 9:1048-1057, 2008. 2. Ornish D, Lin J, Chan JM, et al: Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol 14:1112-1120, 2013.

ASCOPost.com | FEBRUARY 15, 2014

PAGE 61

Perspective

Impact of Comprehensive Lifestyle Change on Telomere Length and Telomerase Activity in Men With Low-Risk Prostate Cancer By Richard Boxer, MD, FACS, and William J. Aronson, MD

rnish et al at the University of California in San Francisco and the Preventive Medicine Research Institute in Sausalito, California, performed a 5-year study1 including 35 men on active surveillance (10 in a lifestyle-intervention group and 25 in a control group) with lowrisk prostate cancer. The study was a follow-up of a 3-month study performed 6 years ago.2 The authors hypothesized that men compliant with a comprehensive diet and lifestyle change would have improvement in their peripheral blood telomere profile (length and activity), compared to a control group that did not participate in the lifestyle intervention. They noted that short telomere length in peripheral blood mononuclear cells is associated with aging and age-related diseases such as cancer, stroke, vascular dementia, and diabetes.

Considerable Commitment The comprehensive lifestyle intervention required considerable commitment from the patients and the team of investigators to carry out the study procedures. The intervention consisted of whole foods, plantbased protein, fruits, vegetables, unrefined grains, and legumes, and Dr. Boxer is Visiting Professor at the David Geffen School of Medicine at UCLA, Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin (Milwaukee), and former Professor of Clinical Urology at the University of Miami. He is also an Associate Editor of The ASCO Post. Dr. Aronson is Clinical Professor, UCLA Department of Urology, and Chief of Urologic Oncology, VA Medical Center, Greater Los Angeles Healthcare System.

was low in fat (approximately 10% of calories) and refined carbohydrates, with take-home meals being provided to patients for the first 3 months of the intervention. The intervention also consisted of moderate aerobic exercise (eg, walking 30 minutes per day on 6 days per week), stress management (eg, gentle yoga-based stretching, breathing, meditation, imagery, and progressive relaxation for 60 minutes daily), and increased social support (eg, 60-minute support group sessions once per week). At each weekly support session, patients performed 1 hour of moderate exercise supervised by an exercise

staff were available to answer patient questions and to provide counseling at the weekly support sessions. Spouses and partners were encouraged to attend support sessions but were not required to do so.

Hypothesis-Generating Findings The investigators reported that the comprehensive lifestyle group had a relative increase in telomere length compared to the control group, though there was no change in telomere activity and no statistical difference in telomerase activity between the groups. This was a pilot study

Whereas medical scientists will continue to prove benefits to diet and lifestyle changes, social scientists will need to create the incentives to cause people to change their lifestyles. —Richard Boxer, MD, FACS, and William J. Aronson, MD

physiologist and 1 hour of stressmanagement techniques supervised by a certified stress-management specialist. They also attended a 1-hour support group led by a clinical psychologist at each session and a 1-hour lecture during dinner, generally from a dietitian, registered nurse, or physician. All members of the intervention

and, therefore, should be considered hypothesis-generating. Subjects in the control group had slightly higher weight and body mass index and were older than the intervention group (though these differences were not statistically significant), and this may have impacted the results. In addition, this was a non-

randomized trial. Perhaps the healthseeking personalities of the individuals who were willing to participate in the comprehensive lifestyle changes may have factored into the outcome. Nonetheless, the findings are intriguing and form a strong basis for prospective randomized trials. We look forward to more studies on diet and lifestyle interventions in men with prostate cancer from this group of highly experienced and committed investigators.

Further Considerations Whereas medical scientists will continue to prove benefits to diet and lifestyle changes, social scientists will need to create the incentives to cause people to change their lifestyles. Full knowledge that smoking and obesity cause innumerable diseases and hundreds of thousands of deaths has not dissuaded tens of millions of humans from abusing their bodies. With the rapidly evolving field of computer and sensor technology, we would anticipate interactive computer-based, mobile programs as having a positive impact in the future. Hopefully there will soon be a highly effective “app for that.” n Disclosure: Drs. Boxer and Aronson reported no potential conflicts of interest.

References 1. Ornish D, Lin J, Chan JM, et al: Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven lowrisk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol 14: 1112-1120, 2013. 2. Ornish D, Lin J, Daubenmier J, et al: Increased telomerase activity and comprehensive lifestyle changes: A pilot study. Lancet Oncol 9:1048-1057, 2008.

Download

The ASCO Post iPad App FREE from iTunes today!

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse reactions are discussed in greater detail below: Infusion reactions, tumor lysis syndrome, cytopenias, hepatitis B virus reactivation, hepatitis B virus infection, progressive multifocal leukoencephalopathy, intestinal obstruction, and immunizations.

To learn more, please visit www.arzerrahcp.com. Indication ARZERRA® (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.4)]. • Progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.6)]. Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/ infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3

bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has occurred in patients treated with CD20-directed cytolytic antibodies, including ARZERRA. Administer aggressive intravenous hydration and antihyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have 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 also has 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 ARZERRA. For patients

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response.1 Overall response rate with ARZERRA 60 50 40

42%

Patients had received a median of 5 prior therapies The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The effectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

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 ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA 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 ARZERRA in patients who develop HBV reactivation. Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3) received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154), the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see brief summary of the full Prescribing Information, including Boxed Warning, for ARZERRA on the following pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; FEBRUARY 15, 2014

PAGE 64

Announcements

Indiana University Simon Cancer Center Receives $15 Million Pledge

he Vera Bradley Foundation for Breast Cancer recently announced a $15 million pledge to support breast cancer research at the Indiana University Melvin and Bren Simon Cancer Center. This new pledge adds to the previous $20 million in commitments completed

in November 2013 and will continue to fund the Vera Bradley Foundation for Breast Cancer Research Laboratories, named for the Foundation in 2010. The completion of this pledge will bring the total giving to the IU Simon Cancer Center to $35 million.

Precision Therapeutics Focus The gift will support IU researchers as they search for gene alterations driving specific subtypes of breast cancer, identify genetic markers to improve predictive outcomes, and deliver clinical trials to patients with

the goal of improving cure rates and quality of life. The gift will also establish the Vera Bradley Foundation Scholars Program to train scientists and physicians who will be the future leaders in breast cancer research and care. n

SYMPTOMS )F 0-, IS SUSPECTED DISCONTINUE !2:%22! AND INITIATE EVALUATION BRIEF SUMMARY BRIEF SUMMARY FOR 0-, INCLUDING NEUROLOGY CONSULTATION 5.7 Intestinal Obstruction ARZERRAÂ®SYMPTOMS )F 0-, IS SUSPECTED DISCONTINUE !2:%22! AND INITIATE EVALUATION (ofatumumab) Injection, for intravenous infusion FOR 0-, INCLUDING NEUROLOGY CONSULTATION 5.7 Intestinal Obstruction /BSTRUCTION OF THE SMALL INTESTINE CAN OCCUR IN PATIENTS RECEIVING !2:%22! ARZERRAÂ® (ofatumumab) Injection, for intravenous infusion /BSTRUCTION OF THE SMALL INTESTINE CAN OCCUR IN PATIENTS RECEIVING !2:%22! The following is a brief summary only; see full prescribing information for %VALUATE IF SYMPTOMS OF OBSTRRUCTION SUCH AS ABDOMINAL PAIN OR REPEATED The following is a brief summary only; see full prescribing information complete for %VALUATE IF SYMPTOMS OF OBSTRRUCTION SUCH AS ABDOMINAL PAIN OR REPEATED product information. VOMITING OCCUR 5.8 Immunizations 4HE SAFETY OF IMMUNIZATION WITH LIVE complete product information. VOMITING OCCUR 5.8 Immunizations 4HE SAFETY OF IMMUNIZATION WITH LIVE VIRAL VACCINES DURING OR FOLLOWING ADMINISTRATION OF !2:%22! HAS NOT BEEN VIRAL VACCINES DURING OR FOLLOWING ADMINISTRATION OF !2:%22! HAS NOT BEEN WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE STUDIED $O NOT ADMINISTER LIVE VIRAL VACCINES TO PATIENTS WHO HAVE RECENTLY WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL STUDIED $O NOT ADMINISTER LIVE VIRAL VACCINES TO PATIENTS WHO HAVE RECENTLY LEUKOENCEPHALOPATHY RECEIVED !2:%22! 4HE ABILITY TO GENERATE AN IMMUNE RESPONSE TO ANY MULTIFOCAL LEUKOENCEPHALOPATHY RECEIVED !2:%22! 4HE ABILITY TO GENERATE AN IMMUNE RESPONSE TO ANY s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS RECEIVING VACCINE FOLLOWING ADMINISTRATION OF !2:%22! HAS NOT BEEN STUDIED s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS RECEIVING CD20-directed VACCINE FOLLOWING ADMINISTRATION OF !2:%22! HAS NOT BEEN STUDIED cytolytic antibodies, including ARZERRA, in some CD20-directed cytolytic antibodies, including ARZERRA, in some 6 ADVERSE REACTIONS cases resulting in fulminant hepatitis, hepatic failure, and death 6 ADVERSE REACTIONS cases resulting in fulminant hepatitis, hepatic failure, and death 4HE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN [see Warnings and Precautions (5.4)]. 4HE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN [see Warnings and Precautions (5.4)]. other sections of the labeling: s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING IN DEATH other sections of the labeling: s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED CYTOLYTIC ANTIBODIES s )NFUSION 2EACTIONS [see Warnings and Precautions (5.1)] s )NFUSION 2EACTIONS [see Warnings and Precautions (5.1)] CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED CYTOLYTIC ANTIBODIES including s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.2)] [see Warnings andWarnings Precautions s ARZERRA 4UMOR ,YSIS 3YNDROME [see and(5.6)]. Precautions (5.2)] including ARZERRA [see Warnings and Precautions (5.6)]. s #YTOPENIAS [see Warnings and Precautions (5.3)] s #YTOPENIAS [see Warnings and Precautions (5.3)] s (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.4)] 1 INDICATIONS AND USAGE s (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.4)] 1 INDICATIONS AND USAGE s (EPATITIS " 6IRUS )NFECTION [see Warnings and Precautions (5.5)] ARZERRAÂ® OFATUMUMAB IS INDICATED FOR THE TREATMENT OF PATIENTS s (EPATITIS " 6IRUS )NFECTION [see Warnings and Precautions (5.5)] ARZERRAÂ® OFATUMUMAB IS INDICATED FOR THE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA #,, REFRACTORY TO FLUDARABINE AND s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and WITH CHRONIC LYMPHOCYTIC LEUKEMIA #,, REFRACTORY TO FLUDARABINE AND ALEMTUZUMAB 4HE EFFECTIVENESS OF !2:%22! IS BASED ON THE DEMONSTRATION Precautions (5.6)] Precautions (5.6)] ALEMTUZUMAB 4HE EFFECTIVENESS OF !2:%22! IS BASED ON THE DEMONSTRATION s )NTESTINAL /BSTRUCTION [see Warnings and Precautions (5.7)] OF DURABLE OBJECTIVE RESPONSES [see Clinical Studiesand (14)Precautions of full prescribing s )NTESTINAL /BSTRUCTION [see Warnings (5.7)] OF DURABLE OBJECTIVE RESPONSES [see Clinical Studies (14) of full prescribing 4HE MOST COMMON ADVERSE REACTIONS â&#x2030;¥ IN 3TUDY WERE NEUTROPENIA information] .O DATA DEMONSTRATE AN IMPROVEMENT IN DISEASE RELATED 4HE MOST COMMON ADVERSE REACTIONS â&#x2030;¥ IN 3TUDY WERE NEUTROPENIA information] .O DATA DEMONSTRATE AN IMPROVEMENT IN DISEASE RELATED SYMPTOMS OR INCREASED SURVIVAL WITH !2:%22! PNEUMONIA PYREXIA COUGH DIARRHEA ANEMIA FATIGUE DYSPNEA RASH PNEUMONIA PYREXIA COUGH DIARRHEA ANEMIA FATIGUE DYSPNEA RASH SYMPTOMS OR INCREASED SURVIVAL WITH !2:%22! nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, and upper respiratory tract infections. The most common 4 CONTRAINDICATIONS SERIOUS ADVERSE REACTIONS IN 3TUDY WERE INFECTIONS INCLUDING PNEUMONIA 4 CONTRAINDICATIONS SERIOUS ADVERSE REACTIONS IN 3TUDY WERE INFECTIONS INCLUDING PNEUMONIA None. AND SEPSIS NEUTROPENIA AND PYREXIA )NFECTIONS WERE THE MOST COMMON None. AND SEPSIS NEUTROPENIA AND PYREXIA )NFECTIONS WERE THE MOST COMMON ADVERSE REACTIONS LEADING TO DRUG DISCONTINUATION IN 3TUDY 6.1 Clinical 5 WARNINGS AND PRECAUTIONS ADVERSE REACTIONS LEADING TO DRUG DISCONTINUATION IN 3TUDY 6.1 Clinical 5 WARNINGS AND PRECAUTIONS Trials Experience "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions Experience "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING 5.1 Infusion Reactions ARZERRA can cause serious infusion reactionsmanifestingTrials as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, CONDITIONS ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CONDITIONS ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, cannot be directly compared to rates in the clinical trials of another drug and flushing, hypertension, hypotension, syncope, cardiac cannot be directly compared to rates in theischemia/infarction, clinical trials of another drug and flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE 4HE SAFETY OF MONOTHERAPY BACK PAIN ABDOMINAL PAIN PYREXIA RASH URTICARIA AND ANGIOEDEMA )NFUSION MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE 4HE SAFETY OF MONOTHERAPY BACK PAIN ABDOMINAL PAIN PYREXIA RASH URTICARIA AND ANGIOEDEMA )NFUSION WITH !2:%22! WAS EVALUATED IN PATIENTS WITH RELAPSED OR REFRACTORY reactions occur more frequently with the first 2 infusions [see Adverse WITH !2:%22! WAS EVALUATED IN PATIENTS WITH RELAPSED OR REFRACTORY reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)] 0REMEDICATE WITH ACETAMINOPHEN AN ANTIHISTAMINE AND A #,, IN OPEN LABEL NON RANDOMIZED SINGLE ARM STUDIES )N THESE STUDIES #,, IN OPEN LABEL NON RANDOMIZED SINGLE ARM STUDIES )N THESE STUDIES Reactions (6.1)] 0REMEDICATE WITH ACETAMINOPHEN AN ANTIHISTAMINE AND A ARZERRA was administered at 2,000 mg beginning with the second dose corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing ARZERRA was administered at 2,000 mg beginning with the second dose corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing FOR DOSES 3TUDY ;N = OR DOSES 3TUDY ;N = 4HE DATA information] )NTERRUPT INFUSION WITH !2:%22! FOR INFUSION REACTIONS OF FOR DOSES 3TUDY ;N = OR DOSES 3TUDY ;N = 4HE DATA information] )NTERRUPT INFUSION WITH !2:%22! FOR INFUSION REACTIONS OF ANY SEVERITY )NSTITUTE MEDICAL MANAGEMENT FOR SEVERE INFUSION REACTIONS DESCRIBED IN 4ABLE AND OTHER SECTIONS BELOW ARE DERIVED FROM PATIENTS DESCRIBED IN 4ABLE AND OTHER SECTIONS BELOW ARE DERIVED FROM PATIENTS ANY SEVERITY )NSTITUTE MEDICAL MANAGEMENT FOR SEVERE INFUSION REACTIONS IN 3TUDY !LL PATIENTS RECEIVED MG WEEKLY FROM THE SECOND DOSE including angina or other signs and symptoms of myocardial ischemia [see IN 3TUDY !LL PATIENTS RECEIVED MG WEEKLY FROM THE SECOND DOSE including angina or other signs and symptoms of myocardial ischemia Dosage [see and Administration (2.3) of full prescribing information] )N A STUDY ONWARD .INETY PERCENT OF PATIENTS RECEIVED AT LEAST INFUSIONS OF !2:%22! ONWARD .INETY PERCENT OF PATIENTS RECEIVED AT LEAST INFUSIONS OF !2:%22! Dosage and Administration (2.3) of full prescribing information] )N A STUDY AND RECEIVED ALL INFUSIONS 4HE MEDIAN AGE WAS YEARS RANGE OF PATIENTS WITH MODERATE TO SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND RECEIVED ALL INFUSIONS 4HE MEDIAN AGE WAS YEARS RANGE OF PATIENTS WITH MODERATE TO SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO YEARS WERE MALE AND WERE 7HITE AN INDICATION FOR WHICH !2:%22! IS NOT APPROVED OF PATIENTS DEVELOPED TO YEARS WERE MALE AND WERE 7HITE AN INDICATION FOR WHICH !2:%22! IS NOT APPROVED OF PATIENTS DEVELOPED Grade 3 bronchospasm during infusion. 5.2 Tumor Lysis Syndrome Tumor Table 1. Incidence of All Adverse Reactions Occurring in â&#x2030;¥5% of Patients Grade 3 bronchospasm during infusion. 5.2 Tumor Lysis Syndrome Tumor Table 1. Incidence of All Adverse Reactions Occurring in â&#x2030;¥5% of Patients LYSIS SYNDROME 4,3 HAS OCCURRED IN PATIENTS TREATED WITH #$ DIRECTED in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset LYSIS SYNDROME 4,3 HAS OCCURRED IN PATIENTS TREATED WITH #$ DIRECTED in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset CYTOLYTIC ANTIBODIES INCLUDING !2:%22! !DMINISTER AGGRESSIVE INTRAVENOUS of Study 1 (MedDRA 9.0) CYTOLYTIC ANTIBODIES INCLUDING !2:%22! !DMINISTER AGGRESSIVE INTRAVENOUS of Study 1 (MedDRA agents, 9.0) correct electrolyte abnormalities, hydration and antihyperuricemic hydration and antihyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.3 Cytopenias 0ROLONGED â&#x2030;¥ WEEK SEVERE Fludarabine- and and monitor renal function. 5.3 Cytopenias 0ROLONGED â&#x2030;¥ WEEK SEVERE Fludarabine- and NEUTROPENIA AND THROMBOCYTOPENIA CAN OCCUR WITH !2:%22! -ONITOR Alemtuzumab4OTAL 0OPULATION NEUTROPENIA AND THROMBOCYTOPENIA CAN OCCUR WITH !2:%22! -ONITOR COMPLETE BLOOD COUNTS #"# AND PLATELET COUNTS AT REGULAR INTERVALS DURING Alemtuzumab4OTAL 0OPULATION Refractory N COMPLETE BLOOD COUNTS #"# AND PLATELET COUNTS AT REGULAR INTERVALS DURING THERAPY AND INCREASE THE FREQUENCY OF MONITORING IN PATIENTS WHO DEVELOP Refractory N N THERAPY AND INCREASE THE FREQUENCY OF MONITORING IN PATIENTS WHO DEVELOP Grade 3 or 4 cytopenias. 5.4 Hepatitis B Virus Reactivation (EPATITIS " N Grade 3 or 4 cytopenias. 5.4 Hepatitis B Virus Reactivation (EPATITIS " Grade All Grade All VIRUS ("6 REACTIVATION IN SOME CASES RESULTING IN FULMINANT HEPATITIS Grade All Grade All VIRUS ("6 REACTIVATION IN SOME CASES RESULTING IN FULMINANT HEPATITIS hepatic failure and death, has occurred in patients "ODY 3YSTEM â&#x2030;¥3 Grades â&#x2030;¥3 Grades treated with ARZERRA. "ODY 3YSTEM â&#x2030;¥3 Grades â&#x2030;¥3 Grades hepatic failure and death, has occurred in patients treated with ARZERRA. !DVERSE %VENT % % % % #ASES HAVE BEEN REPORTED IN PATIENTS WHO ARE HEPATITIS " SURFACE ANTIGEN !DVERSE %VENT % % % % #ASES HAVE BEEN REPORTED IN PATIENTS WHO ARE HEPATITIS " SURFACE ANTIGEN )NFECTIONS AND INFESTATIONS ("S!G POSITIVE AND ALSO IN PATIENTS WHO ARE ("S!G NEGATIVE BUT ARE )NFECTIONS AND INFESTATIONS ("S!G POSITIVE AND ALSO IN PATIENTS WHO ARE ("S!G NEGATIVE BUT ARE HEPATITIS " CORE ANTIBODY ANTI ("C POSITIVE 2EACTIVATION ALSO HAS OCCURRED 0NEUMONIAa 23 14 HEPATITIS " CORE ANTIBODY ANTI ("C POSITIVE 2EACTIVATION ALSO HAS OCCURRED 0NEUMONIAa 23 14 IN PATIENTS WHO APPEAR TO HAVE RESOLVED HEPATITIS " INFECTION I E ("S!G Upper respiratory tract IN PATIENTS WHO APPEAR TO HAVE RESOLVED HEPATITIS " INFECTION I E ("S!G 11 0 3 0 Upper respiratory tract NEGATIVE ANTI ("C POSITIVE AND HEPATITIS " SURFACE ANTIBODY ;ANTI ("S= 11 0 3 0 infection NEGATIVE ANTI ("C POSITIVE AND HEPATITIS " SURFACE ANTIBODY ;ANTI ("S= infection POSITIVE ("6 REACTIVATION IS DEFINED AS AN ABRUPT INCREASE IN ("6 REPLICATION "RONCHITIS 11 <1 2 POSITIVE ("6 REACTIVATION IS DEFINED AS AN ABRUPT INCREASE IN ("6 REPLICATION "RONCHITIS 11 <1 2 MANIFESTING AS A RAPID INCREASE IN SERUM ("6 $.! LEVEL OR DETECTION OF 3EPSISb 10 10 MANIFESTING AS A RAPID INCREASE IN SERUM ("6 $.! LEVEL OR DETECTION OF ("S!G IN A PERSON WHO WAS PREVIOUSLY ("S!G NEGATIVE AND ANTI ("C 3EPSISb 10 10 ("S!G IN A PERSON WHO WAS PREVIOUSLY ("S!G NEGATIVE AND ANTI ("C POSITIVE 2EACTIVATION OF ("6 REPLICATION IS OFTEN FOLLOWED BY HEPATITIS I E Nasopharyngitis 0 0 Nasopharyngitis 0 0 POSITIVE 2EACTIVATION OF ("6 REPLICATION IS OFTEN FOLLOWED BY HEPATITIS I E (ERPES ZOSTER 1 2 INCREASE IN TRANSAMINASE LEVELS AND IN SEVERE CASES INCREASE IN BILIRUBIN (ERPES ZOSTER 1 2 INCREASE IN TRANSAMINASE LEVELS AND IN SEVERE CASES INCREASE IN BILIRUBIN 3INUSITIS 2 3 2 LEVELS LIVER FAILURE AND DEATH 3CREEN ALL PATIENTS FOR ("6 INFECTION BY 3INUSITIS 2 3 2 LEVELS LIVER FAILURE AND DEATH 3CREEN ALL PATIENTS FOR ("6 INFECTION BY MEASURING ("S!G AND ANTI ("C BEFORE INITIATING TREATMENT WITH !2:%22! "LOOD AND LYMPHATIC "LOOD AND LYMPHATIC MEASURING ("S!G AND ANTI ("C BEFORE INITIATING TREATMENT WITH !2:%22! system disorders &OR PATIENTS WHO SHOW EVIDENCE OF HEPATITIS " INFECTION ("S!G POSITIVE system disorders &OR PATIENTS WHO SHOW EVIDENCE OF HEPATITIS " INFECTION ("S!G POSITIVE Anemia ;REGARDLESS OF ANTIBODY STATUS= OR ("S!G NEGATIVE BUT ANTI ("C POSITIVE Anemia ;REGARDLESS OF ANTIBODY STATUS= OR ("S!G NEGATIVE BUT ANTI ("C POSITIVE CONSULT PHYSICIANS WITH EXPERTISE IN MANAGING HEPATITIS " REGARDING 0SYCHIATRIC DISORDERS CONSULT PHYSICIANS WITH EXPERTISE IN MANAGING HEPATITIS " REGARDING MONITORING AND CONSIDERATION FOR ("6 ANTIVIRAL THERAPY -ONITOR PATIENTS WITH 0SYCHIATRIC DISORDERS )NSOMNIA 0 10 0 MONITORING AND CONSIDERATION FOR ("6 ANTIVIRAL THERAPY -ONITOR PATIENTS WITH )NSOMNIA 0 10 0 EVIDENCE OF CURRENT OR PRIOR ("6 INFECTION FOR CLINICAL AND LABORATORY SIGNS .ERVOUS SYSTEM DISORDERS EVIDENCE OF CURRENT OR PRIOR ("6 INFECTION FOR CLINICAL AND LABORATORY SIGNS .ERVOUS SYSTEM DISORDERS OF HEPATITIS OR ("6 REACTIVATION DURING AND FOR SEVERAL MONTHS FOLLOWING (EADACHE 0 0 OF HEPATITIS OR ("6 REACTIVATION DURING AND FOR SEVERAL MONTHS FOLLOWING (EADACHE 0 0 TREATMENT WITH !2:%22! ("6 REACTIVATION HAS BEEN REPORTED FOR AT LEAST TREATMENT WITH !2:%22! ("6 REACTIVATION HAS BEEN REPORTED FOR AT LEAST #ARDIOVASCULAR DISORDERS MONTHS FOLLOWING COMPLETION OF THERAPY )N PATIENTS WHO DEVELOP #ARDIOVASCULAR DISORDERS MONTHS FOLLOWING COMPLETION OF THERAPY )N PATIENTS WHO DEVELOP REACTIVATION OF ("6 WHILE RECEIVING !2:%22! IMMEDIATELY DISCONTINUE (YPERTENSION 0 0 (YPERTENSION 0 0 REACTIVATION OF ("6 WHILE RECEIVING !2:%22! IMMEDIATELY DISCONTINUE ARZERRA and any (YPOTENSION 0 3 0 concomitant chemotherapy, and institute appropriate (YPOTENSION 0 3 0 ARZERRA and any concomitant chemotherapy, and institute appropriate Tachycardia <1 2 TREATMENT 2ESUMPTION OF !2:%22! IN PATIENTS WHOSE ("6 REACTIVATION Tachycardia <1 2 TREATMENT 2ESUMPTION OF !2:%22! IN PATIENTS WHOSE ("6 REACTIVATION RESOLVES SHOULD BE DISCUSSED WITH PHYSICIANS WITH EXPERTISE IN MANAGING Respiratory, thoracic, and Respiratory, thoracic, and RESOLVES SHOULD BE DISCUSSED WITH PHYSICIANS WITH EXPERTISE IN MANAGING mediastinal disorders HEPATITIS " )NSUFFICIENT DATA EXIST REGARDING THE SAFETY OF RESUMING mediastinal disorders HEPATITIS " )NSUFFICIENT DATA EXIST REGARDING THE SAFETY OF RESUMING !2:%22! IN PATIENTS WHO DEVELOP ("6 REACTIVATION 5.5 Hepatitis B Virus Cough 0 0 !2:%22! IN PATIENTS WHO DEVELOP ("6 REACTIVATION 5.5 Hepatitis B Virus Cough 0 0 Infection &ATAL INFECTION DUE TO HEPATITIS " IN PATIENTS WHO HAVE NOT BEEN Dyspnea 14 2 Infection &ATAL INFECTION DUE TO HEPATITIS " IN PATIENTS WHO HAVE NOT BEEN Dyspnea 14 2 PREVIOUSLY INFECTED HAS BEEN OBSERVED WITH !2:%22! -ONITOR PATIENTS Gastrointestinal disorders PREVIOUSLY INFECTED HAS BEEN OBSERVED WITH !2:%22! -ONITOR PATIENTS for clinical and Gastrointestinal disorders laboratory signs of hepatitis. 5.6 Progressive Multifocal Diarrhea 0 0 for clinical and laboratory signs of hepatitis. 5.6 Progressive Multifocal Diarrhea 0 0 Leukoencephalopathy 0ROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Nausea 11 0 12 0 Leukoencephalopathy 0ROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 0-, RESULTING IN DEATH HAS OCCURRED WITH !2:%22! #ONSIDER 0-, IN ANY Nausea 11 0 12 0 0-, RESULTING IN DEATH HAS OCCURRED WITH !2:%22! #ONSIDER 0-, IN ANY PATIENT WITH NEW ONSET OF OR CHANGES IN PRE EXISTING NEUROLOGICAL SIGNS OR (contâ&#x20AC;&#x2122;d) PATIENT WITH NEW ONSET OF OR CHANGES IN PRE EXISTING NEUROLOGICAL SIGNS OR (contâ&#x20AC;&#x2122;d)

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Announcements

NIH Makes Palliative Care More Attainable for Pediatric Patients and Their Families

campaign â&#x20AC;&#x153;Palliative Care: Conversations Matterâ&#x20AC;? recently launched by the National Institute of Nursing Research (NINR) aims to increase the use of palliative care

for children with serious illness. Palliative care can reduce a childâ&#x20AC;&#x2122;s pain, help manage other distressing symptoms, and provide important emotional support to the child and

family throughout the course of an illness. Pediatric palliative care services may also increase overall satisfaction with care for patients and their families.

Palliative Care for Serious Illness

â&#x20AC;&#x153;Initiating palliative care conversations is often hard for both providers and families, especially in the pediatric setting,â&#x20AC;? said Patricia A. Grady, PhD, RN, FAAN, NINR Director. â&#x20AC;&#x153;While it may not be an easy conversation, recommending palliative care to patients families can improve patient 8.6 Renal Impairmentand No formal studiesearly of ARZERRA in patients with renal Table 1. Incidence of All Adverse Reactions Occurring in â&#x2030;Ľ5% of Patients 8.6 in Renal Impairment No formal studies of ARZERRA in Subset patients with IMPAIRMENT HAVE BEEN CONDUCTED renal Table 1. Incidence of All Adverse Reactions Occurring in â&#x2030;Ľ5% of Patients [see Clinical in Study 1 and the Fludarabineand Alemtuzumab-Refractory experiences with Pharmacology care. We (12.3) hopeof full this IMPAIRMENT HAVE BEEN CONDUCTED [see Clinical Pharmacology (12.3) of full in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA of Study 1 (MedDRA 9.0) (contâ&#x20AC;&#x2122;d) prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA of Study 1 (MedDRA 9.0) (contâ&#x20AC;&#x2122;d) campaign and its resources will help IN PATIENTS WITH HEPATIC IMPAIRMENT HAVE BEEN CONDUCTED IN PATIENTS WITH HEPATIC IMPAIRMENT HAVE BEEN CONDUCTED Fludarabine- and 10 OVERDOSAGE ensure that palliative care is considered Fludarabine- and 10 OVERDOSAGE 4OTAL 0OPULATION Alemtuzumab.O DATA ARE AVAILABLE REGARDING OVERDOSAGE WITH !2:%22! Alemtuzumab4OTAL 0OPULATION for every child and family navigating a .O DATA ARE AVAILABLE REGARDING OVERDOSAGE WITH !2:%22! Refractory N Refractory N 13 NONCLINICAL TOXICOLOGY N serious illness.â&#x20AC;? 13 NONCLINICAL TOXICOLOGY N 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity GradeNo carcinogenicity All of Fertility GradeImpairment 13.1 Carcinogenesis,AllMutagenesis, Grade All Grade All OR MUTAGENICITY STUDIES OF OFATUMUMAB HAVE BEEN CONDUCTED )N A REPEAT DOSE To develop the campaign, NINR, a "ODY 3YSTEM â&#x2030;Ľ3 Grades â&#x2030;Ľ3 Grades OR MUTAGENICITY STUDIES OF OFATUMUMAB HAVE BEEN CONDUCTED )N A REPEAT DOSE "ODY 3YSTEM â&#x2030;Ľ3 Grades â&#x2030;Ľ3 Grades TOXICITY STUDY NO TUMORIGENIC OR UNEXPECTED MITOGENIC RESPONSES WERE NOTED IN !DVERSE %VENT % % % % TOXICITY STUDY NO TUMORIGENIC OR UNEXPECTED MITOGENIC RESPONSES WERE NOTED IN component of the National Institutes !DVERSE %VENT % % % % CYNOMOLGUS MONKEYS TREATED FOR MONTHS WITH UP TO TIMES THE HUMAN DOSE CYNOMOLGUS MONKEYS TREATED FOR MONTHS WITH UP TO TIMES THE HUMAN DOSE 3KIN AND SUBCUTANEOUS OF OFATUMUMAB %FFECTS ON MALE AND FEMALE FERTILITY HAVE NOT BEEN EVALUATED 3KIN AND SUBCUTANEOUS of Health, brought together parents and OF OFATUMUMAB %FFECTS ON MALE AND FEMALE FERTILITY HAVE NOT BEEN EVALUATED tissue disorders in animal studies. 13.3 Reproductive and Developmental Toxicology tissue disorders Toxicology Rashc in animal studies. 13.3 14Reproductive <1 and Developmental 2 palliative care clinicians, scientists, and c 0REGNANT CYNOMOLGUS MONKEYS DOSED WITH OR TIMES THE HUMAN DOSE Rash 14 <1 2 Urticaria0REGNANT CYNOMOLGUS MONKEYS DOSED WITH OR TIMES THE HUMAN DOSE 0 0 OF OFATUMUMAB WEEKLY DURING THE PERIOD OF ORGANOGENESIS GESTATION DAYS professionals to give their input and exUrticaria 0 0 OF OFATUMUMAB WEEKLY DURING THE PERIOD OF ORGANOGENESIS GESTATION DAYS (YPERHIDROSIS 0 0 TO HAD NO MATERNAL TOXICITY OR TERATOGENICITY "OTH DOSE LEVELS OF (YPERHIDROSIS 0 0 TO HAD NO MATERNAL TOXICITY OR TERATOGENICITY "OTH DOSE LEVELS OF OFATUMUMAB DEPLETED CIRCULATING " CELLS IN THE DAMS WITH SIGNS OF INITIAL pertise on what they felt was needed in -USCULOSKELETAL AND OFATUMUMAB DEPLETED CIRCULATING " CELLS IN THE DAMS WITH SIGNS OF INITIAL -USCULOSKELETAL AND " CELL RECOVERY DAYS AFTER THE FINAL DOSE &OLLOWING #AESAREAN SECTION CONNECTIVE TISSUE DISORDERS the field. The campaign emphasizes that " CELL RECOVERY DAYS AFTER THE FINAL DOSE &OLLOWING #AESAREAN SECTION CONNECTIVE TISSUE DISORDERS AT GESTATIONAL DAY FETUSES FROM OFATUMUMAB TREATED DAMS EXHIBITED "ACK PAIN 1 12 2 AT GESTATIONAL DAY FETUSES FROM OFATUMUMAB TREATED DAMS EXHIBITED "ACK PAIN 1 12 2 DECREASES IN MEAN PERIPHERAL " CELL COUNTS DECREASED TO APPROXIMATELY palliative care works along with other -USCLE SPASMS 0 3 0 DECREASES IN MEAN PERIPHERAL " CELL COUNTS DECREASED TO APPROXIMATELY -USCLE SPASMS 0 3 0 OF CONTROL VALUES SPLENIC " CELL COUNTS DECREASED TO APPROXIMATELY General disorders and OF CONTROL VALUES SPLENIC " CELL COUNTS DECREASED TO APPROXIMATELY treatments to enhance quality of life for General disorders and TO OF CONTROL VALUES AND SPLEEN WEIGHTS DECREASED BY FOR THE administration site TO OF CONTROL VALUES AND SPLEEN WEIGHTS DECREASED BY FOR THE administration site LOW DOSE AND BY FOR THE HIGH DOSE GROUP COMPARED TO CONTROL VALUES children of any age living with a broad conditions LOW DOSE AND BY FOR THE HIGH DOSE GROUP COMPARED TO CONTROL VALUES conditions &ETUSES FROM TREATED DAMS EXHIBITING ANTI OFATUMUMAB ANTIBODY RESPONSES 0YREXIA &ETUSES FROM TREATED DAMS EXHIBITING ANTI OFATUMUMAB ANTIBODY RESPONSES 20 3 range of serious illnesses. In particular, 0YREXIA 20 3 HAD HIGHER " CELL COUNTS AND HIGHER SPLEEN WEIGHTS COMPARED TO THE FETUSES Fatigue HAD HIGHER " CELL COUNTS AND HIGHER SPLEEN WEIGHTS COMPARED TO THE FETUSES 0 0 FROM OTHER TREATED DAMS INDICATING PARTIAL RECOVERY IN THOSE ANIMALS Fatigue 0 0 the campaign strives to break the comFROM OTHER TREATED DAMS INDICATING PARTIAL RECOVERY IN THOSE ANIMALS Edema peripheral <1 2 DEVELOPING ANTI OFATUMUMAB ANTIBODIES 7HEN COMPARED TO CONTROL ANIMALS Edema peripheral <1 2 Chills DEVELOPING ANTI OFATUMUMAB ANTIBODIES 7HEN COMPARED TO CONTROL ANIMALS 0 10 0 moninassociation between fetuses from treated dams both dose groups had a 10%palliative decrease incare mean Chills 0 10 0a fetuses from treated dams in both dose groups had a 10% decrease inPLACENTAL WEIGHTS ! DECREASE IN MEAN THYMUS WEIGHT COMPARED TO mean 0NEUMONIA INCLUDES PNEUMONIA LUNG INFECTION LOBAR PNEUMONIA AND a 0NEUMONIA INCLUDES PNEUMONIA LUNG INFECTION LOBAR PNEUMONIA AND bronchopneumonia. and hospice care, stressing that palliaPLACENTAL WEIGHTS ! DECREASE IN MEAN THYMUS WEIGHT COMPARED TO THE CONTROLS WAS ALSO OBSERVED IN FETUSES FROM DAMS TREATED WITH TIMES bronchopneumonia. THE CONTROLS WAS ALSO OBSERVED IN FETUSES FROM DAMS TREATED WITH TIMES b 3EPSIS INCLUDES SEPSIS NEUTROPENIC SEPSIS BACTEREMIA AND SEPTIC SHOCK the human dose of ofatumumab. significance of decreasedilltive careThe is biological appropriate throughout b 3EPSIS INCLUDES SEPSIS NEUTROPENIC SEPSIS BACTEREMIA AND SEPTIC SHOCK the human dose of ofatumumab. The biological significance of decreased c 2ASH INCLUDES RASH RASH MACULAR AND RASH VESICULAR PLACENTAL AND THYMIC WEIGHTS IS UNKNOWN 4HE KINETICS OF " LYMPHOCYTE c 2ASH INCLUDES RASH RASH MACULAR AND RASH VESICULAR PLACENTAL AND THYMIC WEIGHTS IS UNKNOWN 4HE KINETICS OF " LYMPHOCYTE ness, not only at the end of life. RECOVERY AND THE POTENTIAL LONG TERM EFFECTS OF PERINATAL " CELL DEPLETION IN

)NFUSION 2EACTIONS )NFUSION REACTIONS OCCURRED IN OF PATIENTS ON THE RECOVERY AND THE POTENTIAL LONG TERM EFFECTS OF PERINATAL " CELL DEPLETION IN OFFSPRING FROM OFATUMUMAB TREATED DAMS HAVE NOT BEEN STUDIED IN ANIMALS )NFUSION 2EACTIONS )NFUSION REACTIONS OCCURRED IN OF PATIENTS ON THE DAY OF THE FIRST INFUSION MG ON THE DAY OF THE SECOND INFUSION OFFSPRING FROM OFATUMUMAB TREATED DAMS HAVE NOT BEEN STUDIED IN ANIMALS DAY OF THE FIRST INFUSION MG ON THE DAY OF THE SECOND INFUSION MG AND LESS FREQUENTLY DURING SUBSEQUENT INFUSIONS )NFECTIONS A 17 PATIENT COUNSELING INFORMATION Evidence-Based Materials MG AND LESS FREQUENTLY DURING SUBSEQUENT INFUSIONS )NFECTIONS A 17 PATIENT COUNSELING INFORMATION TOTAL OF PATIENTS EXPERIENCED BACTERIAL VIRAL OR FUNGAL INFECTIONS !DVISE PATIENTS TO CONTACT A HEALTHCARE PROFESSIONAL FOR ANY OF THE FOLLOWING TOTAL OF PATIENTS EXPERIENCED BACTERIAL VIRAL OR FUNGAL INFECTIONS !DVISE PATIENTS TO CONTACT A HEALTHCARE PROFESSIONAL FOR ANY OF THE FOLLOWING The campaignâ&#x20AC;&#x2122;s evidence-based ma! TOTAL OF PATIENTS EXPERIENCED â&#x2030;Ľ'RADE INFECTIONS OF WHICH s 3IGNS AND SYMPTOMS OF INFUSION REACTIONS INCLUDING FEVER CHILLS RASH

! TOTAL OF PATIENTS EXPERIENCED â&#x2030;Ľ'RADE INFECTIONS OF WHICH s 3IGNS AND SYMPTOMS OF INFUSION REACTIONS INCLUDING FEVER CHILLS RASH or breathing problems within 24 hours of infusion [see Warnings and WERE FATAL 4HE PROPORTION OF FATAL INFECTIONS IN THE FLUDARABINE AND terials are designed to help providers WERE FATAL 4HE PROPORTION OF FATAL INFECTIONS IN THE FLUDARABINE AND or breathing problems within 24 hours of infusion [see Warnings and ALEMTUZUMAB REFRACTORY GROUP WAS Neutropenia: /F PATIENTS Precautions (5.1) and Adverse Reactions (6.1)] ALEMTUZUMAB REFRACTORY GROUP WAS Neutropenia: /F PATIENTS with NORMAL NEUTROPHIL COUNTS AT BASELINE DEVELOPED â&#x2030;ĽGrade Precautions (5.1) and Adverse Reactions (6.1)] 3 s "LEEDING EASY BRUISING PETECHIAE PALLOR WORSENING WEAKNESS OR FATIGUE initiate palliative care conversations with NORMAL NEUTROPHIL COUNTS AT BASELINE DEVELOPED â&#x2030;ĽGrade 3NEUTROPENIA .INETEEN DEVELOPED 'RADE NEUTROPENIA 3OME PATIENTS s "LEEDING EASY BRUISING PETECHIAE PALLOR WORSENING WEAKNESS OR FATIGUE [see Warnings and Precautions (5.3)] NEUTROPENIA .INETEEN DEVELOPED 'RADE NEUTROPENIA 3OME PATIENTS [see Warnings and Precautions (5.3)] with pediatric patientsWarnings and their EXPERIENCED NEW ONSET 'RADE NEUTROPENIA WEEKS IN DURATION s 3IGNS OF INFECTIONS INCLUDING FEVER AND COUGH [see and famiEXPERIENCED NEW ONSET 'RADE NEUTROPENIA WEEKS IN DURATION 6.2 Immunogenicity s 3IGNS OF INFECTIONS INCLUDING FEVER AND COUGH [see Warnings and There is a potential for immunogenicity with therapeutic Precautions (5.3) and Adverse Reactions (6.1)] lies as soon as possible following diag6.2 Immunogenicity There is a potential for immunogenicity with therapeutic Precautions (5.3) and Adverse Reactions (6.1)] PROTEINS SUCH AS OFATUMUMAB 3ERUM SAMPLES FROM PATIENTS WITH #,, IN s 3YMPTOMS OF HEPATITIS INCLUDING WORSENING FATIGUE OR YELLOW DISCOLORATION PROTEINS SUCH AS OFATUMUMAB 3ERUM SAMPLES FROM PATIENTS WITH #,, IN 3TUDY WERE TESTED BY ENZYME LINKED IMMUNOSORBENT ASSAY %,)3! FOR s 3YMPTOMS OF HEPATITIS INCLUDING WORSENING FATIGUE OR YELLOW DISCOLORATION and continue these OF SKIN OR EYES [seenosis Warnings andtoPrecautions (5.4, 5.5)] discussions 3TUDY WERE TESTED BY ENZYME LINKED IMMUNOSORBENT ASSAY %,)3! FOR ANTI OFATUMUMAB ANTIBODIES DURING AND AFTER THE WEEK TREATMENT PERIOD OF SKIN OR EYES [see Warnings and Precautions (5.4, 5.5)] s .EW NEUROLOGICAL SYMPTOMS SUCH AS CONFUSION DIZZINESS OR LOSS OF throughout the illness to meet changing ANTI OFATUMUMAB ANTIBODIES DURING AND AFTER THE WEEK TREATMENT PERIOD s . EW NEUROLOGICAL SYMPTOMS SUCH AS CONFUSION DIZZINESS OR LOSS OF 2ESULTS WERE NEGATIVE IN PATIENTS AFTER THE th infusion and in 33 patients BALANCE DIFFICULTY TALKING OR WALKING OR VISION PROBLEMS [see Warnings and 2ESULTS WERE NEGATIVE IN PATIENTS AFTER THE th infusion and in 33 patients BALANCE DIFFICULTY TALKING OR WALKING OR VISION PROBLEMS [see Warnings and th needs of the patient and family. after the 12 INFUSION )MMUNOGENICITY ASSAY RESULTS ARE HIGHLY DEPENDENT ON Precautions (5.6)] after the 12th INFUSION )MMUNOGENICITY ASSAY RESULTS ARE HIGHLY DEPENDENT ON Precautions (5.6)] SEVERAL FACTORS INCLUDING ASSAY SENSITIVITY AND SPECIFICITY ASSAY METHODOLOGY s .EW OR WORSENING ABDOMINAL PAIN OR NAUSEA OR A SIGNIFICANT INCREASE IN The Palliative Care: Conversations SEVERAL FACTORS INCLUDING ASSAY SENSITIVITY AND SPECIFICITY ASSAY METHODOLOGY s .EW OR WORSENING ABDOMINAL PAIN OR NAUSEA OR A SIGNIFICANT INCREASE IN sample handling, timing of sample collection, concomitant medications, and feeling unwell [see Warnings and Precautions (5.2, 5.7)] sample handling, timing of sample collection, concomitant medications, and feeling unwell [see Warnings and Precautions (5.2, 5.7)] underlying disease. For these reasons, comparison of incidence of antibodies to s 0REGNANCY OR NURSING [see Use in Specific Populations 8.3)] Matter campaign resources(8.1, include: underlying disease. For these reasons, comparison of incidence of antibodies to with s the 0REGNANCY OR NURSING [seetoUse in Specific (8.1, 8.3)] !DVISE PATIENTS OF THE NEED FOR ARZERRA incidence of antibodies other productsPopulations may be misleading. ARZERRA with the incidence of antibodies to other products may be misleading. !DVISE PATIENTS OF THE NEED FOR â&#x20AC;˘ Informational video vignettes, which s 0ERIODIC MONITORING FOR BLOOD COUNTS [see Warnings and Precautions (5.3)] 7 DRUG INTERACTIONS s 0ERIODIC MONITORING FOR BLOOD COUNTS [see Warnings and Precautionss (5.3)] !VOIDING VACCINATION WITH LIVE VIRAL VACCINES [see Warningsabout and 7 DRUG INTERACTIONS offer advice to providers how .O FORMAL DRUG DRUG INTERACTION STUDIES HAVE BEEN CONDUCTED WITH !2:%22! s !VOIDING VACCINATION WITH LIVE VIRAL VACCINES [see Warnings and Precautions (5.8)] .O FORMAL DRUG DRUG INTERACTION STUDIES HAVE BEEN CONDUCTED WITH !2:%22! Precautions (5.8)] to start palliative care discussions 8 USE IN SPECIFIC POPULATIONS !2:%22! IS A REGISTERED TRADEMARK OF THE 'LAXO3MITH+LINE GROUP OF 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 0REGNANCY #ATEGORY # There are no adequate or well-controlled !2:%22! IS A REGISTERED TRADEMARK OF THE 'LAXO3MITH+LINE GROUP OF with patients and family members companies. 8.1 Pregnancy 0REGNANCY #ATEGORY # There are no adequate or well-controlled STUDIES OF OFATUMUMAB IN PREGNANT WOMEN ! REPRODUCTIVE STUDY IN PREGNANT companies. STUDIES OF OFATUMUMAB IN PREGNANT WOMEN ! REPRODUCTIVE STUDY IN PREGNANT and features a motherâ&#x20AC;&#x2122;s perspective CYNOMOLGUS MONKEYS THAT RECEIVED OFATUMUMAB AT DOSES UP TO TIMES THE -ANUFACTURED BY CYNOMOLGUS MONKEYS THAT RECEIVED OFATUMUMAB AT DOSES UP TO TIMES THE -ANUFACTURED BY recommended human dose of ofatumumab did not demonstrate maternal ',!8/ '2/50 ,)-)4%$ on palliative care after her daughterâ&#x20AC;&#x2122;s recommended human dose of ofatumumab did not demonstrate maternalTOXICITY OR TERATOGENICITY /FATUMUMAB CROSSED THE PLACENTAL BARRIER AND FETUSES ',!8/ '2/50 ,)-)4%$ 'REENFORD -IDDLESEX 5" .. 5NITED +INGDOM TOXICITY OR TERATOGENICITY /FATUMUMAB CROSSED THE PLACENTAL BARRIER AND FETUSES 'REENFORD -IDDLESEX 5" .. 5NITED +INGDOM difficult diagnosis. EXHIBITED DEPLETION OF PERIPHERAL " CELLS AND DECREASED SPLEEN AND PLACENTAL 5 3 ,IC EXHIBITED DEPLETION OF PERIPHERAL " CELLS AND DECREASED SPLEEN AND PLACENTAL 5 3 ,IC weights. ARZERRA should be used during pregnancy only if the potential benefit weights. ARZERRA should be used during pregnancy only if the potential benefit Distributed by: â&#x20AC;˘ Customizable tear-off pads of paTO THE MOTHER JUSTIFIES THE POTENTIAL RISK TO THE FETUS 4HERE ARE NO HUMAN OR Distributed by: TO THE MOTHER JUSTIFIES THE POTENTIAL RISK TO THE FETUS 4HERE ARE NO HUMAN OR ANIMAL DATA ON THE POTENTIAL SHORT AND LONG TERM EFFECTS OF PERINATAL " CELL tient education sheets, in English and ANIMAL DATA ON THE POTENTIAL SHORT AND LONG TERM EFFECTS OF PERINATAL " CELL DEPLETION IN OFFSPRING FOLLOWING IN UTERO EXPOSURE TO OFATUMUMAB /FATUMUMAB DEPLETION IN OFFSPRING FOLLOWING IN UTERO EXPOSURE TO OFATUMUMAB /FATUMUMAB Spanish, which encourage providers DOES NOT BIND NORMAL HUMAN TISSUES OTHER THAN " LYMPHOCYTES )T IS NOT KNOWN DOES NOT BIND NORMAL HUMAN TISSUES OTHER THAN " LYMPHOCYTES )T IS NOT KNOWN IF BINDING OCCURS TO UNIQUE EMBRYONIC OR FETAL TISSUE TARGETS )N ADDITION THE to have discussions with patients and 'LAXO3MITH+LINE IF BINDING OCCURS TO UNIQUE EMBRYONIC OR FETAL TISSUE TARGETS )N ADDITION THE 'LAXO3MITH+LINE KINETICS OF " LYMPHOCYTE RECOVERY ARE UNKNOWN IN OFFSPRING WITH " CELL DEPLETION 2ESEARCH 4RIANGLE 0ARK .# KINETICS OF " LYMPHOCYTE RECOVERY ARE UNKNOWN IN OFFSPRING WITH " CELL DEPLETION their families by providing answers to 2ESEARCH 4RIANGLE 0ARK .# [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers )T IS NOT KNOWN WHETHER [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers )T IS NOT KNOWN WHETHER ÂĽ 'LAXO3MITH+LINE GROUP OF COMPANIES !LL RIGHTS RESERVED OFATUMUMAB IS SECRETED IN HUMAN MILK HOWEVER HUMAN )G' IS SECRETED IN common questions about palliative ÂĽ 'LAXO3MITH+LINE GROUP OF COMPANIES !LL RIGHTS RESERVED OFATUMUMAB IS SECRETED IN HUMAN MILK HOWEVER HUMAN )G' IS SECRETED IN HUMAN MILK 0UBLISHED DATA SUGGEST THAT NEONATAL AND INFANT CONSUMPTION OF 3EPTEMBER HUMAN MILK 0UBLISHED DATA SUGGEST THAT NEONATAL AND INFANT CONSUMPTION OF BREAST MILK DOES NOT RESULT IN SUBSTANTIAL ABSORPTION OF THESE MATERNAL ANTIBODIES 3EPTEMBER care and resources to support conver!2: "23 BREAST MILK DOES NOT RESULT IN SUBSTANTIAL ABSORPTION OF THESE MATERNAL ANTIBODIES INTO CIRCULATION "ECAUSE THE EFFECTS OF LOCAL GASTROINTESTINAL AND LIMITED SYSTEMIC !2: "23 INTO CIRCULATION "ECAUSE THE EFFECTS OF LOCAL GASTROINTESTINAL AND LIMITED SYSTEMIC sations. EXPOSURE TO OFATUMUMAB ARE UNKNOWN CAUTION SHOULD BE EXERCISED WHEN EXPOSURE TO OFATUMUMAB ARE UNKNOWN CAUTION SHOULD BE EXERCISED WHEN ÂĽ 'LAXO3MITH+LINE GROUP OF COMPANIES ARZERRA is ÂĽ 'LAXO3MITH+LINE GROUP OF COMPANIES administered to a nursing woman. 8.4 Pediatric Use 3AFETY AND For more information, visit www. ARZERRA is administered to a nursing woman. 8.4 Pediatric Use 3AFETY AND !LL RIGHTS RESERVED 0RINTED IN 53! 2 $ECEMBER EFFECTIVENESS OF !2:%22! HAVE NOT BEEN ESTABLISHED IN CHILDREN 8.5 Geriatric !LL RIGHTS RESERVED 0RINTED IN 53! 2 $ECEMBER EFFECTIVENESS OF !2:%22! HAVE NOT BEEN ESTABLISHED IN CHILDREN 8.5 Geriatric ninr.nih.gov and search â&#x20AC;&#x153;Palliative Care: Use Clinical studies of ARZERRA did not include sufficient numbers of subjects Use Clinical studies of ARZERRA did not include sufficient numbers of subjects AGED AND OVER TO DETERMINE WHETHER THEY RESPOND DIFFERENTLY FROM YOUNGER Conversations Matter.â&#x20AC;? n AGED AND OVER TO DETERMINE WHETHER THEY RESPOND DIFFERENTLY FROM YOUNGER subjects [see Clinical Pharmacology (12.3) of full prescribing information]. subjects [see Clinical Pharmacology (12.3) of full prescribing information].

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In the Clinic

Trametinib and Dabrafenib in Combination for Unresectable or Metastatic Melanoma With BRAF V600E or V600K Mutations 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 January 9, 2014, the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) was granted accelerated approval for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The approval of the combination is based on demonstration of durable response rate. Improvements in disease-related symptoms and overall survival have not yet been shown for the combination. Both drugs were approved for use as single agents in this setting in May 2013.

Efficacy Findings Approval of the combination is based on findings in an open-label trial in which 162 patients with no prior exposure to BRAF or MEK inhibitors were randomized to receive trametinib at 2 mg (n = 54) or 1 mg (n = 54) orally once daily plus dabrafenib at 150 mg orally twice daily or dabrafenib at 150 mg alone (n = 54).1-3 Patients had a median age of 53 years, 57% were male, > 99% were white, 66% had Eastern Cooperative Oncology Group performance status of 0, 67% had M1c disease, 54% had normal lactate dehydrogenase levels, 8% had a history of brain metastases, and 81% had not received prior therapy for unresectable or metastatic disease; 85% had BRAF V600E mutations and 15% had BRAF V600K mutations. Median follow-up was 14 months. Investigator-assessed overall response rate, the primary endpoint, was 76% in

patients receiving trametinib at 2 mg plus dabrafenib (including complete response in 9%), vs 54% in those receiving dabrafenib alone (including complete response in 4%). Median duration of response was 10.5 vs 5.6 months. On independent radiology review committee assessment, objective response rates were 57% (complete response in 9%) vs 46% (complete response in 7%) with median duration of response of 7.6 months in both groups. Outcomes were similar in patients with BRAF V600E mutations and BRAF V600K mutations.

How They Work Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation–positive melanoma cell lines in vitro and

OF NOTE Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. The combination inhibits growth of BRAF V600 mutation–positive melanoma cell lines more than either drug alone.

prolonged inhibition of tumor growth in BRAF V600 mutation–positive melanoma xenografts compared with either drug alone. Trametinib is a reversible inhibitor of MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation–positive mela-

Trametinib/Dabrafenib for Melanoma ■■ Trametinib (Mekinist) plus dabrafenib (Tafinlar) was granted accelerated approval for the treatment of unresectable or metastatic melanoma associated with BRAF V600E or V600K mutations as detected by an FDA‑approved test. ■■ The recommended dose of the combination is trametinib at 2 mg once daily and dabrafenib at 150 mg twice daily.

noma cell growth in vitro and in vivo. Dabrafenib is an inhibitor of some mutated forms of BRAF kinases, and some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that stimulate tumor cell growth. Dabrafenib inhibits BRAF V600 mutation–positive melanoma cell growth in vitro and in vivo.

How the Combination Is Used The recommended dose of the combination is trametinib at 2 mg once daily and dabrafenib at 150 mg twice daily, taken at least 1 hour before or 2 hours after a meal. No dose modifications of either drug are required for new primary noncutaneous malignancies. Dabrafenib should be permanently discontinued in patients who develop RAS mutation– positive noncutaneous malignancies. Concurrent administration of strong inhibitors of CYP3A4 (eg, ritonavir, clarithromycin, ketoconazole) or CYP2C8 (eg, gemfibrozil) and strong inducers of CYP3A4 (eg, carbamazepine, phenobarbital, St. John’s wort) or CYP2C8 (eg, rifampicin) should be avoided when trametinib and dabrafenib are used in combination. Concomitant use of the combination with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 (eg, tacrolimus, imatinib, anastrozole, paclitaxel, sorafenib), may result in loss of efficacy of these agents.

Safety Profile Patients with abnormal left-ventricular ejection fraction, history of acute coronary syndrome within 6 months, current evidence of class II or greater congestive heart failure (New York Heart Association), history of retinal pigment epithelial detachment or retinal vein occlusion, QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of glucose6-phosphate dehydrogenase deficiency were excluded from the trial supporting approval of the combination. The most common adverse events of any grade in patients receiving trametinib at 2 mg or 1 mg in combination with dabrafenib were pyrexia (71% and 69% vs 26% with dabrafenib alone),

OF NOTE The trametinib/dabrafenib combination carries warnings/precautions for new primary malignancies, hemorrhage, and venous thromboembolism.

chills (58% and 50% vs 17%), fatigue (53% and 57% vs 40%), rash (45% and 43% vs 53%), nausea (44% and 46% vs 21%), and vomiting (40% and 43% vs 15%). The most common grade 3 or 4 adverse events were pyrexia (5% and 9% vs 0%), nausea (2% and 6% vs 0%), renal failure (7% and 0% vs 0%), back pain (5% and 0% vs 2%), and hemorrhage (5% and 0% vs 0%). Serious side effects included bleeding, clot formation, heart failure, skin problems, and eye problems. The development of a new squamous cell carcinoma of the skin, a known adverse effect of dabrafenib, was reduced from 19% in the dabrafenib-alone group to 7% in the combination group. Adverse events led to dose reduction in 49% of combination patients, with the most common reasons being pyrexia, chills, and nausea, and dose interruption in 67%, with the most common reasons being and pyrexia, chills, and decreased ejection fraction. Adverse events led to permanent discontinuation of study treatment in 13% of combination patients, with the most common cause being pyrexia (4%). Fever was more common and more severe with the combination vs dabrafenib alone. QTcF prolongation to > 500 msec occurred in 4% of patients receiving trametinib at 2 mg/dabcontinued on page 67

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

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In the Clinic Trametinib/Dabrafenib continued from page 66

rafenib and in 2% of dabrafenib-only recipients. QTcF increased more than 60 msec from baseline in 13% of the combination group and in 2% of the dabrafenib group. In the entire safety population of 202 patients, clinically important adverse events that occurred with a frequency < 10% in combination recipients included blurred vision, transient blindness, stomatitis, pancreatitis, asthenia, cellulitis, folliculitis, paronychia, pustular rash,

skin papilloma, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis, and hypertension. The combination of trametinib and dabrafenib carries warnings/precautions for new primary cutaneous and noncutaneous malignancies (during and after treatment), hemorrhage (including major hemorrhagic events), and venous thromboembolism (deepvein thrombosis and pulmonary embolism). Trametinib alone carries warnings/precautions for cardiomyopathy, ocular toxicities (including retinal vein

occlusion), interstitial lung disease, serious febrile reactions, serious skin toxicity, hyperglycemia, and embryofetal toxicity. Dabrafenib alone carries warnings/precautions for tumor promotion in BRAF wild-type melanoma, cardiomyopathy, ocular toxicities, serious febrile reactions, serious skin toxicity, hyperglycemia, glucose-6-phosphate dehydrogenase deficiency, and embryofetal toxicity. n References 1. MEKINISTTM (trametinib) tablets

prescribing information, GlaxoSmithKline, January 2014. Available at http:// us.gsk.com/products/assets/us_mekinist.pdf. 2. TAFINLAR® (dabrafenib) capsules prescribing information, GlaxoSmithKline, January 2014. Available at http:// gsksource.com/gskprm/htdocs/documents/TAFINLAR-PI-MG.PDF. 3. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694-1703, 2012.

City of Hope Receives $10 Million Gift to Launch Lymphoma Research and Treatment Center

$10 million gift from Internet publishing entrepreneurs and philanthropists Emmet and Toni Stephenson and their daughter Tessa Stephenson Brand will fund the creation of the Toni Stephenson Lymphoma Center at City of Hope, Duarte, California, the cornerstone of the institution’s new Hematologic Malignancies Institute. The gift was announced January 11 at a gala at City of Hope, which culminated a year-long celebration of the institution’s centennial. The gift will enable City of Hope researchers to deepen their investigation of the biological mechanisms of lymphoma, identify new molecular targets, and expedite production of immunotherapies to treat this deadly disease. In launching the lymphoma center, the gift will help shape the structure of City of Hope’s new Hematologic Malig-

nancies Institute. The institute, now in development, will help speed the translation of new discoveries to patients diagnosed with hematologic malignancies and will bring additional resources and commitment to their ultimate cure and prevention. Toni Stephenson is currently being treated at City of Hope for T cell lymphoma, and the new center will be named in her honor. The family’s gift will help City of Hope scientists further develop immune-based, nontransplant therapies that have already shown promise in their laboratories. “For decades, doctors and researchers at City of Hope have worked to prolong the lives and relieve the suffering of thousands of people with leukemia, lymphoma, myeloma and other blood cancers,” said Stephen J. Forman, MD, the Francis & Kathleen McNamara Dis-

Emmet Stephenson, his wife Toni, and their daughter Tessa Stephenson Brand. (Photo: Business Wire)

tinguished Chair in Hematology and Hematopoietic Cell Transplantation at City of Hope. “Our success shows not just how committed we are to those patients, but also just how much more we

can achieve. The Stephenson family’s generosity will enable us to improve the longevity—and the quality—of our patients’ lives and, ultimately, to cure lymphoma and other diseases.” n

Radiation Oncology Institute Awards $200,000 Grant to Christopher Slatore, MD

he Radiation Oncology Institute (ROI) has named Christopher G. Slatore, MD, recipient of a $200,000 award, distributed over 2 years, for a project to examine the comparative value of radiation therapy and patient outcomes among patients with lung cancer. Dr. Slatore is Assistant Professor in the Division of Pulmonary and Critical Care Medicine at the Portland VA Medical Center in Portland, Oregon.

Overview of Study Goals Dr. Slatore will conduct a prospective,

longitudinal, quantitative, and qualitative study among patients with early-stage non–small cell lung cancer undergoing routine care to better understand patient-centered outcomes associated with the differing treatments (ie, surgical resection, stereotactic body radiotherapy, MD, external beam radiation, treat- Christopher G. Slatore, MD Theodore L awrence, PhD, FASTRO ment deferral). In addition, he will evaluate patient-clinician communi“We are proud to confer this imporcation to determine its influence on out- tant award to Dr. Slatore; he is an exemcomes and decision-making. plary leader in research focused on pa-

tient-centered care for non-small cell lung cancer, and we look forward to the results of this impressive and meaningful study,” said ROI President Theodore Lawrence, MD, PhD, FASTRO. “ROI is committed to supporting research that examines the comparative value of radiation therapy because it can improve cancer care and has the potential to generate the evidence needed to improve cancer outcomes, while slowing the growth of health-care spending,” Dr. Lawrence said. n

At Amgen, biologic medicines are rooted in

quality

and nurtured by

reliability.

Robust quality control and a reliable supply are every bit as important as scientific innovation. For more than 30 years, Amgen has poured commitment, passion, and a drive for perfection into every medicine we make. So you can turn to Amgen for the biologic medicines that matter so much to your patients’ treatment…for generations to come. To learn more about Amgen’s commitment to consistent quality and reliable supply, visit biotechnologybyamgen.com ©2013 Amgen Inc. All rights reserved. 73979-R1-V1

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Inside the Black Box FDA Programs to Expedite Drug and Biologic Product Development A Conversation With FDA’s Office of Hematology and Oncology Products Clinical Data Requirements INSIDE THE BLACK BOX is an occasional column provid‑ ing insight into the FDA and its policies and procedures. In this installment, FDA Clinical Reviewers Paul Kluetz, MD, and Martha Donoghue, MD, discuss the FDA’s four pro‑ grams intended to expedite the development of promis‑ ing anticancer agents, including the new Breakthrough Therapy designation. Dr. Kluetz and Dr. Donoghue are Medical Officers with the Genitourinary Malignancies Team and the Neuro-oncology/Rare Tumors/Pediatric Solid Tumors Team, respectively, in the Office of Hematol‑ ogy and Oncology Products (OHOP).

ith the advent of Breakthrough Therapy designation, there are now four FDA programs to expedite the development of promising new agents: Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval (Table 1). These programs complement one another and serve a common goal: to speed the approval of effective treatments for serious conditions. Because the names of the programs convey the theme of speeding drug development and because there is some overlap between programs (such as Fast Track and Breakthrough Designation), they can be easily confused with one another. In this article, FDA reviewers Dr. Kluetz and Dr. Donoghue, address questions relating to the role of expedited programs for the development of cancer therapies.

New Expedited Programs Guidance What has the agency done to help stakeholders better understand these expedited programs? Dr. Kluetz: In June 2013, the FDA published a draft guidance, available online,1 describing the agency’s expedited programs for serious conditions. Multiple offices at the FDA, including OHOP, are currently in the process of revising the document based on public comment. In addition to clarifying Breakthrough Therapy designation and changes to Accelerated Approval, the guidance provides more detail on what is meant by regulatory terms such as “serious condition,” “available ther-

apy,” and “unmet medical need.” The guidance is intended to be appropriate for all therapeutic areas developing drugs for serious conditions, not just oncology.

Fast Track and Breakthrough Therapy Designations What are the differences and similarities between Fast Track and Breakthrough Therapy designations? Dr. Donoghue: Both Fast Track and Breakthrough Therapy designation are designed to speed up drug development, but the level of evidence required to qualify, and the degree of FDA interaction provided by these designations differ. The FDA may grant Fast Track designation at any time during development, including prior to initiation of the first-in-human trial in cases where the nonclinical data provide convincing evidence of the potential of the therapy to address an unmet medical need. In contrast, Breakthrough Therapy designation requires preliminary clinical data showing a drug’s potential to provide a substantial improvement over available therapy. Breakthrough Therapy designation confers all the benefits of Fast Track designation in addition to intensive interaction and guidance from the FDA throughout the drug development process. Given the amount of resources that are expected to be allocated to a Breakthrough Therapy product’s development, Breakthrough Therapy designation requires a higher level of evidence compared to Fast Track designation.

Can you be more specific about what degree of preliminary clinical data might be necessary to qualify for Breakthrough Therapy designation? Dr. Donoghue: In essence, we endeavor to confer Breakthrough Therapy designation to investigational therapies that we think have the potential to be transformative. While we would love to give a specific threshold for the degree of clinical evidence that would support a Breakthrough Therapy designation, the reality is that there are many factors that we consider. In addition to clinical activity, we consider the relationship between the therapy’s mechanism of action and tumor biology, toxicity profile, and the context for its proposed use, including disease incidence and available therapies. With respect to clinical activity, recent Breakthrough Therapy designations for cancer therapies have largely been based on data from early phase clinical trials of drugs with acceptable toxicity profiles documenting durable response rates that are markedly higher than those of approved or standard treatments.

Designated Indications How specific does the intended indication need to be for a Breakthrough Therapy or Fast Track designation? Will the drug always carry the Fast Track and/or Breakthrough Therapy designation once they are granted? Dr. Donoghue: Both designations apply to a specific use for which a therapy is being studied, so a therapy being developed for multiple indications may have Breakthrough Therapy or Fast Track designation for one or more potential indications, but not for others. Additionally, the FDA may rescind Breakthrough Therapy or Fast Track designation if data accumulated during later stages of drug development are not as promising as the data supporting the initial designation, or if the treatment landscape changes due to the approval of new therapies of superior or comparable efficacy compared to the therapy under development.

FDA Clinical Reviewers

Paul Kluetz, MD

Martha Donoghue, MD

Processing Breakthrough Therapy Requests Has your office received many Breakthrough Therapy requests? Dr. Kluetz: As of November 8, 2013, OHOP has received approximately half of the 104 Breakthrough Therapy designation requests submitted to the FDA. Of those submitted to OHOP that have had decisions rendered, we have granted Breakthrough Therapy designation to approximately one-third of the requests. Is there any way to make the process of requesting a Breakthrough Therapy designation more efficient? Dr. Donoghue: Actually, the process is pretty efficient, as long as companies provide sufficient information to support the Breakthrough Therapy designation request in a format that is well organized. We recommend that sponsors contact us to arrange a brief teleconference prior to submitting a request for Breakthrough Therapy designation. This provides an opportunity for sponsors to get an early read from continued on page 71

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ASCOPost.com | FEBRUARY 15, 2014

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Inside the Black Box Expediting Drug Development continued from page 69

our office regarding a therapy’s potential for Breakthrough Therapy designation, and an understanding of the format and types of information required for a Breakthrough Therapy designation request. This can save both the sponsor and the FDA a great deal of time. Advice communicated during the teleconference is not binding and would not prejudice the submission of a request for Breakthrough Therapy designation. Have any of the products granted Breakthrough Therapy designation gone on to FDA approval? Dr. Kluetz: Yes. Ibrutinib (Imbruvica) for previously treated patients with mantle cell lymphoma and obinutuzumab (Gazyva) in combination with chlorambucil (Leukeran) for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) were the first two Breakthrough Therapy–designated products approved by the FDA. Given that Breakthrough Therapy designation is a new addition to the expedited programs, both of these products received the designation late in product development. Not surprisingly, products that receive Breakthrough Therapy designation early in development are

likely to derive the most benefit from intensive interaction with FDA. Nonetheless, both of these products benefited from enhanced communications and an “all-hands-on-deck” expedited review.

Accelerated Approval and Priority Review What is Priority Review and how does it expedite drug development? Dr. Kluetz: Unlike the other three programs, Priority Review affects only one aspect of drug development: the goal date for FDA review and action on a New Drug Application (NDA) or Biologics License Application (BLA). Priority Review designation shortens the FDA’s goal date by 4 months. In OHOP, we have a track record of completing reviews ahead of the Priority Review goal date. The bottom line is that when we receive an application for a drug providing an improvement over available therapy, we do everything we can to complete the review and get the therapy out to patients as quickly as possible. What is the Accelerated Approval program? Dr. Kluetz: Accelerated Approval is one of the two types of approval pathways (regular approval or accelerated

approval) available in the United States. The key to the Accelerated Approval program is the ability to use a surrogate endpoint or intermediate clinical endpoint that is considered “reasonably likely” to predict clinical benefit. For instance, response rate may provide an earlier assessment of drug activity and allow for shorter and smaller clinical trials. If the investigational drug shows a meaningful benefit over available therapy using such an endpoint, Accelerated Approval may be granted. However, by allowing a surrogate endpoint to be used, we accept a degree of uncertainty that, for example, the improvement in response rate may not predict overall clinical benefit (improvement in survival, patient function or amelioration of disease-related symptoms). To counter this risk, we require the company to conduct at least one confirmatory clinical trial to verify that the earlier endpoint truly predicts a meaningful benefit for patients.

Role of Response Rate Speaking of surrogate endpoints, why is response rate supportive of Accelerated Approval in some cases and regular approval in others? Dr. Kluetz: Overall response rate, the percentage of all partial and complete responders, is only one factor to

Table 1: Summary of key requirements and features of FDA-expedited programs Fast Track

Breakthrough Therapy

Priority Review

Accelerated Approval

Type

Designation

Approval pathway

Timing of Application

With or following IND application; ideally prior to pre-BLA or preNDA meeting

With or following IND; ideally no later than end-of-phase II meeting

With BLA, NDA, or efficacy supplement

Discuss potential with FDA during drug development

Requirements

Intended to treat or treats a serious condition Nonclinical or clini‑ cal data demonstrate potential to address unmet medical need

Features

Opportunity for fre‑ quent FDA interaction; rolling review and pos‑ sible priority review

Preliminary clinical evidence indicating potential for substan‑ tial improvement over available therapies on clinically significant endpoint(s)

All Fast Track desig‑ nation features plus intensive multidisci‑ plinary FDA guidance to increase efficiency of drug development program

If approved, would provide a signifi‑ cant improvement in safety or effec‑ tiveness over avail‑ able therapy

Decreases the goal for completion of the review and ap‑ proval decision by 4 months

Provides a meaningful advantage over available therapies and demon‑ strates an effect on a surro‑ gate or intermediate clini‑ cal endpoint reasonably likely to predict clinical benefit Approval based upon a surrogate or intermediate clinical endpoint. Approval contingent upon applicant’s agreement to conduct additional studies to verify and describe the drug’s clinical benefit. These studies should nor‑ mally be underway prior to approval.

BLA = Biologics License Application; FDA = U.S. Food and Drug Administration; IND = Investigational New Drug; NDA = New Drug Application.

Guest Editor

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. consider. Other important variables include the location of the tumor and the likelihood it is causing symptoms; how long on average the responses last; the magnitude of response rate compared to available therapies; and the degree of tumor shrinkage being demonstrated. For instance, in the case of vismodegib (Erivedge) for recurrent locally advanced or metastatic basal cell carcinoma following surgery, the location of the lesions (disfiguring and often symptomatic skin lesions) coupled with the magnitude and duration of responses were felt to demonstrate substantial evidence that these responses were clinically meaningful. In this context, vismodegib was granted regular approval based on response rate. On the other hand, a drug demonstrating a 30% to 35% response rate (all partial responses) of moderate duration in a singlearm trial in a refractory population of unselected non–small cell lung cancer patients holds a greater uncertainty that this finding is going to predict clinical benefit in the long run. In this case, response rate could be considered reasonably likely to predict benefit and Accelerated Approval would be more appropriate.

Pitfalls of Expedited Programs What can prevent timely approval of a promising new cancer therapy despite use of one or more of the FDA’s expedited programs? Dr. Donoghue: Pitfalls can occur during the course of drug development and NDA or BLA review, particularly when development occurs on a compressed timeline. With the emergence of targeted therapies designed for use in a subset of patients with tumors that harbor a particular molecular characteristic, issues relating to the codevelopment of an in vitro diagnostic device with accontinued on page 72

The ASCO Post | FEBRUARY 15, 2014

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Inside the Black Box Expediting Drug Development continued from page 71

ceptable performance characteristics can arise. For this reason, we strongly recommend that sponsors of new targeted therapies that rely on a device for patient selection interact early in the development process with the FDA’s Center for Devices and Radiologic Health. In addition, there have been cases, particularly with biologics, where our ability to review and approve an effective drug has outpaced a sponsor’s ability to scale the manufacturing process appropriately to support marketing and distribution of a new drug. Lack of appropriate planning for verification of clinical benefit can also delay the approval process of a therapeutic candidate for accelerated approval. Therefore, it is vital that sponsors work with the FDA prior to submission of the NDA or BLA to reach agreement on the design of confirmatory trials. In fact, we strongly recommend that such trials be underway on or before the time of approval. Finally, problems related to poor data quality, lack of readiness for clinical and manufacturing inspections and slow or incomplete responses to our information requests can hamper timely review of an NDA or BLA. Expediting drug development taxes the resources of both the FDA and the sponsor. It is therefore imperative that sponsors dedicate the appropriate resources and work with the FDA in advance to ensure that the necessary infrastructure is in place to prevent delays due to these avoidable problems. Are there risks to expediting drug development? Dr. Kluetz: Expediting the development of promising agents through use of these programs often entails smaller trials, which pose both efficacy and safety risks. With regard to efficacy, the risk is that the effect size may be overestimated and not confirmed in subsequent trials. Concerning safety, the risk is that there may be an underestimation of toxicity rates or an inability to detect infrequent but severe toxicities. We have already seen examples of these risks with the withdrawal of the metastatic breast cancer indication for bevacizumab (Avastin) due to an inability to confirm the initial efficacy results, and the suspension of marketing and sales of ponatinib (Iclusig) after reports of substantially higher rates of serious vascular events than were originally seen. Neither of these cases is considered a failure of expedited programs such as Accelerated Approval; rather, they represent

the calculated risks we accept in order to bring promising new agents to patients with life-threatening malignancies. If these risks are known, what is FDA doing to mitigate them? Dr. Kluetz: As previously mentioned, postmarketing trials required as a condition of Accelerated Ap-

proval will provide data intended to verify the efficacy demonstrated by the initial surrogate endpoint. These trials should be completed as quickly as possible in order to identify drugs that fail to verify benefit. Additionally, the smaller trials frequently seen with expedited development will require that safety be rigorously exam-

ined in the postmarketing period. Postmarketing safety data are not only captured in clinical trials as postmarketing requirements and/or commitments, but also through spontaneous reporting to the FDA Adverse Event Reporting System once the product is on the market. We continue to work on effective strategies to analyze postmar-

Tumor lines of defense merit closer examination

References: 1. Batist G, Wu JH, Spatz A, et al. Resistance to cancer treatment: the role of somatic genetic events and the challenges for targeted therapies. Front Pharmacol. 2011;2:59. doi:10.3389/fphar.2011.00059. 2. Verheul HMW, Pinedo HM. Clinical implications of drug resistance. In: Pinedo HM, Giaccone G, eds. Drug Resistance in the Treatment of Cancer. Cambridge, United Kingdom: Cambridge University Press; 1998:199-231. In: Sikora K, ed. Cancer: Clinical Science in Practice. 3. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615-627. 4. Morin PJ. Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat. 2003;6(4):169-172. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. 6. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324-1337. 7. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432(7015):307-315. 8. Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281(5381):1317-1322. 9. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest. 2008;118(6):1979-1990. 10. Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol. 2012;44(10):1646-1656. 11. So A, Hadaschik B, Sowery R, Gleave M. The role of stress proteins in prostate cancer. Curr Genomics. 2007;8(4):252-261. 12. Jäättelä M, Wissing D. Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J Exp Med. 1993;177(1):231-236. 13. Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25(3):95-98. 14. Gleave M, Miyake H, Zangemeister-Wittke U, Jansen B. Antisense therapy: current status in prostate cancer and other malignancies. Cancer Metastasis Rev. 2002;21(1):79-92. 15. Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene. 2003;22(47):7414-7430. 16. Zoubeidi A, Ettinger S, Beraldi E, et al. Clusterin facilitates COMMD1 and I-κB degradation to enhance NF-κB activity in prostate cancer cells. Mol Cancer Res. 2010;8(1):119-130. 17. Sensibar JA, Sutkowski DM, Raffo A, et al. Prevention of cell death induced by tumor necrosis factor α in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 1995;55(11):2431-2437. 18. Hassan MK, Watari H, Han Y, et al. Clusterin is a potential molecular predictor for ovarian cancer patient’s survival: targeting clusterin improves response to paclitaxel. J Exp Clin Cancer Res. 2011;30:113. 19. July LV, Beraldi E, So A, et al. Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 2004;3(3):223-232. 20. Miyake H, Nelson C, Rennie PS, Gleave ME. Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 2000;60(1):170-176.

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Inside the Black Box keting safety data, which will be increasingly important as we consider accepting smaller amounts of safety data for initial approval of novel therapies with large magnitude efficacy results.

Closing Thoughts Any final considerations you’d like to convey about these programs?

Dr. Donoghue: I hope that we have shed some light on the four programs that sponsors and the FDA have at their disposal to expedite drug development for serious conditions. I believe these programs have been effective in hematology and oncology drug development and will continue to be used to hasten the approval of effective

products for the benefit of patients. Dr. Kluetz: As someone interested in genitourinary malignancies, it has been very rewarding to be involved with the review and approval of two recent therapies altering the treatment landscape for patients with metastatic prostate cancer. Both of these products took advantage of various expe-

Cytoprotective proteins and the evasion of apoptosis

Clusterin may promote cancer resistance in multiple ways

Resistance is a fundamental challenge in all forms of cancer and at all stages of disease.1 Its primary clinical manifestation is tumor progression.2 Resistance may result from changes in the tumor microenvironment, genetic factors, or cellular mechanics.3,4 In almost 50% of cases, intrinsic resistance is present before treatment begins, and resistance will be acquired in a large number of the remaining cases.2

Research suggests that stress-induced clusterin contributes to cancer’s ability to resist apoptosis by:

Avoiding apoptosis is a fundamental biologic capability acquired by cancer to enable its growth, survival, and resistance.5-9 Mechanisms such as upregulation of cytoprotective proteins, including HSP27, HSP70, and HSP90, have evolved to protect cells against environmental stress.3,10-12 Clusterin, possibly the first identified secreted chaperone protein, is one such molecule.13 While secretory clusterin is involved in many normal biologic processes, its overexpression has been implicated in a wide variety of cancers.10,14 It is thought that clusterin contributes to both cancer cell survival and resistance by disrupting important cell death pathways, thus protecting the cancer cell from apoptosis.5-10,15-21

• Inhibiting proapoptotic signaling through interaction with surface proteins (eg, receptors) on stressed cells10,22,23 • Inhibiting the proapoptotic protein Bax to prevent its activation of the intrinsic pathway through the mitochondria24 • Promoting cell survival by enhancing activity of NF-κB transcriptional activity16 • Inhibiting endoplasmic reticulum stress and the aggregation of proteins to maintain protein homeostasis and prevent apoptosis10,22,25-27

dited programs. I look forward to continuing to work together with drug developers using expedited programs, in addition to other strategies, to bring novel cancer therapies to the patients who need them. n

Disclosure: Dr. Kluetz and Dr. Donoghue reported no potential conflicts of interest.

Reference 1. U.S. Food and Drug Administration: Guidance for Industry on Expedited Programs for Serious Conditions—Drugs and Biologics. Posted June 2013. Available at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf. Accessed January 27, 2014.

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

In studies, clusterin expression has also been notably associated with poor prognosis, advanced stage of cancer, higher tumor grade, and invasion and metastasis.18,20,28-35

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

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

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Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 21. Hoeller C, Pratscher B, Thallinger C, et al. Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005;124(6):1300-1307. 22. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16(4):1088-1093. 23. Carver JA, Rekas A, Thorn DC, Wilson MR. Small heat-shock proteins and clusterin: intra- and extracellular molecular chaperones with a common mechanism of action and function? IUBMB Life. 2003;55(12):661-668. 24. Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005;7(9):909-915. 25. Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39(51):15953-15960. 26. Nizard P, Tetley S, Le Dréan Y, et al. Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic. 2007;8(5):554-565. 27. Li N, Zoubeidi A, Beraldi E, Gleave ME. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer [published online ahead of print June 11, 2012]. Oncogene. doi:10.1038/onc.2012.212. 28. Miyake H, Gleave M, Kamidono S, Hara I. Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology. 2002;59(1):150-154. 29. Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M, Petito CK. Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000;157(2):393-399. 30. Hazzaa SM, Elashry OM, Afifi IK. Clusterin as a diagnostic and prognostic marker for transitional cell carcinoma of the bladder. Pathol Oncol Res. 2010;16(1):101-109. 31. Ekici S, Eroglu A, Dogan Ekici AI, Türkeri L. Clusterin immunoreactivity as a predictive factor for progression of non-muscle-invasive bladder carcinoma. Urol Int. 2011;86(1):31-35. 32. Pucci S, Bonanno E, Pichiorri F, Angeloni C, Spagnoli LG. Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene. 2004;23(13):2298-2304. 33. Shannan B, Seifert M, Leskov K, et al. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 2006;13(1):12-19. 34. Yang GF, Li XM, Xie D. Overexpression of clusterin in ovarian cancer is correlated with impaired survival. Int J Gynecol Cancer. 2009;19(8):1342-1346. 35. Steinberg J, Oyasu R, Lang S, et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin Cancer Res. 1997;3(10):1707-1711. ©2013 Teva Pharmaceutical Industries Ltd. All rights reserved. ONC-40235 August 2013.

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The Quality Oncology Practice Initiative (QOPI®) is a practice-based quality assessment and reporting program designed to help practice staff examine the quality of care they provide to patients and demonstrate high quality care and/or identify areas to focus improvement efforts.

Your Patients Look to You for the Best Care. QOPI® Can Help Assess and Demonstrate the Quality of Care You Provide. QOPI participation offers: • Library of Quality Metrics: More than 160 measures based on ASCO guidelines and expert consensus • Comparative Results: Performance scores aggregated across all participants that show your performance relative to that of your peers • Standardized Process and Tool: ASCO provides the methodology and online system to collect data and report results • Key Component of Rapid Cycle Quality Improvement: Plan, Do, Study, Act. QOPI helps you know where you stand and evaluate the impact of your actions. Facilitates completion of performance improvement activity assessment for ABIM MOC Part IV, PI_CME activities, and fellowship program performance assessment activity • Gateway to QOPI Certification: Provides reports indicating achievement of performance thresholds and eligibility to apply for QOPI Certification

PARTICIPATE IN QOPI AND DEMONSTRATE YOUR COMMITMENT TO QUALITY CARE.

The Spring 2014 QOPI collection starts March 20th. Practices new to QOPI are encouraged to register by the end of February. Contact us at qopi@asco.org or 571-483-1660 for more information. (http://qopi.asco.org)

Quality Cancer Care: Pursuing Excellence

ASCOPost.com | FEBRUARY 15, 2014

PAGE 75

Historical Timeline Milestones in Oncology, From ASCO’s CancerProgress.Net

Visit CancerProgress.Net to View the Comprehensive Interactive Timeline National Cancer Institute established

o help tell the story of progress against cancer, ASCO launched CancerProgress.Net in 2011. The site is intended as a resource for media, policymakers, oncologists, advocates, and the public. One central feature of the site is an interactive timeline of major milestones in cancer treatment, prevention, and detection, covering 18 different cancer types. The site was developed under the guidance of an ASCO editorial board of oncologists. In recognition of ASCO’s 50th Anniversary, The ASCO Post is publishing selected milestones as noted in the interactive timeline throughout 2014. To view the complete interactive timeline, please visit CancerProgress.Net. n Editor’s note: The ASCO Post invites readers to share your own recollections of clinical milestones and personal experiences in oncology over the past 50 years. Write to editor@ ASCOPost.com. Photos encouraged in high-resolution jpg or tiff file. All correspondence will be acknowledged and will be considered for publication.

President Franklin D. Roosevelt signs legislation es‑ tablishing the National Cancer Institute to support re‑ search on the causes, diagnosis, and treatment of can‑ cer. The new agency’s 1938 budget is $400,000 (Fig. 1).

1937

Fig. 1: President Franklin D. Roosevelt dedicated the new NIH campus in Bethesda on October 31, 1940. This event was held to celebrate NIH’s historic move from one building in Washington, DC, to its new campus setting in Maryland on 45 acres of land donated by Luke and Helen Wilson. Source: National Library of Medicine.

Introduction of Pap test leads to dramatic declines in cervical cancer deaths

1943

The Pap test, named for its inventor, George Papanicolaou, MD, PhD, enables doctors to detect and treat cervical cancers or precancers before they have a chance to spread. Since the 1950s, widespread use of the Pap test has helped to reduce U.S. cervical cancer death rates by nearly 70%. Yet cervical cancer remains a major cause of cancer death in developing countries, where access to screening and treatment is limited (Fig. 2).

Fig 2: George Papanicolaou, MD, PhD. Photo by Michael Hollander. Courtesy of Medical Center Archives of New York-Presbyterian/Weill Cornell.

First-ever remission of pediatric leukemia

Weigh in on which milestones of the last 50 years were the most important by voting on your “Top 5 Advances” at CancerProgress.Net/vote. Voting will continue through the 2014 ASCO Annual Meeting and results will be announced shortly thereafter.

Sidney Farber, MD, a physician at Children’s Hospital Bos‑ ton, achieves the first partial remission of pediatric leukemia in a 4-year-old girl using the drug aminopterin. He soon doc‑ uments 10 cases of remission in a landmark scientific paper. Until this time, children with acute leukemia usually died within weeks of being diagnosed. While early remissions prove temporary, they pave the way for therapies that cure thousands of patients in the decades to come, allowing most childhood cancer patients to live long, healthy lives (Fig. 3).

1947

Fig. 3: Sidney Farber, MD, founder of the Chil‑ dren’s Hospital Cancer Research Foundation, with a young patient. Source: National Cancer Institute.

The ASCO Post | FEBRUARY 15, 2014

PAGE 76

ASCO State Affiliates Focus on the Michigan Society of Hematology and Oncology By Jo Cavallo

ounded nearly 3 decades ago in response to unfavorable changes in Medicare reimbursement regulations and growing coverage issues with Michigan’s private payers that threatened

oncologists’ ability to provide quality cancer care to patients, the Michigan Society of Hematology and Oncology (MSHO) remains one of the most legislatively active of ASCO’s State Affiliates.

In 1989, MSHO successfully helped to pass the state’s first law mandating oncology drug coverage, which was later expanded to include off-label indications. The legislation

Two phase 3, randomized, double-blind, multicenter studies of Palbociclib, an oral CDK4/6 inhibitor Palbociclib in combination with letrozole vs letrozole alone for ﬁrst-line treatment of postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer Primary endpoint: progression-free survival

(PD-0332991)

2:1 R A N D O M I Z A T I O N

N=450

Study 1008

Postmenopausal women with ER+/HER2- breast cancer; no prior systemic anticancer treatment for advanced disease

Palbociclib 125 mg QD (21 days on/7 days off) + Letrozole 2.5 mg QD

Placebo (21 days on/7 days off) + Letrozole 2.5 mg QD

Palbociclib in combination with fulvestrant vs fulvestrant alone in the treatment of women with HR+/HER2- locally advanced or metastatic breast cancer N=417

Study 1023

Palbociclib

Women of any menopausal status with HR+/HER2- breast cancer who progressed on or after prior endocrine therapy

125 mg QD (21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

Placebo

(21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

For more information about these trials, including secondary endpoints and eligibility criteria, please visit www.pﬁzercancertrials.com and www.clinicaltrials.gov (PALOMA-2: NCT01740427; PALOMA-3: NCT01942135). Palbociclib (PD-0332991) is an investigational compound.

These trials are part of the clinical trial program.

(Cyclin-Dependent Kinase inhibitor in cancer)

later led to the development of an OffLabel Oncology Panel review process that is now modeled throughout the country and was used to help craft the 1994 Medicare Cancer Coverage Act. Today, the Society is using its clout to pass an oral chemotherapy parity law in Michigan. Since its founding in 1985, MSHO has also devoted a great deal of effort to recruiting and retaining members. Its roster currently includes nearly 400 medical oncologists and hematologists, representing 93% of Michigan’s cancer specialists. The ASCO Post talked with MSHO’s President, Mohammed Ogaily, MD, FACP, about his Society’s past accomplishments, its goals for the future, and the impact of the Patient Protection and Affordable Care Act on MSHO’s members and their patients.

High-Level Professional Opportunity

Primary endpoint: progression-free survival

2:1 R A N D O M I Z A T I O N

NOW ENROLLING

Palbociclib Clinical Trials

Mohammed Ogaily, MD, FACP

Why was it important for MSHO to become an ASCO State Affiliate? We were early adopters of ASCO’s State Affiliate program because we saw the value of leveraging ASCO’s resources and reputation in our advocacy efforts. ASCO provided a highlevel professional opportunity to network, share best practices, and address concerns of mutual interest with other state society leaders.

Multitude of Meetings How many programs and meetings do you hold each year and what is the purpose of those meetings? Over the past 12 months, we have seen MSHO continue to provide and participate in many fine educational offerings that are well attended, in addition to providing many valuable training programs and reimbursement meetings. In 2013, we staged a total of

ASCOPost.com | FEBRUARY 15, 2014

PAGE 77

ASCO State Affiliates

26 educational activities in live and webinar formats and had 1,671 attendees. Our annual meeting in September was not only a big success, but also our largest event ever. Our ASCO highlights meeting and updates from the American Society of Hematology Annual Meeting, our Breast Cancer Symposium, and our state-of-the-art program for oncology fellows continue to receive great reviews. This year, we launched a new initiative for pharmacists, the Oncology Pharmacist Symposium. For these meetings, we recruit outstanding speakers and address relevant topics identified by our members. In addition, our meetings provide an opportunity for our members to come together to not only learn, but to network as well.

Payer and Legislative Advocacy

payer and legislative advocacy. We have a contracted government affairs consultant who keeps us abreast of any Michigan legislative initiatives that may impact our members. MSHO also has a contracted reimbursement specialist who follows-up on coverage and processing issues that are of concern to our members. We maintain good relationships with the Wisconsin Physician Services Insurance Corporation (WPS, our Medicare contractor), Michigan Medicaid, and our local private payers. In addition, MSHO appoints the Oncol-

is working to achieve oral parity legislation in our state. We also provide comments and expertise on healthcare–related issues to our Michigan congressional delegation by using the resources of our national cancer organizations’ public policy departments.

changes. As organized systems of care evolve and payment methodology changes, we are concerned that our members may become more competitive with their colleagues and relinquish some of their advocacy interest and efforts to larger organizations, such as accountable care organizations. We are hopeful that our Society can stay true to its mission of providing exemplary care to our patients regardless of the changes in the health-care environment, which is what we all trained to do.

Affordable Care Act

Community Practices

How is MSHO being impacted by the Patient Protection and Affordable Care Act? The health-care provisions in the Affordable Care Act will have great impact in every state, including Michi-

How are changes in the way health care is delivered and in Medicare and Medicaid reimbursements in Michigan affecting community practices? The impact of the rapid-pace changes in health care has been felt across the state. Over the past 3 years, we have seen more than 50% of community practices either shutdown or transition to a hospital-based setup. The remaining practices are struggling to maintain financial viability without compromising the delivery of quality patient care. Consequently, patient access to health-care delivery is being restricted, and we find that patients have to drive longer distances to receive badly needed medical care.

MSHO is an organization that delivers programs to all of those involved in oncology, a bridge to reach out to policymakers, and a navigator in the turbulent world of oncology economics and business. —Mohammed Ogaily, MD, FACP

MSHO is very active in relevant legislative and public policy issues that impact cancer care in the state. Please talk about your current activities. We are active on multiple fronts. MSHO members participate in both

■■ MSHO has nearly 400 members, which include medical oncologists and hematologists in private practice and in academic medical centers. In addition, the Society offers free membership to 71 hematology fellows.

gan. Our state has set up health-care exchanges to organize and oversee the private market for health insurance and has expanded the Medicaid program to increase eligibility for the poor. Without any doubt, the Affordable Care Act will pose a significant challenge to an already overstretched health-care system, including the challenge of providing cost-effective health-care delivery with our current limited resources and with the existing oncology workforce shortage.

■■ The mission of MSHO is to promote exemplary care for patients with cancer and blood disorders through advocacy, education, and research.

Remaining Relevant

ogy and Hematology Carrier Advisory Committee Members to serve on WPS. With the Leukemia & Lymphoma Society, we are co-conveners of the Oral Cancer Fairness Coalition, which

Fast Facts ■■ The Michigan Society of Hematology and Oncology was founded in 1985. ■■ The current President is Mohammed Ogaily, MD.

■■ MSHO holds an annual meeting every September and 26 educational meetings throughout the year, including highlights from the ASCO and American Society of Hematology annual meetings.

What are some challenges you face that are unique to your society? Our challenge is to remain relevant to our members as the delivery of care

Future Goals What are MSHO’s future goals? We have been the voice of Michigan’s oncologists, both in the community practice and academic institution settings, and a resource and asset to the oncology community. MSHO is an organization that delivers programs to all of those involved in oncology, a bridge to reach out to policymakers, and a navigator in the turbulent world of oncology economics and business. Our goal is to continue to see our Society thrive and evolve, while staying at the forefront of change and remaining in a true leadership position. n

Visit The ASCO Post website at ASCOPost.com

Markers in Cancer

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ASCOPost.com | FEBRUARY 15, 2014

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Pioneers in Oncology An Early Chemotherapy Innovator, Franco M. Muggia, MD, Now Focuses on Advancing Therapies for Ovarian Cancer By Jo Cavallo

Franco M. Muggia, MD

ooking over an illustrious career in medical oncology that spans 5 decades, Franco M. Muggia, MD, told The ASCO Post that he is excited about the future and hopes to continue making contributions to the field of oncology in years to come. At the forefront of the early clinical development of chemotherapies in the treatment of leukemia and lymphoma and a variety of solid tumors, including breast, lung, ovarian, and gastrointestinal cancers, Dr. Muggia credits a talk given by David Karnofsky, MD, in his first year of medical school with steering him toward a career in oncology. However, his interest in medicine took root much earlier.

The Family Tradition Dr. Muggia was born in Turin, Italy. Three years later, his family fled to Quito, Ecuador, to escape the rising power of Fascist dictator Benito Mussolini. Although the move altered the course of the career of Dr. Muggia’s father Aldo, a prominent pediatrician— and later codirector of the Ecuadorian pharmaceutical company LIFE (Laboratorios Industriales Farmacéuticos Ecuatorianos)—Dr. Muggia was influenced by his father’s work as a physician/scientist. Interested in math and science, Dr. Muggia excelled in his studies at the American School of Quito and immigrated to the United States in 1952 to complete his senior year in high school at the Wooster School in Danbury, Connecticut, a path that had been forged earlier by his older brother Albert and one that would be continued through medical school. “I followed in the footsteps of my brother who had come to Wooster 2 years earlier. He later went to Yale Medical School, while I obtained my under-

graduate degree in biophysics at Yale College and then headed to New York and Cornell University Medical College,” said Dr. Muggia. After receiving his medical degree in 1961, Dr. Muggia interned at Bellevue Hospital in New York and completed his residency at Hartford Hospital in Connecticut, followed by a fellowship in hematology and oncology at Columbia University College of Physicians in New York. His colleagues (Gianni Bonadonna, MD, and Joseph F raumeni, MD) and mentors ( John Ultmann, MD, and Alfred Gellhorn, MD) during training are a Who’s Who of renowned innovators in cancer research.

Learning From the Oncology Masters Although Dr. Muggia’s tutelage under Dr. Ultmann focused on the hematologic malignancies, in his first academic position at the Albert Einstein School of Medicine he turned his attention to the treatment of solid tu-

laboratory and clinical research. “My main thrust during that time was to be part of NCI drug research in the pharmacology of new agents such as camptothecin, a forerunner of the topoisomerase I inhibitors; teniposide (Vumon); nitrosoureas, a group of alkylating agents; bleomycin; and eventually paclitaxel and cisplatin, which have since become mainstream chemotherapies in testicular, lung, bladder, breast, and lung cancers,” said Dr. Muggia. In 1975, after becoming Associate Director of the Cancer Therapy Evaluation Program (CTEP) at the NCI, he was joined by Daniel Von Hoff, MD, Marcel Rozencweig, MD, and William McGuire, MD, among other burgeoning oncologists, in getting these new therapies tested in academic institutions and into the hands of patients through collaborative agreements with industry as a path to approval by the U.S. Food and Drug Administration (FDA). While at the NCI, Dr. Muggia was

Further building on knowledge and experience, I hope to be involved in a number of substantial contributions to oncology that are yet to come. Most importantly, I consistently learn that whatever I may have accomplished has been through collaboration and appreciation of the qualities of my coworkers. —Franco M. Muggia, MD

mor cancers and was a Co-Chair with Charles Moertel, MD, on the Eastern Cooperative Oncology Group’s Gastrointestinal Committee. Dr. Muggia became a U.S. citizen in 1964, just as the country’s involvement in Vietnam was starting to escalate. After 2 years at Albert Einstein College of Medicine, he volunteered for the Public Health Service, landing a position at the Medicine Branch of the National Cancer Institute (NCI) in 1969. “The unit was headed by Paul Carbone, MD, and I spent a few months in the NCI’s solid tumor service and in the laboratory of Vincent DeVita, MD, and George Canellos, MD. With Heine Hansen, MD, I was integrated into a new unit that was developing drug regimens for lung cancer,” said Dr. Muggia. That experience gave him a taste for

exposed not only to the curative potential of cisplatin in germ cell tumors, but also to the concept of regional intraperitoneal therapy in the treatment of ovarian cancer and the importance of drug formulation. “My time at CTEP was instrumental in terms of my professional development and in applying what I had learned from our oncology masters,” said Dr. Muggia. In 1979, Dr. Muggia left the NCI to become Professor of Medicine and Director of the Division of Medical Oncology at New York University (NYU) School of Medicine. “The first thing I did there was to look at new drugs that seemed promising in the treatment of gynecologic and breast cancers, such as doxorubicin and cisplatin, and with recently recruited medical oncology colleagues,

saw an opportunity to improve the way we deliver these drugs and obtain better outcomes for our patients,” said Dr. Muggia. He left NYU in 1986 and held similar appointments at the University of Southern California (USC) Norris Comprehensive Cancer Center and Los Angeles County–USC Hospital and joined gynecologic oncology colleagues to continue work on intrapetioneal platinum-based delivery, and the clinical development of liposomal doxorubicin for recurrent ovarian cancer. In 1996, he returned to NYU, where he served as Director of the NCI-designated Cancer Center for 1 year, and also led the Division of Medical Oncology and its expanded Fellowship Program until 2009.

Pursuing a Multifaceted Career Dr. Muggia’s main focus today is patient care and teaching, while still actively involved with NYU Medical and Gynecologic Oncology colleagues in the development of phase I studies of new agents and treatment regimens. He is Chairman of the Gynecologic Oncology Group’s Medical Oncology Committee and is Editor-in-Chief of the NCI’s Physician Data Query (PDQ) Adult Treatment Board. Dr. Muggia is also Chairman and Medical Director of The Chemotherapy Foundation, a position he has held since the passing of the Foundation’s founder, Ezra Greenspan, MD, in 2004. Dr. Muggia served on ASCO’s Cancer Education Committee from 2001 to 2004 and was an editorial board member of the Journal of Clinical Oncology ( JCO) as well as the first editor of JCO’s Spanish edition.

Looking Forward to Future Achievements Dr. Muggia credits the support he received from his wife Anna and their four daughters with helping him advance his early clinical and research career, leading to the contributions he has made in the development of effective chemotherapy agents that have improved the lives of thousands of patients. He also takes satisfaction in knowing that his mentorship of oncology fellows will impact the lives of thousands more. “One of the great satisfactions of becontinued on page 80

The ASCO Post | FEBRUARY 15, 2014

PAGE 80

Announcements

Richard J. Gannotta, DHA, FACHE, Named President Northwestern Memorial Hospital

orthwestern Memorial HealthCare (NMHC) has announced that it has named Richard J. Gannotta, DHA, FACHE, President, Northwestern Memorial Hospital and Senior Vice President, NMHC effective this month. Dr. Gannotta was President of Duke Raleigh Hospital

dent early last year. At Duke, he worked closely with department chairs at the Duke University School of Medicine on clinical alignment, program development, and physician recruitment to expand the hos-

pital’s primary and specialty care practices. A nurse practitioner, Dr. Gannotta was also faculty for the Duke School of Nursing’s Nursing and Health Leadership Program. He received a BSN

degree from Florida International University, an MBA degree from Campbell University, and a doctorate in health administration from the Medical University of South Carolina. n

Richard J. Gannotta, DHA, FACHE

of the Duke University Health System. “Rick is an accomplished health-care executive who understands academic health systems like ours,” said Dean M. Harrison, NMHC President and CEO. “He has a track record for working collaboratively and achieving results. We expect Rick to play an important role in the leadership of Northwestern Medicine.” Dr. Gannotta will lead hospital operations in support of Northwestern Memorial’s Patients First mission. He will work closely with the leadership of NMHC and Northwestern University Feinberg School of Medicine to advance Northwestern Medicine, the health system’s and medical school’s shared vision. Dr. Gannotta joined Duke Raleigh Hospital as its Chief Operating Officer in 2006, before becoming presi-

Franco M. Muggia, MD continued from page 79

ing an elder statesmen is guiding young faculty in their careers and seeing what they become,” said Dr. Muggia. He also takes pride in influencing the medical careers of those closer to home. His daughter Victoria is Assistant Professor in the Department of Medicine in Infectious Diseases at Albert Einstein College of Medicine, and his oldest grandchild is also planning a career in medicine. “I have had a wonderful life, and I count my blessings,” said Dr. Muggia. “Further building on knowledge and experience, I hope to be involved in a number of substantial contributions to oncology that are yet to come. Most importantly, I consistently learn that whatever I may have accomplished has been through collaboration and appreciation of the qualities of my coworkers, too numerous to mention here.” n

References: 1. Hanna JA, Bordeaux J, Rimm DL, Agarwal S. The function, proteolytic processing, and histopathology of Met in cancer. Adv Cancer Res. 2009;103:1-23. 2. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 3. Quint LE, Tummala S, Brisson LJ, et al. Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 1996;62:246-250. 4. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22:309-325. 5. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-925. 6. Lai AZ, Abella JV, Park M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 2009;19:542-551.

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Perspective Jamie H. Von Roenn, MD continued from page 1

and the major changes this year to the American Board of Internal Medicine’s (ABIM’s) Maintenance of Certification (MOC) requirements.

A New Role at ASCO What do you hope to accomplish

in your new role as Director of Education, Science and Professional Development, and what are your goals to expand ASCO’s education programs? I have a long list. But I think the bottom line is to make education more learner-centric and to address the broad issues that oncologists face across their training from medical school to residen-

cy and fellowship and throughout their careers. The field is changing quickly, and education needs to be responsive to those changes. Medical societies as a whole have not taken advantage of adult learning theory as much as they might. We can be more creative and innovative in the ways we present our education pro-

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grams to make them more effective. A variety of teaching methods are necessary to address different learning styles. Health professionals are increasingly pressed for time. Our education programs need to meet the requirements physicians now face for continuing education in as efficient a manner as possible. Additionally, we want to develop education that is learner-centered: education that is responsive to the needs of the individual learner. What are your biggest challenges? There are several. One big challenge is keeping up with the scientific breakthroughs in molecular biology and molecular genetics and their impact on cancer diagnosis and therapy. Scientific discovery is rapidly moving the oncology field forward, and the need to keep current and to apply the new knowledge efficiently is becoming a greater and greater challenge for individuals and oncology practices. Figuring out the most efficient way to teach people about the actionable mutations in different tumors across disease sites is going to be a huge challenge for both physician education and patient care. ASCO is addressing how to help physicians use genomic information appropriately and efficiently with CancerLinQ™. From an education viewpoint, we need to address the broad range of knowledge in genomics and develop programs that are, in part, pathway based. For example, the ASCO Annual Meetings will organize part of the education program around a selected molecular pathway to integrate biology, diagnostics, and treatment. Diagnoses and treatments will increasingly be driven by the identification of a tumor-specific biologic pathway. Our education programs need to be targeted as well and connect the science with the clinic. Another big issue for oncologists, and one that ASCO is committed to addressing, is how to define and assess value in oncology care.1 Presenting this concept clearly to both physicians and patients in a way that is useful and productive is going to be very important. We are also exploring how to expand our current educational programs so that they are readily accessible to our international members. As we look to the future, another big project is to evaluate how cancer education is provided in medical school. When you consider that cancer is likely to outpace heart disease as the numberone cause of death over the next decontinued on page 82

The ASCO Post | FEBRUARY 15, 2014

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Perspective Jamie H. Von Roenn, MD continued from page 81

cade, it will be necessary for every physician, regardless of specialty, to assess for cancer risk and care for long-term cancer survivors and people living with cancer as a chronic disease. We need to support the training of nononcologists about cancer care.

Maintenance of Certification Please talk about your plans to help oncologists comply with the major changes this year in the Maintenance of Certification program. We are making the Maintenance of Certification (MOC) program easier to access and use. For example, physicians planning to attend an ASCO meeting ought to be able to take a pretest, go to the meeting, and then take a post-test, demonstrating the knowledge gained, and get MOC credit for the activity. That is active learning. There is no reason for physicians to go to a meeting to hear about cuttingedge research and then sit at their computers to review similar content to fulfill their MOC requirements. This is already in place for the 2014 Annual Meeting, and MOC

credit will be available at some of our thematic meetings this year as well. Beginning with ASCO’s Breast Cancer Symposium in September and followed by the 2015 Gastrointestinal and Genitourinary Cancers Symposia, we are initiating this active learning concept. Meeting attendees can register to take an MOC-related pretest, go to the sessions, and then

Physicians can no longer be ‘grandfathered in’ to avoid participating in the MOC program. Everyone will now be required to have some MOC activity every 2 years, accrue 100 MOC points for practice improvement activities every 5 years, and take a board exam every 10 years. —Jamie H. Von Roenn, MD

take a post-test. If the attendee demonstrates knowledge of the content, MOC credit is awarded for attending the meeting and answering the questions.

Jamie H. Von Roenn, MD, and ASCO: A Perfect Fit

Time-efficient means for physicians to meet MOC requirements are essential. We are also planning to develop MOC activities based on the virtual meeting. The current MOC requirements apply to all physicians; there are no longer those who can be “grandfathered in” to avoid participating in the MOC program. Everyone will now be required to have some

r. Von Roenn’s history with ASCO spans nearly 3 decades. She has served on ASCO’s Board of Directors, the ASCO Palliative Care Task Force, the Scientific Program, Cancer Education, and Cancer Communications Committees, among others. In 2011, Dr. Von Roenn received the ASCO-ACS Award at the Annual Meeting and presented the accompanying lecture, Personalized Medicine: A Comprehensive Definition. Dr. Von Roenn’s clinical and research interests have focused on breast cancer and palliative care, and she served as the Director of the Palliative Medicine Fellowship Training Program at Northwestern before taking her new position with ASCO. It was while on a 6-month sabbatical from Northwestern last year that Dr. Von Roenn realized it might be time to pursue challenges outside of patient care. “I’ve loved clinical practice, but I thought it was time to do something different,” said Dr. Von Roenn. “I’ve long had an interest in education and I felt I was ready to contribute to medicine in a slightly different way. I have always held ASCO in the highest regard and see the Society as a committed, productive organization, so the position seemed like a perfect fit for me.” n

MOC activity every 2 years—accruing at least 100 MOC points every 5 years with a minimum of 20 points in practice assessment and improvement and at least 20 points in medical knowledge—and take a board exam every 10 years. To make it more efficient for oncologists to comply with the new requirements and make the choices pertinent to what happens in an oncology practice, we are developing MOC templates for the required practice assessment and improvement points based on information from our QOPI® measures and standards database. The templates will be housed on the ASCO website and launched in the fall or early next year. [Editor’s note: For more information on the changes to ABIM MOC requirements, visit www.moc2014.abim.org. For ASCO’s collection of MOC courses, go to www.university.asco.org.]

Progress in Palliative Care A main area of your interest is the integration of palliative care into oncology

clinical care. Please talk about the progress that has been made in that area and what still needs to be done to fully implement palliative care into clinical care. A lot of progress has been made as a result of the growing discussions and literature around this topic. The need to integrate palliative care into oncology care—and medical care in general—is better recognized. We still have a way to go to educate physicians and other health-care professionals and the public. People still too frequently equate palliative care with end-of-life care. End-of-life care is the smallest component of palliative care; it is palliative care during the last months and weeks of life. Palliative care, the relief of suffering, in the broadest sense is an essential component of curative therapy, chronic illness, and end-oflife care. One problem that has prevented the next step of full integration of palliative care into oncology care is our current payment structure, which doesn’t support the time needed to add palliative care conversations and strategies to physicians’ already busy schedules. The other missing piece is training in palliative care. Until physicians recognize that knowing patients’ pain score is as important as knowing their white blood count and has just as important an impact on care, integration won’t be mainstream. Changes are needed in training, education, systems of care delivery, and attitude to make the routine integration of palliative care into clinical care possible. n Disclosure: Dr. Von Roenn reported no potential conflicts of interest.

Reference 1. ASCO in Action Brief: Value in Cancer Care. Posted January 21, 2014. Available at www.asco.org/advocacy/ asco-action-brief-value-cancer-care.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | FEBRUARY 15, 2014

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Clinical Trials Resource Guide

Ongoing NCI-Funded Clinical Trials Actively Recruiting Patients With Hematologic Cancers Compiled by Jo Cavallo

his Clinical Trials Resource Guide is meant to increase awareness of NCI-funded phase I, II, and III clinical studies for your patients with hematologic cancers. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov and include non-randomized, randomized, and observational studies. The clinical trials included here are currently recruiting patients with non-Hodgkin B-cell and T-cell lymphomas; lymphoblastic leukemia and acute myelogenous leukemia; and multiple myeloma.

LYMPHOMA Study Type: Randomized Phase II/Interventional Study Title: Phase II Study of Dose-Adjusted EPOCH/Rituximab in Adults With Untreated Burkitt Lymphoma or c-MYC Positive Diffuse Large B-Cell Lymphoma, and DoseAdjusted EPOCH in Adults with c-MYC Positive Plasmablastic Lymphoma Study Sponsor and Collaborators: National Cancer Institute Purpose: Burkitt lymphoma is highly treatable, but because most of the standard therapies require multiple doses of intensive chemotherapy that may require long hospital stays and frequently have severe side effects, new approaches are needed to treat Burkitt lymphoma with the same efficiency but with reduced side effects. This study is meant to determine the safety and effectiveness of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in treating Burkitt lymphoma. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No

Primary Outcome Measures: To determine progression-free survival, event-free survial, and overall survival of risk-adaptive DA-EPOCH-R in newly diagnosed Burkitt lymphoma and c-MYC positive diffuse large B-cell lymphoma; and to determine progression-free survival, event-free survial, and overall survival of riskadaptive DA-EPOCH in c-MYC positive plasmablastic lymphoma; Time Frame: 8 years. Principal Investigator: Kieron M.Dunleavy, MD, National Cancer Institute For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01092182 Study Type: Non-Randomized Phase I /Interventional Study Title: Phase I Study of Bortezomib and Romidepsin in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, Peripheral T-Cell Lymphoma or Cutaneous T-Cell Lymphoma Study Sponsor and Collaborators: Virginia Commonwealth University; National Cancer Institute Purpose: To study the side effects and best dose of giving bortezomib and romidepsin together in treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), indolent B-cell lymphoma, peripheral T-cell lymphoma (PTCL), or cutaneous T-cell lymphoma (CTCL). Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose; Time Frame: 2 years. Principal Investigator: Beata Holkova, MD, Virginia Commonwealth University/Massey Cancer Center For More Information: Visit

ClinicalTrials.gov and refer to this study by its identifier: NCT00963274

LEUKEMIA Study Type: Non-Randomized Phase I /Interventional Study Title: A Phase I Study of GNKG168 in Pediatric Patients With Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia (IND#113600) Study Sponsor and Collaborators: Therapeutic Advances in Childhood Leukemia Consortium Purpose: To investigate GNKG168, a Toll-like receptor agonist, in patients with relapsed and refractory acute lymphoblastic leukemia and acute myelogenous leukemia who are in morphologic remission but are positive for minimum residual disease. Ages Eligible for Study: 1 year to 21 years Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Number of patients with dose-limiting toxicity; Time Frame: 2 months Principal Investigator: Nobuko Hijiya, MD, Associate Professor of Pediatrics, Therapeutic Advances in Childhood Leukemia Consortium; Ann and Robert H. Lurie Children’s Hospital of Chicago For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01743807

MULTIPLE MYELOMA Study Type: Non-Randomized Phase I/Interventional Study Title: Multicenter Phase I Study of Th1/Tc1 Immunotherapy Following Autologous Hematopoietic Progenitor Cell Transplantation in High-Risk Multiple Myeloma Study Sponsor and Collaborators: National Cancer Institute; Hackensack University Medical Center Purpose: To determine the safety

and effectiveness of the infusion of modified Th1 white blood cells, in conjunction with standard treatment, as a treatment for individuals who have been diagnosed with high-risk forms of multiple myeloma. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: To evaluate the feasibility and toxicity of an infusion of autologous, ex vivo rapamycin-generated, anti-CD3 and anti-CD28 co-stimulated, Th1/Tc1 lymphocytes in subjects with newly diagnosed high-risk multiple myeloma. Principal Investigator: Daniel H. Fowler, MD, National Cancer Institute For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01239368 Study Type: Observational [Patient Registry] Study Title: Buckeye Surveillance, Contact, and Research for Multiple Myeloma and Amyloidosis Study Sponsor and Collaborators: Ohio State University Comprehensive Cancer Center Purpose: To improve the quality and length of life for patients with diseases of their plasma cells Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Develop a data and sample resource that can be used to facilitate research with the ultimate goal of reducing the morbidity and/or mortality of patients diagnosed or living with multiply myeloma in the state of Ohio Principal Investigator: Craig Hofmeister For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01408225 n

Visit ClinicalTrials.gov for more information

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 | FEBRUARY 15, 2014

PAGE 88

Integrative Oncology By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center

Kava Scientific Name: Piper methysticum Common Names: Kava-kava, kawa, kavain, rauschpfeffer, intoxicating long pepper, tonga, yagona, and yaqona.

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. We chose kava for this issue because of its popularity among cancer patients.

Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan-Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, Lac, Memorial Sloan-Kettering Cancer Center.

Overview

Kava, a perennial shrub indigenous to the Hawaiian Islands and the Pacific Rim, is known for its relaxant effects

and used for social and recreational purposes. The roots and rhizome are used in preparation of a nonfermented beverage that has served as a ceremonial drink in the Pacific Islands for hundreds of years. Kava is also used in traditional medicine to relieve stress, anxiety, fatigue, and insomnia, as well as to treat menopausal symptoms and urinary tract infections. Over the past 2 decades, it gained popularity in the West, where the supplemental form is promoted for the relief of anxiety, stress, and insomnia. Clinical data indicate that kava does reduce anxiety, and is viewed by some as an alternative to anxiolytic drugs. However, following concerns about hepatotoxicity, kava and kava-containing products were withdrawn from several European countries and from Australia and Canada. The U.S. Food and Drug Administration issued an advisory about the potential risks of liver injury associated with use of kava. Based on recommendations made by the World Health Organization, studies of aqueous extracts of kava are underway (all previous studies were conducted with ethanolic or acetonic extracts). Initial research findings support the use of kava for the management of anxiety and depression.

The Science

Kavapyrones are the physiologically active compounds in kava. They function as centrally acting skeletal muscle relaxants, anticonvulsants, and local anesthetics.

Guest Editor

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 SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD 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, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. Current clinical evidence indicates that kava effectively relieves anxiety,1,2 but a few studies found that it is not superior to placebo.3,4 A systematic review found no negative effects of kava on cognition.5 Because kava causes hepatotoxicity,

kava-containing products have been withdrawn in many countries.6,7 Suggested mechanisms for kava-associated hepatotoxicity include inhibition of cytochrome P450, reduction in liver glutathione content, or inhibition of cyclooxygenase activity.6,8 Interestingly, analyses of hepatic injury resulting from kava reveal that low-quality products, overdose, prolonged use, and co-medication represent the causative factors.9 Moreover, recent studies conducted with aqueous extracts of kava found the extracts to be safe and effective against anxiety and depression.10,11 Kava also may have anticancer potential. Data from many Pacific island nations suggest an inverse association between kava consumption and cancer

Learn More About

Herbs, Botanicals, & Other Products Visit the free About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | FEBRUARY 15, 2014

PAGE 89

Integrative Oncology OF NOTE Kava is a popular herb promoted as an anxiolytic. Physicians should be aware of the hepatotoxicity and drug interactions associated with its use.

incidence.12 One of kava’s constituents, however, was found to stimulate growth of melanoma cells in vitro.13

Adverse Effects

Hepatotoxicity,6,7 urticaria,14 and reversible dermopathy15 were reported following consumption of kava. An overdose of kava led to altered mental status and ataxia.16

Herb-Drug Interactions

Benzodiazepines: Kava increases sedation when administered concurrently.17 Cytochrome P450 substrates: Kava inhibits CYP2E118 CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4,19-21 and can affect the intracellular concentration of drugs metabolized by these enzymes. Acetaminophen: Kava increases the acetaminophen-induced hepatic cell-cytotoxicity in vitro.22 n Disclosure: Ms. Gubili and Drs. Cassileth and Yeung reported no potential conflicts of interest.

References 1. Lehrl S: Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. J Affect Disord 78:101-110, 2004. 2. Witte S, Loew D, Gaus W: Metaanalysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with non-psychotic anxiety disorders. Phytother Res 19:183-188, 2005. 3. Jacobs BP, Bent S, Tice JA, et al: An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine (Baltimore) 84:197-207, 2005. 4. Sarris J, Scholey A, Schweitzer I, et al: The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: A randomized, placebocontrolled, double-blind study. Psychopharmacol 27:262-269, 2012. 5. LaPorte E, Sarris J, Stough C, et al: Neurocognitive effects of kava (Piper methysticum): A systematic review. Hum Psychopharmacol 26:102-111, 2011. 6. Clouatre DL: Kava kava: Examining new reports of toxicity. Toxicol Lett 150:85-96, 2004. 7. Escher M, Desmeules J, Giostra E, et al: Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 322:139, 2001.

8. Raman P, Dewitt DL, Nair MG: Lipid peroxidation and cyclooxygenase enzyme inhibitory activities of acidic aqueous extracts of some dietary supplements. Phytother Res 22:204-212, 2008. 9. Teschke R: Kava hepatotoxicity: Pathogenetic aspects and prospective considerations. Liver Int 30:1270-1279, 2010. 10. Sarris J, Kavanagh DJ, Byrne G, et al: The Kava Anxiety Depression Spectrum Study (KADSS): A randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl) 205:399-407, 2009. 11. Singh YN, Devkota AK: Aqueous kava extracts do not affect liver function tests in rats. Planta Med 69:496-499, 2003. 12. Steiner GG: The correlation between cancer incidence and kava consumption. Hawaii Med J 59:420-422, 2000. 13. Matsuda H, Hirata N, Kawaguchi Y, et al: Melanogenesis stimulation in murine B16 melanoma cells by kava (Piper methysticum) rhizome extract and kavalactones. Biol Pharm Bull 29:834-837, 2006. 14. Grace R: Kava-induced urticaria. J Am Acad Dermatol 53:906, 2005. 15. Norton SA, Ruze P: Kava skin condition. Kava dermopathy. J Am Acad Dermatol 31:89-97, 1994. 16. Perez J, Holmes JF: Altered mental

status and ataxia secondary to acute kava ingestion. J Emerg Med 28:49-51, 2005. 17. Almeida JC, Grimsley EW: Coma from the health food store: Interaction between kava and alprazolam. Ann Intern Med 125:940-941, 1996. 18. Gurley BJ, Gardner SF, Hubbard MA, et al: In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 77:415-426, 2005. 19. Russmann S, Lauterburg BH, Barguil Y, et al: Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens? Clin Pharmacol Ther 77:453-454, 2005. 20. Russmann S, Lauterburg BH, Helbling A: Kava hepatotoxicity. Ann Intern Med 135:68-69, 2001. 21. Unger M, Frank A: Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom 18:2273-2281, 2004. 22. Yang X, Salminen WF: Kava extract, an herbal alternative for anxiety relief, potentiates acetaminophen-induced cytotoxicity in rat hepatic cells. Phytomedicine. 18:592-600, 2011.

Announcements

NIH Names First Chief Officer for Scientific Workforce Diversity, Hannah Valantine, MD

ational Institutes of Health (NIH) Director Francis S. Collins, MD, PhD, has appointed Hannah Valantine, MD, to Chief Officer for Scientific Workforce Diversity. Dr. Valantine will lead NIH’s effort to diversify the biomedical research workforce by developing a vision and comprehensive strategy to expand recruitment and retention, and promote inclusiveness and equity throughout the biomedical research enterprise. Dr. Valantine is expected to begin her new role this spring.

Position Dedicated to Diversity “Recruiting and retaining the brightest minds regardless of race, ethnicity, gender, disability, and socioeconomic status, is critically important not only to NIH, but to the entire U.S.

cated to diversity. Dr. Valantine will work closely with the NIH institutes and centers, NIH grantee community, and community stakeholders to ensure engagement on the issue at all levels. Dr. Valantine comes to the NIH from Stanford UniversiHannah Valantine, MD Francis S. Collins, MD, PhD ty where she served as Senior Associate Dean for Diversity scientific enterprise,” said Dr. Collins. and Leadership at Stanford School of “Hannah possesses the experience, Medicine, and Professor of Cardiodedication, and tenacity needed to vascular Medicine at Stanford Unimove NIH forward on this critically versity Medical Center. Dr. Valantine important issue.” studied biochemistry at London UniThe appointment stems from a rec- versity and attended St. George’s Hosommendation by the Biomedical Re- pital Medical School. She completed search Workforce Diversity Working her postgraduate work in the field of Group of the Advisory Committee to cardiology at two London hospitals, the Director (ACD) that called for a Brompton and Hammersmith. She newly created position entirely dedi- moved to the United States to train as

a fellow with leading cardiologists. Dr. Valantine is a past recipient of the NIH Director’s Pathfinder Award for Diversity in the Scientific Workforce and has a proven record on implementing diversity initiatives in academic medicine. “I’d like to extend my gratitude to Roderic Pettigrew, MD, who served as the Acting Chief Officer for Scientific Workforce Diversity while a search was underway,” said Dr. Collins. “Roderic did an incredible job of keeping the initiative moving while continuing to serve as Director of the National Institute on Biomedical Imaging and Bioengineering. His tireless efforts and knowledge on this important topic will make him an essential resource to Hannah.” For more information about NIH and its programs, visit www.nih.gov. n

N OW E N RO L L I N G

Pivotal Trial in gpNMBOverexpressing Metastatic Triple-Negative Breast Cancer • METRIC is a pivotal, open-label, prospectively controlled, randomized trial of glembatumumab vedotin in glycoprotein NMB-overexpressing triple-negative breast cancer (TNBC)

• gpNMB is an internalized transmembrane glycoprotein that is frequently overexpressed in TNBC tumors – gpNMB overexpression is associated with reduced recurrence-free survival in TNBC • Glembatumumab vedotin is an investigational antibody-drug conjugate (ADC) that targets tumors

1-4

Patients with metastatic TNBC overexpressing gpNMB* N=300

*Stratified

2:1 Randomization

expressing gpNMB4,5

Glembatumumab vedotin 1.88 mg/kg IV Day 1 of 21-day cycles Treat until unacceptable toxicity or disease progression Capecitabine 1250 mg/m2 BID Days 1-14 of 21-day cycles

by prior receipt of 0 or 1 line of therapy for advanced disease and anthracycline response.

Key Trial Endpoints

• Primary: Objective response rate (ORR) and/or progression-free survival (PFS) • Secondary: Duration of response (DOR) and overall survival (OS) Key Inclusion Criteria

• No more than one prior chemotherapy-containing regimen for advanced breast cancer • Prior receipt of anthracycline-containing chemotherapy in any setting, with no further anthracycline therapy indicated

• Taxane resistance after neoadjuvant/adjuvant therapy or in the advanced disease setting

For more information, visit www.metricstudy.com, www.clinicaltrials.gov/show/NCT01997333, or e-mail info@celldex.com.

References: 1. Weterman MAJ, Ajubi N, van Dinter IMR, et al. Int J Cancer. 1995;60:73-81. 2. Singh M, Del Carpio-Cano F, Belcher JY, et al. Crit Rev Eukaryot Gene Expr. 2010;20(4):341-357. 3. Rose AAN, Grosset A-A, Dong Z, et al. Clin Cancer Res. 2010;16(7):2147-2156. 4. Maric G, Rose AAN, Annis MG, Siegel PM. Onco Targets Ther. 2013;6:839-852. 5. Burris HA III. 2013 ASCO Educ Book. 2013:e99-e102. ©2014 Celldex Therapeutics, Inc.

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Book Review

Lessons Learned in Cancer Care Communication By Ronald Piana

ver the past several decades, outcomes data have traced the success stories in cancer research and therapeutics. However, during those decades of increasingly rapid scientific breakthroughs, certain psychosocial components in the continuum of cancer care were often overlooked. One such element is patient-centered communication, which is now considered central to the delivery of high-quality care. Since oncologists treat people who

wrote this trim book primarily for doctors training in oncology but with the hope that all health-care professionals involved in explaining the complexities of cancer to patients will find it useful. Organized into eight wellwritten chapters, Communicating With Cancer Patients will serve as a valuable tool for those on the front lines of cancer care. It’s potentially a 1-hour read but lends itself to being dog-eared and highlighted.

One of your principal responsibilities is to create the appropriate balance between hope and truthfulness…. [T]his is achieved by explaining the evidence on which we base our management decisions. —John F. Smyth, MD

have a potentially fatal disease, their conversations span several critical phases, from diagnosis to end-of-life care, and each conversation carries its own set of difficulties. A new book by John F. Smyth, MD, Communicating With Cancer Patients, is a valuable addition to the growing body of literature addressing the need for better doctorpatient communication. For several decades, Dr. Smyth served as the Chair of Medical Oncology at the University of Edinburgh Medical School, where he led research in the evaluation and development of new anticancer drugs. He also published more than 300 papers and has served on the boards of numerous prestigious European medical journals. But the underpinning of his fine and accessible guide to communication was summed up in the first line of his acknowledgment, a section of books often overlooked by readers: “Over the past 35 years I have been responsible for the care of more than 6,000 families affected by cancer. It is they who I have to thank for teaching me the lessons that form the background of this book.”

Two Obligations Writing a book about communication for doctors assumes two obligations: It must be highly informative and utterly succinct, given the time constraints of the audience. Dr. Smyth

In the Introduction, Dr. Smyth drives home a message that needs to become the mantra for oncology fellows and residents. “One of your principal responsibilities is to create the appropriate balance between hope and truthfulness…. [T]his is achieved by explaining the evidence on which we base our management decisions.” He stresses that it is important to assess each patient and establish what terminology to use during your conversations. “The choice of specific terms is not important, but it is helpful to establish the language that you will subsequently use to avoid confusion,” writes Dr. Smyth, adding that as soon as possible after being told of their diagnosis, patients should be given an outline of the different phases of management.

Best-Practices Template Chapter 2 begins with a telling sentence: “As a trainee oncologist, one of your most daunting responsibilities is to learn how to conduct a new patient interview.” This chapter, broken into 10 sections, is one of the most important sections of the book. In simple yet powerful language, Dr. Smyth gives a blueprint for establishing a strong doctor-patient relationship. He leaves nothing to chance, and every young oncology trainee should embrace this as a best-practices template. Even his more avuncular advice

is spot-on: “A great deal can be learned about a patient’s state of mind and attitude to their recent diagnosis purely by observing them. For many years I had the luxury of a consulting room that was the furthest walking distance from the waiting area. By observing patients walking even a short distance, you can gain invaluable information.” Most lay people would have a difficult time giving the most rudimentary explanation of the biology of cancer. So discussing the various primary treatment options within the dizzying array of cytotoxic agents and their various side effects can be mind-numbing for the patient with cancer. In chapter 3, Dr. Smyth does a sturdy job separating the necessary information from the optional. There’s a fine line between too much and too little. “Done well the patient gains in confidence—done badly, confusion can be really harmful,” warns Dr. Smyth in this informative section. Dr. Smyth also nimbly addresses the communication issues within today’s multidisciplinary care team, which, unless coordinated between medical and nursing teams can leave a cancer patient feeling like a pinball. Another challenge in today’s new oncology environment is time, something every busy practitioner battles with. To that end, he offers instruction in how to use “invaluable time for communicating the information that is relevant to this particular patient.”

Mixed Emotions Cancer patients can experience an emotional roller-coaster ride during the various phases of their treatment. In chapter 5, “Explaining Follow-up,” Dr. Smyth confronts the mixed emotions faced by patients and their doctors during post-treatment remission. Intuitively, it would seem that patients would be pleased and relieved to hear the word remission, but as Dr. Smyth points out, research shows that for many patients, the period following the completion of their treatment is associated with new anxieties and loss of confidence—the thought of relapse looms. Discussions during this delicate period, when patients have a “newfound aloneness with their condition,” need to be nuanced and delicately tailored to each patient’s personality. Here, Dr. Smyth’s advice is very patient-ori-

Title: Communicating With Cancer Patients Author: John F. Smyth, MD Publisher: CRC Press Publication date: October 14, 2013 Price: $39.95, Paperback, 100 pages; $27.00, eBook More information: www.crcpress.com

ented, with perspectives that will help doctors negotiate their way toward meaningful conversations. In the succeeding chapter, Dr. Smyth deals with “Progression and Terminal Care,” a phase that proves most problematic for oncologists and their patients. This section is perhaps the book’s most diagrammatic guide to communication. From fear to pain management, Dr. Smyth gives sound advice, much of it from his years in the clinic. “At no time in their entire illness will patients benefit more from your medical skills than when you are able to offer emotional and psychological support at the stage when their disease is clearly progressing towards the terminal phase,” writes Dr. Smyth. He wants physicians to know that listening is a big part of communication, especially when patients are at their most vulnerable. The last two chapters deal with clinical research and complementary and integrative oncology. These are necessary discussions for completeness, and they complement the critically important chapters that brought the reader right into the exam room, watching, listening, and talking with the book’s main character—the cancer patient. n

The ASCO Post | FEBRUARY 15, 2014

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2014

2014 Oncology Meetings February European Society for Medical Oncology Sarcoma and GIST 2014 February 18-19 • Milan, Italy For more information: www.esmo.org

38th Annual Meeting of the American Society of Preventive Oncology March 8-11 • Arlington, Virginia For more information: www.aspo.org

ACCC 40th Annual National Meeting March 31-April 2 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ AM2014.asp

2014 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 19 - 23 • Orlando, Florida For more information: www.asbmt.org Multidisciplinary Head and Neck Cancer Symposium February 20-22 • Scottsdale, Arizona For more information: www.headandnecksymposium.org Society of Gynecological Oncology 2014 Winter Meeting February 20-22 • Breckenridge, Colorado For more information: www.sgo.org North Carolina Oncology Association/South Carolina Oncology Society Joint Membership Conference February 21-22 • Charlotte, North Carolina For more information: www.ncoa-northcarolina.com/ American Association for Cancer Research: RAS Oncogenes: From Biology to Therapy February 24-27 • Lake Buena Vista, Florida For more information: www.aacr.og

March 31st Annual Miami Breast Cancer Conference® March 6-9 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/31st-Annual-MiamiBreast-Cancer-Conference Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 7-10 • New York, New York For more information: www.mskcc.org/emoncreviewcourse

ELCC 2014 European Lung Cancer Conference March 26-29 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2014-Lung-Cancer

NCCN 19th Annual Conference: Advancing the Standard of Cancer Care™ March 13–15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp

April ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro.org/congressesmeetings/items/estro-33

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

Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 • Phoenix, Arizona For more information: www.surgonc.org 7th Annual Interdisciplinary Prostate Cancer Congress™ March 15 • New York, New York For more information: www.gotoper.com/conferences/ ipcc/meetings/7th-AnnualInterdisciplinary-Prostate-CancerCongress 24th Annual Interdisciplinary Breast Cancer Conference March 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/ 9th European Breast Cancer Conference March 19-21 • Glasglow, Scotland For more information: www.ecco-org.eu 20th Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 20-22 • Sunriver, Oregon For more information: www.ohsu.edu/bbb Illinois Medical Oncology Society 2014 Membership Conference March 21 • Chicago, Illinois For more information: www.imos-illinois.com/

American Association for Cancer Research Annual Meeting April 5-9 • San Diego, California For more information: www.aacr.org 15th Annual Meeting of the American Society of Breast Surgeons April 30-May 4 • Las Vegas, Nevada For more information: www.breastsurgeons.org/index.php

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org Association for Value-Based Cancer Care – 4th Annual Conference May 6-9 • Los Angeles, California For more information: http:// avbcconline.org/ Accelerating Anticancer Agent Development and Validation Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June 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/

16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

July 2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm continued on page 94

Because your patients have different needs… …Amgen supports a broad range of access programs INDEPENDENT CO-PAY FOUNDATIONS Amgen Assist can check the current funding status at different independent foundations for your office

MEDICARE

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THE SAFETY NET FOUNDATION The Safety Net Foundation provides products at no cost to eligible uninsured and underinsured patients THE NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM The NEULASTA/NEUPOGEN FIRST STEP™ Program helps reduce out-of-pocket (OOP) costs for all eligible commercially insured patients. Go to www.amgenfirststep.com for program eligibility and limitations

NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM For more information regarding these programs, please call 1-888-4ASSIST or visit AmgenAssistOnline.com To enroll your patient into the Amgen FIRST STEP™ Co-pay Coupon Program call 1-888-65-STEP1 (1-888-657-8371) or visit amgenfirststep.com. The NEULASTA/NEUPOGEN FIRST STEP™ Program MasterCard is issued by The Bancorp Bank pursuant to license by MasterCard International and this card may not be used everywhere Debit MasterCard is accepted. No cash or ATM access. MasterCard is a registered trademark of MasterCard International Incorporated. The Bancorp Bank; Member FDIC.

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

The ASCO Post | FEBRUARY 15, 2014

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2014

2014 Oncology Meetings continued from page 92

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

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 American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: http://aonnonline.org

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/ Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org/ Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org/

Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr. org/home/scientists/meetings-workshops/special-conferences/ advances-in-melanoma-frombiology-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: http://steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org 2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ breastcancer/pages/index.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.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

July 21-25, 2014

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: http://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

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

The Kohala Coast, Hawaii

Abstract Submission Deadline: Early Registartion Deadline:

April 11, 2014 May 20, 2014

u nm c . e d u/p a n p a c i fi c l y m p h o m a

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Patient’s Corner

Nothing Prepared Me for Cancer

My first diagnosis of cancer came at age 29. After the second diagnosis 7 years later, I thought, this time I could die. By Suzann Vera, as told to Jo Cavallo

ourteen years ago, when I was just 29, I was feeling weak and fatigued and had severe pain in my abdomen. I’d had these symptoms for about a year, but none of the several doctors I saw or any of the tests they performed could find the source of my problems. I even had one nurse practitioner tell me that I was the cause of my stomach pain because I have a type A personality and that I just needed to relax. Finally, a gastroenterologist suggested that I have a colonoscopy, and he discovered a large stage III malignant tumor. I was given the diagnosis as soon as I awoke from the anesthesia and told that I would need surgery the next day. I never even got the chance to go home first and think things over, and was admitted to the hospital that night. The news couldn’t have been more shocking. I was so young to have a diagnosis of colon cancer, and, at the time, there was very little evidence of a history of cancer in my family—only a great uncle who had had colon cancer at midlife and died years later of old age—so the possibility that I might have such a serious disease never occurred to me. Plus, I had just started a new position in education and was planning my wedding, so I was excited about a future filled with great possibilities.

Facing Cancer Twice Although the surgery went well and the whole tumor was removed, because the pathology report showed that 7 of

the 14 lymph nodes excised contained cancer cells, my oncologist recommended that I have adjuvant chemotherapy for “insurance.” His assurances—and those of my family’s—that my cancer wasn’t a death sentence were so encouraging, I believed I would be okay and consented to the regimen of fluorouracil and irinotecan my oncologist prescribed. My

cancer at such an early age and now put me at an 80% increased risk for endometrial and ovarian cancer. I felt the clock ticking. I was advised by my oncologist and genetic counseling team to have a radical hysterectomy, but I wanted a second child and decided to wait. While trying to get pregnant again, I noticed heavier than usual menstru-

My oncologists have taught me the value of staying positive. They have given me hope and the courage to persevere when I wanted to give in to despair, and I’m grateful. —Suzann Vera

treatments ended 3 weeks before my wedding day, and I was once again looking forward to a great future and starting a family. Four years later, everything I had hoped for was coming true: My health was good, my career was going well, and I was pregnant with my first child. But in the spring of 2004, my mother was diagnosed with stage II endometrial cancer, and once again we rallied together to beat cancer, and once again, we won. After my mother’s diagnosis, my oncologist suggested that I be genetically tested for Lynch syndrome, an inherited disorder. The results were positive, which explained my bout with colon

al bleeding and knew something was wrong. An endometrial biopsy my gynecologist performed tested positive for malignant cells, and in 2007, with no more time to lose, I had a radical hysterectomy.

Surviving Cancer This second cancer diagnosis scared me much more than the first one. I was 36 then and had a 3-year-old son, so the stakes were much higher. I wasn’t as confident that I could beat cancer as I had been the first time, and this time, I thought I could die. Although I’ve been healthy for the last 7 years, with no signs of a cancer re-

currence or the development of a new one, I don’t take anything for granted. I know it sounds like a cliché, but I really try to live every day to its fullest and enjoy every moment. The year after my endometrial cancer diagnosis, my son Robert was diagnosed with neurofibromatosis type 1, a genetic disorder caused by a mutation in the NF1 gene, which may also be linked to Lynch syndrome. Now I have even more reason to stay healthy, so I can make sure that he gets the best care should the disease progress.

Lessons Learned Today, my biggest challenge is keeping fear at bay and not overreacting when a shadow shows up on a mammogram, or a headache lasts too long—issues that people who have never experienced cancer would dismiss as normal occurrences. Even though I’ve been cancer-free for 7 years, I remain vigilant and see my oncologist every 6 months. This year he recommended that I have annual colonoscopies, and I will follow his advice. My oncologists have taught me the value of staying positive. They have given me hope and the courage to persevere when I wanted to give in to despair, and I’m grateful. I don’t know what lies ahead, but once again, I’m looking forward to a future filled with great possibilities. n Suzann Vera is an educator in Austin, Texas.

UN Agency Issues World Cancer Report 2014

new global cancer report1 compiled by the United Nations’ International Agency for Research on Cancer (IARC) shows, as a single entity cancer is the biggest cause of mortality worldwide, and there were an estimated 8.2 million deaths from cancer in 2012. The report also noted that global cancer incidence over 4 years increased by 11% to an estimated 14.1 million cases in 2012, and cancer cases worldwide are forecast to rise by 75% and reach close to 25 million over the next 2 decades. “The rise of cancer worldwide is a major obstacle to human development and well-being,” said Christopher Wild, PhD, Director of IARC and coeditor of the World Cancer Report 2014.

“These new figures and projections send a strong signal that immediate action is needed to confront this human disaster, which touches every community worldwide, without exception,” Dr. Wild added. The World Cancer Report 2014 was released earlier this month to coincide with World Cancer Day. World Cancer Day is an initiative of the Union for International Cancer Control (UICC) and takes place each year on February 4. Cary Adams, Chief Executive Officer, Union for International Cancer Control (UICC), said “The new figures from IARC show that the incidence of cancer globally will continue to grow unless we recognize the threat and act

on it now. On World Cancer Day, we demand that Governments around the world move to stop the millions of pre-

World Cancer Day is an initiative of the Union for International Cancer Control (UICC) and takes place each year on February 4.

dicted, needless, and premature deaths caused by cancer by developing and implementing a national plan which includes proven preventive and early detection measures.” Practical solutions to reduce premature deaths include developing and implementing national cancer control plans, awareness programs against modifiable risks factors, cancer screening programs, and HPV vaccination programs. For more information on the World Cancer Report 2014, visit www.iarc.fr/ n Reference 1. Stewart BW, Wild C (Eds): World Cancer Report 2014. WHO Press, 2014.

IN AL K + N SC LC

reCognize progression

iDentify symptoms

• Prior to 2011, there were no targeted therapies available to treat patients with ALK+ NSCLC1-3

• Symptoms, including cough, dyspnea, fatigue, pain, hemoptysis, and anorexia, can serve as signals of progression7,8

• Inevitably, patients develop resistance to currently available ALK inhibitor therapy and typically progress after 10 months4-6 • Common sites of disease progression include the CNS, lung, and liver6

• Up to half of patients with NSCLC may develop CNS metastases, and symptoms include headaches, seizures, cognitive impairment, and neurological deficits9,10

ALK, anaplastic lymphoma kinase; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors. References: 1. XALKORI® (crizotinib) Prescribing Information. New York, NY: Pfizer Labs; October 2013. 2. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773-1780. 3. US Food and Drug Administration. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Released August 26, 2011. Accessed November 5, 2013. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.2.2014. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed November 4, 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. 5. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):1-12. doi:10.1126/scitranslmed.3003316. 6. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019. 7. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Cancer. 1994;73(8):2087-2098. 8. de Marinis F, Pereira JR, Fossella F, et al. Lung cancer symptom scale outcomes in relation to standard efficacy measures. J Thorac Oncol. 2008;3(1):30-36. 9. Hu C, Chang EL, Hassenbusch SJ III, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106(9):1998-2004. 10. Fokas E, Steinbach JP, Rödel C. Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta. 2013;1835(1):61-75. 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 12. Sánchez de Cos J, Sojo González MA, Montero MV, et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009;63(1):140-145.

A LOT CAN HAPPEN IN A MONTH Can CheCking monthly for symptoms help yoU DeteCt progression earlier? interVene noW • By assessing patient symptoms monthly during routine physical exams, progression may be detected earlier8 • According to RECIST guidelines, a CT scan may be the best method for monitoring response to therapy11 • Early detection of CNS metastases by cranial CT or MRI—even before symptoms develop—may improve prognosis12

Visit www.detectearlier.com to learn how early detection of progression may change the course of disease for your patients with alk+ nsClC.

novartis oncology is committed to advancing research into the alk pathway to help find new options for patients with lung cancer.

Novartis Pharmaceuticals Corporation east hanover, new Jersey 07936-1080

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In the News Screening

Confronting Uncertainty About the Harms and Benefits of Screening Mammography By Charlotte Bath

“I

f women are to truly participate in the decision of whether or not to be screened [for breast cancer using mammography], they need some quantification of its benefits and harms,” asserted H. Gilbert Welch, MD, MPH, Professor of Medicine, and Honor J. Passow, PhD, Instructor, at The Dartmouth Institute for Health Policy & Clinical Practice, Hanover, New Hampshire, in a Special Communication in JAMA Internal Medicine.1 Acknowledging that the task of providing that information is beset with uncertainty, the authors presented their attempt to “bound this uncertainty by providing a range of estimates—optimistic and pessimistic—on the absolute frequency of 3 outcomes important to the mammography decision: breast cancer deaths avoided, false alarms, and overdiagnosis.” The optimistic and pessimistic estimates reflect the most and least favorable results of nine randomized trials of screening mammography. Drs. Welch and Passow reported that for every 1,000 women aged 50 screened annually for a decade, an estimated 0.3 to 3.2 will avoid a breast cancer death, 490 to 670 will have at least one false alarm (requiring recall testing, including biopsies), and 3 to 14 will be overdiag-

nosed and treated needlessly. They also provided estimates for women aged 40 (generally less benefit and greater harm) and women aged 60 (generally greater benefit and less harm). “Because the risk of false-positive results is considerably lower in other countries and with biennial screening, these data should not be general-

Quantified Outcomes for 10 Years The authors explained that they quantified outcomes for 10 years because it is “long enough for benefit to accrue and short enough to be contemplated by an individual.” They also made the assumption that “a 10-year course of mammography results in mortality

My coauthor and I have tried to give some sense of the range of effects, and some might be looking at those ranges and saying, ‘There is a lot of imprecision there.’ Maybe we need to have a better idea of what the benefit of mammography is in this current treatment environment, and that would take another randomized trial. —H. Gilbert Welch, MD, MPH

ized elsewhere,” the authors emphasized. The lower risk of false-positives is partly due to reduced frequency of screening, but “it is more than that,” Dr. Welch told The ASCO Post. “It is because they have a higher threshold for calling a film abnormal.”

reduction extending 15 years. This assumption favors screening because it assumes that the benefit is not delayed at the front end; instead, the reduction in death appears with the first mammogram.” Surveillance, Epidemiology and End Results (SEER) data were used

Expect Questions From Patients

“L

ike all early detection strategies, screening mammography involves trade-offs,” H. Gilbert Welch, MD, MPH, and Honor J. Passow, PhD, of the Dartmouth Institute for Health Policy & Clinical Practice, Hanover, New Hampshire, wrote in a Special Communication in JAMA Internal Medicine.1 They attempted to reduce the uncertainty surrounding these issues by providing a range of estimates on three outcomes that can have an impact on whether a woman chooses to have screening mammography. For the midrange age group (50-year-old women), the estimated ranges are that out of 1,000 women, 0.3 to 3.2 will avoid a breast cancer death, 490 to 670 will have at least one false alarm (requiring recall testing, including biopsies), and 3 to 14 will be overdiagnosed and receive treatment.

While these estimates are intended to make women feel more comfortable about their decision to pursue or not pursue mammography, the authors acknowledge that “for many women these ranges may not be sufficiently precise to make an informed choice.”

Analogies to Prostate Cancer Screening Individual patients may or may not have strong opinions about the value of screening. Dr. Welch, whose clinical work is with men at the Department of Veterans Affairs, told The ASCO Post that he views screening for prostate cancer and breast cancer as analogous issues. “Some men are full-on ready to be screened. Others don’t want to be screened: ‘Doc, if it ain’t broke, don’t fix it.’ And then

there is the in-between group who want to consider this more carefully, want to understand what the debate is about,” he said. “The same is probably true of women, and I think it is a close enough call that if women come in with a very strong prior opinion about wanting or not wanting to be screened, those are women we shouldn’t try to dissuade either way. But there may be a middle group who really want to consider this, and if they do, I think that consideration should be informed by some data. We tried to provide that.” n Reference 1. Welch HG, Passow HJ: Quantifying the benefits and harms of screening mammography. JAMA Intern Med. December 30, 2013 (early release online).

to calculate the risk of dying with and without screening. The authors resisted the temptation to provide a “best” estimate because “doing so would convey a false sense of certainty and thus be misleading,” they stated. In a related op-ed piece in The New York Times, Dr. Welch noted that the decision to pursue screening is “a close call.” He continued, “Different people in the same situation can rationally make different choices. But first patients need some quantification of the benefits and harms.”

Changing Attitudes It has only been in the last decade or so that people have begun to consider the possible harms, as well as the benefits, of screening mammography, Dr. Welch noted. “Part of the cost—and I am talking about human cost, not dollar cost—is that when you look hard for disease, you end up worrying a lot of people unnecessarily about it. And it also leads some people to be treated for a disease that will never bother them. That is the overdiagnosis problem.” The report noted that the anxiety of false alarms may persist for at least 3 years and produce psychological morbidity. Dr. Welch said there is anecdotal evidence that false alarms can also cause women to become “so frustrated and scared by the process, they want to stop, which can become a major issue” he said. “One of the most important changes we’ve undergone in the past 10 or 20 years is that advocacy groups for breast cancer have moved from being 100% behind screening to recognizing that there are some limitations, and it is not as simple as it seems on first blush,” Dr. Welch said. “Some of the women’s advocacy groups are worried that this has created an epidemic of overtreatment and having women excessively worried about their health,” he added. “That is not the road to a healthy society either. So I think there is a recognition that we’ve got to have a better balance.”

Shift to Biennial Screening? According to the study, decreasing the frequency of screening mammography to every 2 years has been shown to minimize the harm of false-positives and like-

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In the News

ly also reduces the harm of overdiagnosis. “The harm it will most clearly affect is the cumulative risk of false-positives,” said Dr. Welch, “but it is a pretty crude way to reduce the rate of false-positives. It doesn’t really change the character of the test; it just reduces a patient’s exposure to it. I would hope in the long run that we would have more sophisticated ways of lowering the false-positive rate.” Switching to biennial screening might also be expected to lower the rate of preventable deaths, but not by much. “Randomized trial data suggest that the interval between 2 years and 1 year does not have a big effect on preventable death,” Dr. Welch said. “Reducing the harms of both overdiagnosis and false alarms was the primary motivation behind efforts of the U.S. Preventive Services Task Force (and others) to lengthen the screening interval from annual to biennial,” the article noted. But letters to the editor in response to Dr. Welch’s Times op-ed point out that other organizations continue to adhere to an annual schedule. “Every medical organization experienced in breast cancer (including the

American Cancer Society, American Congress of Obstetricians and Gynecologists, American College of Radiology, Society of Breast Imaging and National Accreditation Program for Breast Centers) recommends annual mammograms for women ages 40 and older,” wrote Barbara Monsees, MD, Chairwoman of the Breast Imaging Commission of the American College of Radiology, and Murray Rebner, MD, President of the Society of Breast Imaging.3

Moving Target As noted in the JAMA Internal Medicine article, “the better we are at treating clinically evident disease, the less benefit there is to screening.” It has been more than 50 years since the last randomized trial of screening mammography in the United States. “Now that treatment is so much better, how much benefit does screening actually provide? What we need is a clinical trial in the current treatment era,” Dr. Welch wrote in his New York Times op-ed article. “We have a moving target here, as we always do in medicine. We have

an intervention that is done on a massive scale; it literally involves millions of women. It comes with benefits, but it also comes with harms,” Dr. Welch commented in the interview with The ASCO Post. “My coauthor and I have tried to give some sense of the range of effects, and some might be looking at those ranges and saying, ‘There is a lot of imprecision there.’ Maybe we need to have a better idea of what the benefit of mammography is in this current treatment environment, and that would take another randomized trial.”

Two Trials Suggested Dr. Welch stressed that he knows of no plans or protocols for such trials. In the op-ed, he suggested, “Two randomized trials could begin to answer the central question of mammography interpretation: How hard should the radiologist look? Women who view mammography favorably might be willing to be screened under either the current approach or a high-threshold approach—meaning their radiologist would ignore small, likely harmless abnormalities found on a mammo-

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gram. Those who view it less favorably might choose that high-threshold approach (knowing that the harms of false alarms and overdiagnosis would be minimized) or forgo mammography completely,” he wrote. “Putting the two trials together, we could finally learn what level of screening minimizes false alarms and overdiagnosis while saving the most lives,” he continued. He questioned, however, whether there was the will, interest, or money for such an undertaking. “It is not going to be small, and it is not going to be easy,” he told The ASCO Post. n

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

References 1. Welch HG, Passow HJ: Quantifying the benefits and harms of screening mammography. JAMA Intern Med. December 30, 2013 (early release online). 2. Welch HG: Breast cancer screening: What we still don’t know. New York Times, December 29, 2013. 3. Monsees B, Rebner M: Weighing the value of mammograms. Letter. New York Times, January 2, 2014.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology TUMOR MICROENVIRONMENT Intact Gut Microbe Populations Improve Response to Chemotherapy Gut microflora affect local and systemic inflammatory responses, and inflammation is involved in both pathogenesis and treatment of cancers, but it is unclear whether gut microflora affect inflammation in the sterile tumor microenvironment. In a study reported in Science, Iida and colleagues assessed whether disruption of commensal gut flora in mice had an effect on response to immunotherapy or chemotherapy in tumor models. In the study, mice received antibiotic treatment for 3 weeks before subcutaneous tumor inoculation and continuously throughout the studies. EL4 lymphoma, MC38 colon cancer, or B16 melanoma tumors were grown to ≥ 4 mm prior to immunotherapy with CpG-oligonucleotide plus anti–interleukin 10 receptor antibody or chemotherapy with oxaliplatin or cisplatin. Gene-expression analysis of MC38 and EL4 tumors prior to anticancer therapy showed downregulation of genes involved in inflammation, phagocytosis, antigen presentation, and adaptive immune responses and upregulation of genes involved in tissue development, cancer, and metabolism in antibiotic-treated mice. Levels of bacteria were restored to pretreatment levels 1 week after stopping antibiotics, and bacterial diversity and composition gradually increased but did not reach pre-antibiotic levels. In antibiotic-treated or germ-free mice, tumor-infiltrating myeloid-derived cells had a blunted response to immunotherapy in mice with MC38 and B16 tumors, with antibiotic-treated mice having reduced tumor necrosis and reduced survival compared with control mice. Antibiotic-treated and germ-free mice with EL4 or MC38 tumors had reduced tumor regression and survival compared with control mice receiving platinum therapy, with the antibiotic-treated mice exhibiting reduced production of reactive oxygen species and cytotoxicity. Gene-expression analysis showed that induction of proinflammatory genes was decreased in the absence of microbiota after oxaliplatin treatment, indicating that inflammation was essential to the antitumor effect of the drug. The investigators concluded:

[O] ptimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

Iida N, et al: Science 342:967-970, 2013.

Effect of Cyclophosphamide Mediated by Gut Microflora In a study reported in Science, Viaud and colleagues showed that the antitumor activity of cyclophosphamide is dependent on the effect of this agent on gut microflora. In mouse studies, the investigators found that cyclophosphamide altered the composition of microbiota in the small intestine, inducing translocation of select Gram-positive organisms into secondary lymphoid organs. This drove a conversion of splenicnaive CD4-positive T cells into a predominance of “pathogenic” TH17 (pTH17) cells, which share characteristics of TH1 cells (nuclear expression of transcription factor T-bet, cytoplasmic expression of IFN-gamma, and surface exposure of the chemokine receptor CXCR3) and TH17 cells (expression of ROR-gamma-t, interleukin [IL]-17 and CCR6). This conversion into IL-17–producing cells was not observed in the absence of the gut microbiota. IL-17 release by stimulated splenocytes occurred in specific-pathogen–free mice but not in germ-free mice and was suppressed in mice receiving broadspectrum antibiotic treatment or treatment with vancomycin, which is specific for Gram-positive bacteria. The antitumor effects of cyclophosphamide were reduced by broadspectrum antibiotic treatment in mice with P815 mastocytomas and reduced in germ-free mice vs specific-pathogen–free mice with MCA205 sarcomas. Vancomycin treatment reduced the tumor inhibitory effects of cyclophosphamide compared with treatment with colisitin, which acts against Gram-negative bacteria. Vancomycin inhibited the efficacy of a cyclophosphamide-based regimen in a transgenic model of autochthonous lung carcinogenesis driven by oncogenic KRAS coupled to conditional p53 deletion. Further, vancomycin prevented cyclophospha-

mide-induced splenic accumulation of pTH17 cells and reduced the frequencies of tumor-infiltrating CD3-positive T cells and TH1 cells. The investigators concluded, “Although much of the detailed molecular mechanisms governing the complex interplay between epithelial cells, gut microbiota, and intestinal immunity remain to be deciphered, the present study unveils the unsuspected impact of the intestinal flora on chemotherapy-elicited anticancer immune responses. Our data underscore new risks associated with antibiotic medication during cancer treatments, as well as the potential therapeutic utility of manipulating the gut microbiota.” Viaud S, et al: Science 342:971-976, 2013.

BIOMARKERS CYB5A Induces Autophagy, and Higher Expression Improves Survival in Pancreatic Cancer Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma. In a study reported in the Journal of the National Cancer Institute, Giovannetti and colleagues assessed the role of 18q22.3-encoded CYB5A in pancreatic cancer prognosis and autophagy modulation. In the study, both resected (n = 130) and metastatic (n = 50) patients with low CYB5A mRNA or protein expression had significantly shorter overall survival compared with patients with higher expression levels (eg, median 16.7 vs 24.8 months, P = .02, among patients with radical resection). Studies in pancreatic ductal adenocarcinoma cell lines showed that increased CYB5A expression was associated with autophagy induction and reduced proliferation and migration/invasion of cancer cells. Network analysis of pro-autophagic signaling pathways indicated an interaction of CYB5A with TRAF6, an interaction that was confirmed by observation of downregulation of TRAF6 after CYB5A reconstitution (–69% in SU.86.86-CYB5A-positive cell lines, P = .005). CYB5A silencing restored TRAF6 expression and wound healing. Studies in CYB5A-positive orthotopic mouse models showed that CYB5A-induced autophagy, inhibited

pancreatic tumor growth/metastasis, and increased survival (median, 57 vs 44 days, P = .03). The investigators concluded, “These results define CYB5A as a novel prognostic factor for [pancreatic ductal adenocarcinoma] that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.” Giovannetti E, et al: J Natl Cancer Inst 106(1):djt346, 2014.

High Plasma Alkylresorcinols Associated With Reduced Risk of Distal Colon but Not Overall Colorectal Cancer In a study reported in Journal of the National Cancer Institute, Kyrø and colleagues found that high levels of plasma alkylresorcinols, biomarkers of dietary whole-grain wheat and rye intake, were associated with reduced risk of distal colon cancer. The study involved prediagnostic plasma samples from 1,372 colorectal cancer patients from Scandinavia, the Mediterranean, and Central Europe and 1,372 matched control subjects, all from the European Prospective Investigation into Cancer and Nutrition. High plasma total alkylresorcinol levels were associated with lower incidence of distal colon cancer, with an adjusted incidence rate ratio of 0.48 (95% confidence interval [CI] = 0.28–0.83) for the highest vs lowest quartile of plasma levels, but were not associated with reduced risk of overall colorectal cancer, proximal colon cancer, or rectal cancer. There was a significant inverse association between total alkylresorcinol concentrations and colon cancer in Scandinavian subjects (incidence rate ratio per doubling = 0.83, 95% CI = 0.70–0.98). Plasma alkylresorcinol concentrations were associated with colon and distal colon cancer only in subjects from Central Europe and Scandinavia, the areas where alkylresorcinol levels were highest. The investigators concluded, “High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.” Kyrø C, et al: J Natl Cancer Inst 106(1):djt352, 2014. n Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Emerging Clinical Data on Cancer Management PANCREATIC CANCER High Expression of hENT1 Can Predict Better Survival Among Patients on Postsurgical Gemcitabine High levels of expression of the human equilibrative nucleoside transporter 1 (hENT1) were associated with longer median survival of patients with pancreatic adenocarcinoma receiving gemcitabine, according to an analysis of clinical data and cancer tissue collected from the European Study Group for Pancreatic Cancer (ESPAC)-3 trial. That trial found that after resection for pancreatic ductal carcinoma, adjuvant gemcitabine was not superior to fluorouracil (5-FU)/ leucovorin. The final analysis included 380 patients, 176 in each of the two treatment groups, and 28 in the observation group. Levels of hENT1 were not predictive of survival for patients in the observation group. The median age of patients was 64, and 59.5% were male. The median number of days from surgery to randomization was 49, and 75.7% of patients had standard resection, 14.3% had radical resection, and 9.9% had extended radical resection.

Study Data The study showed that although patients treated with gemcitabine vs 5-FU/leucovorin had similar median overall survivals (23.4 vs 23.5 months), median survival for patients treated with gemcitabine was 26.2 months for those with high hENT1 expression vs 17.1 months for those with low hENT1 expression (P = .002), a difference of 9.1 months. For patients receiving 5-FU/leucovorin, median survival was 21.9 months for those with high hENT1 expression vs 25.6 for those with low hENT1 expression (P = .36). “Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ2 = 9.16; P = .003) but not [5-FU]– treated (Wald χ2 = 1.22; P = .27) patients,” the ESPAC researchers reported. Calling hENT1 a “promising biomarker,” the investigators explained that it “permits the bidirectional passage into cells of pyrimidine nucleosides,” such as gemcitabine and 5-FU. Results were reported in the Jour-

nal of the National Cancer Institute. The chief investigator was John P. Neoptolemos, MD, of the Liverpool Cancer Research UK Centre, United Kingdom. “Taken together, the results of this study have provided powerful evidence that adjuvant gemcitabine should not be used after resection for patients with low tumor hENT1 expression, the alternative being 5FUbased regimens, and by implication vice versa,” the researchers concluded. They also stated that their study “paves the way for the introduction of hENT1 assessment for a stratified medicines approach in pancreatic cancer, not only in the adjuvant setting but also potentially in the advanced setting.” Greenhalf W, et al: J Natl Cancer Inst 106(1):djt347, 2014.

LEUKEMIA In CLL With Coexisting Conditions, Chlorambucil Produces Better Outcomes With Obinutuzumab Than With Rituximab A randomized phase III trial conducted in 26 countries found that combining chlorambucil (Leukeran) with an anti-CD20 antibody—either obinutuzumab (Gazya) or rituximab (Rituxan)—produced better outcomes among patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions than treating these patients with chlorambucil alone. “Obinutuzumab-chlorambucil provided an overall advantage over chlorambucil alone and induced deeper and longer remissions than did rituximab-chlorambucil,” the researchers concluded. The study involved 781 patients with a median age of 73 years. Patients were required to have “a clinically meaningful burden of coexisting conditions, as reflected by a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or a creatinine clearance of 30 to 69 mL per minute,” the investigators explained in the report published in The New England Journal of Medicine. The median CIRS score at baseline was 8, and the median creatinine clearance was 62. “Most patients (82%) had more

than three coexisting conditions, and nearly one-third (27%) had at least one coexisting condition that was not well controlled at baseline according to CIRS grading,” the researchers noted. The study was designed by the German CLL Study Group and the sponsor, F. Hoffmann–La Roche.

Key Findings Median progression-free survival was 11.1 months for chlorambucil alone, 16.3 months with rituximabchlorambucil, and 26.7 months with obinutuzumab-chlorambucil. “Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival [hazard ratio = 0.39; 95% CI = 0.31–0.49; P < .001] and higher rates of complete response [20.7% vs 7.0%] and molecular response,” reported Valentin Goede, MD, of the Center of Integrated Oncology Cologne-Bonn and University Hospital Cologne, Germany, and colleagues. “Infusion-related reactions and neutropenia were more common among patients treated with the combination including obinutuzumab than with rituximab, but the risk of infection was not increased,” the investigators stated. “The rate of induction of negative status for minimal residual disease was more than 10 times as high with obinutuzumab-chlorambucil as it was with rituximab-chlorambucil. The capacity of a treatment to result in low levels of minimal residual disease in bone marrow or peripheral blood was recently associated with improved overall survival, irrespective of the clinically assessed response status,” they wrote. “With longer follow-up,” the authors continued, “the higher rate of eradication of minimal residual disease that was observed with obinutuzumab as compared with rituximab may lead to an overall survival benefit in addition to the improvement in progression-free survival.” Goede V, et al: N Engl J Med. January 8, 2014 (early release online).

Role for Reduced-Intensity Conditioning Regimen in AML After Allogeneic Transplantation Reduced-intensity conditioning and myeloablative-conditioning regimens following allogeneic hemato-

poietic cell transplantation in children with acute myeloid leukemia (AML) resulted in comparable survival, according to a study published in Blood. The study evaluated 181 patients, 39 treated with reduced-intensity conditioning and 141 treated with myeloablative-conditioning regimens. “Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-vs-host disease, leukemia-free and overall survival between treatment groups,” reported Menachem Bitan, MD, PhD, of Tel Aviv Sourasky Medical Center, Israel, and colleagues. “The 5-year probabilities of overall survival with [reduced-intensity conditioning] and [myeloablative-conditioning] regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with [reduced-intensity conditioning] compared to [myeloablativeconditioning] regimens (39% vs 39%, P = .95), and recipients of [myeloablative-conditioning] regimens were not at higher risk for transplant-related mortality compared to recipients of [reduced-intensity conditioning] regimens (16% vs 16%, P = .73),” the investigators noted. The study relied on data from the Center for International Blood and Marrow Transplant Research. Eligible patients were less than 18 years old (median age, 14), had received a first allogeneic transplant for AML between 2000 and 2009, and received reduced-intensity conditioning or myeloablative-conditioning conditioning regimens. Regimens were considered to be of reduced intensity if busulfan was given at < 8 mg/kg orally or < 6.4 mg/kg intravenously, melphalan was given at < 150 mg/m2, and total-body irradiation was administered at 200 or 400 cGy as a single fraction or at 550 or 600 cGy in fractionated doses. Other regimens were defined as myeloablative, the authors explained. About 50% of patients in the myeloablative-conditioning group received total-body irradiation, and the most frequently used non–total-body irradiation regimen was busulfan (Busulfex, Myleran) plus cyclophosphamide. About 20% of reduced-intensity conditioning regimens included low-dose total-body irradiation, and most of these regimens consisted of

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alkylating agents and fludarabine, the investigators noted. “In this relatively modest study population and after carefully controlled analyses,” the authors concluded, “the data support a role for [reduced-intensity conditioning] regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provide justification for a designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population.” The authors pointed out that the results of observational trials comparing reduced-intensity conditioning and myeloablative-conditioning regimens in adults with AML and myelodysplastic syndrome have led to a national trial in the United States through the Blood and Marrow Transplant Clinical Trials Network. Bitan M, et al: Blood. January 16, 2014 (early release online).

MULTIPLE MYELOMA Pomalidomide Plus Low-Dose Dexamethasone: Important New Option in Relapsed/ Refractory Multiple Myeloma Pomalidomide (Pomalyst) plus low-dose dexamethasone significantly improved progression-free survival compared to pomalidomide alone in patients with relapsed and refractory multiple myeloma enrolled in a multicenter, open-label study, the phase II part of the MM-002 trial. The study confirmed the synergistic activity of pomalidomide combined with low-dose dexamethasone, and the combination therapy “provides an important new treatment option for [relapsed/refractory multiple myeloma] patients who have received multiple prior therapies,” reported Paul G. Richardson, MD, of DanaFarber Cancer Institute, Boston, and colleagues in Blood. Patients in the trial had received two or more prior therapies (median, 5; range, 1–13), including lenalidomide (Revlimid) and bortezomib (Velcade), and had shown disease progression within 60 days of their last therapy. A total of 221 patients from 18 centers in the United States and Canada were randomly assigned to 4 mg/day of pomalidomide on days 1 to 21 of each 28-day cycle plus low-dose dexamethasone (40 mg/week)(n = 113) or pomalidomide alone (n = 108). The

median age of patients was 63 years, 81% were white, 54% were male, and 27% had high-risk cytogenetics.

Primary Endpoint At a median follow-up of 14.2 months, median progression-free survival, the primary endpoint of the trial, was 4.2 months for pomalidomide plus low-dose dexamethasone vs 2.7 months for pomalidomide alone (hazard ratio = 0.68, P = .003). The respective overall response rates were 33% and 18% (P = .013). Median response durations were 8.3 months for pomalidomide plus lowdose dexamethasone and 10.7 months for pomalidomide alone. Median overall survival in the intent-to-treat population was 16.5 for pomalidomide plus low-dose dexamethasone and 13.7 months with pomalidomide alone, “which compares favorably with historically reported 9-month survival rates for patients in whom currently approved novel therapies have failed,” the investigators noted. Refractoriness to lenalidomide or resistance to both lenalidomide and bortezomib did not affect outcomes with pomalidomide and low-dose dexamethasone. The investigators noted a limited cross-resistance between pomalidomide and lenalidomide, which “supports the effectiveness of sequential use of immunomodulatory drugs, as well as combinations.” They added, “There is a clear unmet need for new treatments, particularly for patients who are relapsed and refractory to novel agents.” Patients with cytogenetic abnormalities had an overall response rate of 23% and median response duration of 4.9 months with the combination therapy, “suggesting encouraging activity in patients with high-risk cytogenetic profiles and poor prognosis,” the authors stated. The most common grade 3/4 adverse event was neutropenia, occurring in 41% of patients receiving combination therapy and 48% of those receiving pomalidomide alone. No grade 3/4 peripheral neuropathy was reported. “With appropriate management, the rates of discontinuations due to treatment-related [adverse events] were low [2%–3%],” the researchers reported. A total of 19 deaths occurred during the study period, 10 among patients receiving combination therapy and 9 among those receiving pomalidomide alone, with most deaths attributed to multiple

myeloma and disease progression. Richardson PG, et al: Blood. January 13, 2014 (early release online).

ONCOLOGY WORKFORCE Anticipated Shortage of Oncologists Will Strain Ability to Provide Quality Cancer Care An update of the ASCO 2007 oncology workforce study found that the Patient Protection and Affordable Care Act, when fully implemented, may “modestly exacerbate” anticipated workforce shortages, increasing the demand for oncologists and radiation oncologists by 500,000 visits per year. “Unless oncologist productivity can be enhanced, the anticipated shortage will strain the ability to provide quality cancer care,” the authors of the updated analysis wrote in the Journal of Oncology Practice. “Beginning in 2012, 16,347 oncologists and radiation oncologists were active and supplying 15,190 fulltime equivalents of patient care,” the researchers reported. They defined a full-time equivalent as “the expected number of patient visits that an average oncologist or radiation oncologist engaged full time in clinical care would provide in a year.” Summarizing their analysis, the authors noted, “Without consideration of the Affordable Care Act, overall demand for oncologist services is projected to grow 40% (21,255 [full-time equivalents]), whereas supply may grow only 25% (18,997 [full-time equivalents]), generating a shortage of 2,258 [full-time equivalents] in

2025. When fully implemented, the [Affordable Care Act] could increase the demand for oncologists and radiation oncologists by 500,000 visits per year, increasing the shortage to 2,393 [full-time equivalents] in 2025.” Closing the gap between baseline supply and demand projections by the year 2025 would require increasing entering residency and fellowship positions by 210 for oncology and 120 for radiation oncology between 2014 and 2022, the authors estimated. “Because it is unlikely that the US health system will expand physician training programs so dramatically on such a short time horizon, strategies to improve the productivity of oncologists and radiation oncologists should be considered and evaluated to mitigate the shortfall,” they wrote. Among those possible strategies is more collaborative and coordinated care by oncologists, radiation oncologists, and advanced practitioners with oncology-specific training. “This scenario may be the most likely strategy to increase supply because the funding to increase fellowship training slots is uncertain,” the authors noted. The updated study was supported by Susan G. Komen for the Cure and ASCO. The authors represented the Lewin Group in Falls Church, Virginia; ASCO; South Texas Oncology and Hematology in San Antonio; the Scripps Clinic in La Jolla, California; Memorial Sloan Kettering Cancer Center in New York; and Beth Israel Deaconess Medical Center in Boston. n Yang W, et al: J Oncol Pract 10:3946, 2014.

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

ignite survival in first-line mPAC Important Safety Information 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

CONTRAINDICATIONS 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 dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • 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 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 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 • 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%)

Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months

0.4

(95% CI: 6.0-7.2)

0.3

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

0.2

P<0.0001b

0.1 0.0 0

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)

Patients at risk A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

STUDY DESIGN The multinational, randomized, phase III 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, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with mPAC. The primary end point was OS.

T:14”

B:14.25”

S:13”

• 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%) • 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%)

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

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

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages. For more information, please visit www.abraxane.com. ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 01/14 US-ABR130068a(1)

Geriatric • 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 • 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

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary for metastatic adenocarcinoma of the pancreas; 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 (6.3)]. • 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 1.3 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 2.3 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. 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) Levels Bilirubin Levels ABRAXANE Dosea Pancreatic c Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended 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. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations 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 1st dose reduction 100 800 75 600 2nd dose reduction 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 ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine < 1500 OR < 100,000 Delay doses until recovery 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. Cycle Day Day 1 Day 8

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 next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to ≤ Grade 1; No dose reduction Grade 3 or 4 resume at next 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 next Grade 3 mucositis or diarrhea 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 a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. 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)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (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 for 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. 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%). 6.3 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 gemcitabinetreated 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 Gemcitabine ABRAXANE(125 mg/m2)/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.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 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 (125 mg/m2) and gemcitabine (N=421)

Gemcitabine (N=402)

System Organ Class

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

General disorders and administration site conditions

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral 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%)

Gastrointestinal disorders

Skin and subcutaneous tissue disorders Nervous system disorders

Metabolism and nutrition disorders Respiratory, thoracic and mediastinal disorders

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

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%)

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%) 3 (1%)

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

Dysgeusia

68 (16%)

33 (8%)

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%)

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

6 (1%)

Cough

72 (17%)

30 (7%)

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%) 1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

Psychiatric disorders

Depression

51 (12%)

1 (<1%)

24 (6%)

T:14”

B:14.25”

S:13”

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. 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

10 16

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. 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. 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 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. 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. 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. 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_PANC_HCP_BSv007 10_2013

The ASCO Post | FEBRUARY 15, 2014

PAGE 112

In Memoriam

Donald L. Morton, MD, an Icon in Surgical Oncology, Dies By Ronald Piana “Tomorrow is the most important thing in life. Comes into us at midnight very clean. It’s perfect when it arrives and it puts itself in our hands. It hopes we’ve learned something from yesterday.” —John Wayne

onald L. Morton, MD, transformed the management of melanoma and breast cancer by introducing the sentinel node biopsy, giving surgeons an accurate roadmap for treat-

Donald L. Morton, MD

ment, and sparing generations of cancer patients from the morbidity associated with unnecessary surgery. Throughout his distinguished career, his work and discoveries have profoundly changed the treatment of cancer. Dr. Morton died on January 10, 2014, in Santa Monica, California. He was 79.

Overcoming Poverty Dr. Morton was born in 1934 in Richwood, West Virginia, a small coalmining town tucked away in the Appalachians. The son of a coal miner, Dr. Morton grew up dirt poor during the Great Depression, reared in a house built by his father that had no electricity or indoor plumbing. He tended pigs, cows, and chickens in the morning before school, and then again after school. “Only after all my chores were done could I do my homework by the light of a kerosene lamp,” noted Dr. Morton in an interview with Innovations, a publication of the John Wayne Cancer Institute. Dr. Morton’s self-determination and a supportive mother overcame the limitations imposed by poverty. His searing intellect was seen early on, and following high school he enrolled in Berea College in Kentucky, which provided free education to qualified students

from poor families. After graduating from Berea, Dr. Morton completed his undergraduate education at the University of California, Berkeley, in 1955 and then received his medical degree from the University of California, San Francisco (UCSF), in 1958.

Early Career Dr. Morton interned at UCSF Medical Center and began a surgical residency in general surgery, which was put on hold by a fellowship grant at the National Cancer Institute (NCI). Following his fellowship, Dr. Morton completed his surgical residency at UCSF Medical Center, after which he returned to the NCI in 1960 to serve as senior surgeon in the surgery branch. He eventually became the head of NCI’s tumor immunology section. During this period, Dr. Morton’s lifelong interest in surgical oncology and melanoma began to bloom. Also at the NCI, Dr. Morton’s observations of

lymph node biopsy, which has become the standard of care for patients with early-stage malignant melanoma and breast cancer. It is widely accepted that the sentinel node concept saves the U.S. health-care system about $3.8 billion per year in unnecessary procedures and their subsequent harms.

Groundbreaking Research Dr. Morton’s early interest in immunotherapy led to his pioneering work with intratumoral bacille CalmétteGuerin (BCG) for nonspecific melanoma immunotherapy, the first successful application of immunotherapy in metastatic cancer. His studies also laid the foundation for the use of intravesical BCG in superficial bladder cancer, which became the first U.S. Food and Drug Administration–approved cancer immunotherapy. During this period of groundbreaking research, Dr. Morton also became known as being one of the last physicians

Donald Morton is truly a legend in surgical oncology, an icon as a surgical investigator, a pioneer in melanoma, a valued mentor, an authentic role model, and a cherished friend. —Charles M. Balch, MD

spontaneous remissions in melanoma sparked his interest in immunotherapy, which would become a central line of inquiry during his career. In 1971, Dr. Morton assumed the role of Professor and Chief of the Division of Surgical Oncology, UCLA School of Medicine. At that time, surgical oncology was not yet recognized as a specialty within general surgery. Dr. Morton’s work changed the approach to melanoma surgery by introducing cutaneous lymphoscintigraphy to identify the regional lymphatic basin receiving drainage from a primary cutaneous melanoma. During the late 1970s, Dr. Morton further refined lymphatic mapping, defining the sentinel lymph node as the first tumor-draining node, leading to the development of the sentinel

to treat the Hollywood icon John Wayne, who died in 1979 of stomach cancer. Dr. Morton—who slightly resembled Wayne in his stature and rugged good looks—became quite close to the famous actor. In later interviews, Dr. Morton would remark about Wayne’s dignity in dealing with his terminal condition. In 1981, with the help of the Wayne family, Dr. Morton established the John Wayne Cancer Clinic at UCLA. Ten years later, seeking more space for patients and research, Dr. Morton, along with John Wayne’s eldest son, Michael Wayne, moved to St. John’s Health Center, founding the John Wayne Cancer Institute.

Valued Mentor In a 2011 editorial in the Journal of Surgical Oncology, former ASCO Executive Vice President, Charles M. Balch,

MD, of Johns Hopkins University wrote, “Donald Morton is truly a legend in surgical oncology, an icon as a surgical investigator, a pioneer in melanoma, a valued mentor, an authentic role model, and a cherished friend.” For those who were lucky enough to have personally known and worked with Dr. Morton, the term “valued mentor” stands out in Dr. Balch’s comment. As a teacher, Dr. Morton worked tirelessly to establish the next generation of oncologists, training more than 135 surgical fellows. “I’m proud that about 80% of those I’ve trained are now deans or department chairs and are widely distributed throughout the country. They will continue to make contributions to cancer long after I’m gone,” Dr. Morton said during his interview in Innovations.

Dedication to Patients Dr. Morton’s scientific contributions to the field of oncology will endure as a living legacy, carried on by generations of future doctors. That said, his groundbreaking research work in the lab did not separate him from cancer patients; it brought him closer to them. His dedication to patients was best captured during an interview in the Los Angeles Daily News, when he said, “Cancer patients are the nicest patients in the world. I truly believe there is a genetic link between kindness and those who are diagnosed with cancer. After all of these years, I still cannot help but get emotionally involved with my patients and their situations. It is truly rewarding when a patient with a fatal diagnosis is still alive after 5 years, but it is crushing when I lose a patient because, in essence, I am losing a friend.” Dr. Morton’s unlikely rise from Depression era rural poverty to a doctor of international renown evokes an inspirational and extraordinary life, one that touched the lives of hundreds of aspiring oncologists and millions of cancer patients. He is survived by his wife, five children, eight grandchildren, a brother, and a sister. n

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In Memoriam

Leukemia/Lymphoma Pioneer Geoffrey P. Herzig, MD, Dies By Ronald Piana

any of the advances that have bettered mankind are attributed to those who were driven by a primary passion. Geoffrey P. Herzig, MD, lived the better part of his life with a primary passion: conducting research to

attend the same medical school, and he frequently tells a story about his interview for admission. The dean had his and his older brother’s files on his desk. The dean cut the interview short, asking Roger whether he was as smart as Geoff, who was by then the brightest student in his class and a member of the medical honor society Alpha Omega Alpha. Roger’s reply: “Not as smart but a lot more normal.” He was accepted the next day.

Early Cryopreservation Efforts

Geoffrey P. Herzig, MD

increase the cure rate of leukemia and lymphoma patients. His friend and colleague, Robert Peter Gale, MD, PhD, who has contributed greatly to basic science and clinical research in bone marrow transplantation, commented, “If you’re a young physician who does bone marrow transplants or treats people with leukemia, you may not realize how much you and your patients owe to Geoff Herzig.” Dr. Herzig was born on December 6, 1941, the day before Japan launched its infamous strike on Pearl Harbor, signaling the beginning of World War II. He and his brother Roger had an itinerant childhood, growing up in Cincinnati, Cleveland, and Georgia. Dr. Herzig attended the University of Cincinnati, where he graduated with honors in chemistry. He then pursued a career in medicine at the Case Western Reserve University School of Medicine in Cleveland. Roger, several years younger, would

After receiving his medical degree, Dr. Herzig did his internship and residency at Albert Einstein College of Medicine in New York. Following his residency, he trained in hematology and oncology at the National Cancer Institute and later at Washington University in St. Louis, where he joined the faculty. While at Washington University, he further developed his concept of using high doses of anticancer drugs in leukemia, whose dose-limiting toxicity was bone marrow suppression, which he could overcome with an autologous transplant. However, the bone marrow cells needed to be cryopreserved at an appropriate time before the side effects of multiple cycles of chemotherapy. To accomplish this, the ever-inventive and extremely handy Dr. Herzig built his own cryopreservation device. Gordon L. Phillips, MD, Dr. Herzig’s mentee, colleague, and friend added some clarity to these early efforts in cryopreservation. “Geoff did not invent cryopreservation of bone marrow, but he worked diligently to perfect the process at a time well before computerized, rate-controlled

freezing. He also created the ‘software’ (long before this word was widely used), hand-calibrating the freezing curve and putting some of the machinery in one of his old cigar boxes,” he recounted. “One of my most enduring memories is of Geoff working late in the lab, refining the ‘software,’ smoking a cigar, and cursing (mildly and softly) at his slow progress. Finally, we ‘perfected’ it—meaning it was usable—but it was very labor-intensive and nerve-wracking as Geoff and I froze our first marrows together,” Dr. Phillips continued.

row Transplant Program. In 1991, Dr. Herzog, along with others including Dr. Bloomfield, joined Roswell Park Cancer Institute in Buffalo, NY, to concentrate on clinical trials in acute leukemia, particularly his special interest, acute myeloid leukemia (AML). When Dr. Herzig was at Roswell Park, he worked closely with Dr. Bloomfield to define the predictive role of cytogenetics and molecular abnormalities in predicting AML therapy outcomes. He was also an important contributor to evolving concepts in how to best treat Hodgkin lym-

If you’re a young physician who does bone marrow transplants or treats people with leukemia, you may not realize how much you and your patients owe to Geoff Herzig. —Robert Peter Gale, MD, PhD

His associates, Dr. Gale and renowned leukemia expert Clara D. Bloomfield, MD, recalled a 1973 study conducted by Dr. Herzig in which he described attempts to rescue Rhesus monkeys with early acute graft-vs-host disease by destroying the graft and infusing frozen autologous bone marrow. His work provided insights for future work in preventing fatal graft-vshost disease.

Transplant Program Director In 1975, Dr. Herzig founded the adult bone marrow transplant program at Barnes Hospital, one of the earliest programs of its type in the country. And in 1980 he was named first Director of Washington University’s Bone Mar-

 In Memoriam

Donald L. Morton, MD 1935 – 2014

Geoffrey P. Herzig, MD 1941 – 2013 

phoma, including novel drug regimens and autologous transplants. After a 20-year marriage, Dr. Herzig lived as a bachelor, which, as colleagues pointed out, suited his quirky, introspective personality. He was an avid sailor, keeping a boat in New York Harbor. A man of interesting contradictions, he could be a very demanding mentor, but hundreds of mentees remember an underlying gentleness and random acts of kindness. He is survived by his son Andrew, his grandchildren, and his brother Roger, who is a Professor of Hematology at the University of Louisville and the Director of the University’s Blood and Bone Marrow Program. n

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The ASCO Post | FEBRUARY 15, 2014

Errata

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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.

Corrections to Note

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).]

n the January 15, 2014, issue of The ASCO Post, three errors occurred. These errors have since been corrected and revised versions of the articles may be viewed online at ASCOPost.com or via the QR code here. The errors were as follows below.

Trastuzumab Dosing In the article “HER2-Positive Breast Cancer Patients With Small Tumors Benefit From Low-Toxicity Regimen,” dosing information provided for trastuzumab (Herceptin) in regard to a more tolerable regimen was incorrectly reported on page 33. The sentence should have read as follows below; revised text is underlined: “Patients received only paclitaxel at 80 mg/m2 weekly plus trastuzumab weekly at 2 mg/kg for 12 weeks, followed by 9 months of trastuzumab every 3 weeks at 6 mg/kg alone.”

Mistaken Identity In the article “Adjuvant Bisphosphonates in Early Breast Cancer: PracticeChanging Findings?” there was an incorrectly identified photograph of the lead study author, breast cancer expert

Robert Coleman, MD

Robert Coleman, MD, of the University of Sheffield, United Kingdom. The published photo was actually one of Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center. A photograph of Dr. Coleman, the study author from the United Kingdom, is shown here.

Pioneers in Oncology In the article “With the Goal of Curing Cancer, Ezra M. Greenspan, MD, Helped Usher in the Modern Era of Chemotherapy,” the final sentence of the article was incorrect. It should have read as follows: Dr. Ezra M. Greenspan and his wife, Ann, had three children— Karen, Ellen, and David. The editorial staff regret these errors and apologize to the individuals mentioned in the respective stories as well as to readers of The ASCO Post. n

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).]

Winter 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

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.

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).]

In combination with IV 5-FU–based chemotherapy in first- or second-line MCRC or fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival Avastin is the only FDA-approved biologic proven to increase OS in 3 large Phase III trials in first- and second-line MCRC

4.7 4.7

2.2 2.2

months months months

months months

Median OS Median MedianOS OS improvement* improvement* improvement*

Median MedianOS OS improvement improvement† †

1.4 1.4 months months

months

Median MedianOS OS OS ‡‡ ‡ improvement improvement improvement

First-line Study 2107:

Second-line Study E3200:

The TML study§:

A double-blind, controlled clinical trial in patients with previously untreated MCRC1,2

An open-label, controlled clinical trial in Avastin-naive MCRC patients1

An open-label, controlled clinical trial in patients who progressed on an Avastincontaining regimen1,3

*20.3 months with Avastin plus IFL (n=402) vs 15.6 months with placebo plus IFL (n=411) (HR=0.66 [95% CI, 0.54–0.81], P<0.001).1,4 13.0 months with Avastin plus FOLFOX4 (n=286) vs 10.8 months with FOLFOX4 alone (n=291) (HR=0.75 [95% CI, 0.63–0.89], P=0.001).1,4 ‡ 11.2 months with Avastin plus fluoropyrimidine-based chemotherapy|| (n=409) vs 9.8 months with fluoropyrimidine-based chemotherapy|| alone (n=411) (HR=0.81 [95% CI, 0.69–0.94], P=0.0057).1 § TML=Treatment through Multiple Lines (first and second line). || Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin → irinotecan or irinotecan → oxaliplatin.1 †

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; OS=overall survival; IFL=5-FU/leucovorin (LV)/irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indications

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 fluoropyrimidineoxaliplatin-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

AVA0001557002

Printed in USA.

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 — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

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 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.

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2013. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14:29-37. 4. Data on file. Genentech, Inc.

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