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

European Cancer Congress 2013

Ipilimumab Conveys Long-Term Survival in Pooled Analysis of Metastatic Melanoma Patients

Standardizing the Interpretation of PET Scans: An INR Equivalent

By Caroline Helwick

n the treatment of metastatic or locally advanced unresectable melanoma, the anti–CTLA-4 monoclonal antibody ipilimumab (Yervoy) conveys long-term survival benefits, with some patients alive out to 10 years, according to the largest survival analysis of the immunomodulating agent, presented at the 2013 European Cancer Congress by Stephen F. Hodi, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute, Boston.1 “The observed ipilimumab overall survival curve demonstrated greater durability of survival, relative to historical data in the pre-BRAF inhibitor era,” he said. “This analysis adds to the evidence supporting a durable, long-term survival effect of ipilimumab in patients with advanced melanoma.”

Study Details The pooled analysis included 1,861 patients from 12 prospective and retrospective trials, and an addi-

tional 2,985 patients who were treated with ipilimumab outside of a clinical trial in the expanded access program. The findings are the most precise estimate yet of the benefit of ipilimumab, Dr. Hodi said. The analysis of the 1,861 patients in trial regisStephen F. Hodi, MD tries found median overall survival to be 11.4 months, with 254 patients (22%) alive 3 years after initiating treatment with ipilimumab. Median overall survival for the whole population, including the 2,985 patients in the expanded access program, was 9.5 months, with 3-year survival in 21% of patients. Dr. Hodi attributed the slightly shorter survival time in this group to limited data and to the possibility that this was a sicker population. continued on page 4

Health-Care Policy

IOM Report Illuminates U.S. Cancer Care Crisis and Offers Framework for Change

ASCOPost.com

By Matthew Lunning, DO, and James O. Armitage, MD

ince its introduction, the positron-emission tomography (PET) scan has shown great potential to improve our ability to care for patients with lymphoma. By demonstrating which masses seen on a computed tomography (CT) scan represent viable tumor, and by identifying viable tumor in places that were not seen on the CT scan, PET scans offer a major advance. However, PET scanning is complicated. A wide variety of factors—including time from injection to scan, the patient’s blood glucose, the method of calculating the area of interest for standardized uptake value (SUV) calculations, the method of interpretation (ie, visual/Gestalt interpretation vs basing the continued on page 52

Dr. Lunning is Assistant Professor, and Dr. Armitage is Professor, Department of Internal Medicine, and Joe Shapiro Distinguished Chair of Oncology, University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

By Jo Cavallo

n September, the Institute of Medicine (IOM) of the National Academies issued its report, Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis,1 published more than a decade after its first study on the quality of cancer care in the United States. The authors of the new publication acknowledged that the “barriers to achieving excellent care for all cancer patients remain daunting,” and declared that the current cancer delivery system is in crisis.

New Challenges

The study authors agreed that much has been accomplished in the 14 years since the IOM’s previous report, Ensuring Quality Cancer Care,2 including increased screening, more precise diagnostics and surgical techniques, and the development of targeted molecular therapy. However, those advances, plus an aging population, rising cancer incidence, projected workforce shortages and soaring medical costs are also helping drive the current crisis—and potentially an even more calamitous one if nothing is done. Cancer care needs to be “The extreme chaltailored to every patient’s needs, lenges that we face now are different from and communication is central the ones we faced in to that effort. the late 1990s,” said —Patricia A. Ganz, MD Patricia A. Ganz, MD, Chair of the 17-member

MORE IN THIS ISSUE Oncology Meetings Coverage European Cancer Congress �� 3-6, 11, 13 World Conference on Lung Cancer 36, 67 Leonard B. Saltz, MD, on Colon Cancer �� 20 Fadlo R. Khuri, MD, on Molecular Targeted Therapy in Lung Cancer �� 35 Inside the Black Box: A Conversation with FDA’s Office of Hematology & Oncology Products �� 49 Direct From ASCO �� 69-71 Richard J. Boxer, MD, FACS, on Choosing Wisely �� 145

continued on page 54

November Is Lung and Pancreatic Cancers Awareness Month

A Harborside Press® Publication

The ASCO Post | NOVEMBER 15, 2013

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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

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Associate Editors

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Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

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

Philip D. Bonomi, MD Rush University Medical Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Michael P. Link, MD Stanford University Medical Center

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

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Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

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

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

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

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John Cox, DO Texas Oncology

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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.

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Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

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

ASCOPost.com | NOVEMBER 15, 2013

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European Cancer Congress Breast Cancer

Strong Showing for Ado-Trastuzumab Emtansine in Advanced HER2-Positive Heavily Pretreated Breast Cancer By Alice Goodman

esults of the phase III TH3RESA trial show that the antibodyconjugate ado-trastuzumab emtansine (Kadcyla), formerly known as T-DM1, extends progression-free survival in women with advanced HER2-positive breast cancer that progressed on two or more previous HER2-directed therapies including trastuzumab (Herceptin) and lapatinib (Tykerb). The findings were presented at the European Cancer Congress 2013 in Amsterdam.1

Building on EMILIA Trial These results build on those of the EMILIA trial, which showed that adotrastuzumab emtansine extended progression-free survival compared with capecitabine/lapatinib in HER2-positive advanced breast cancer in women previously treated with trastuzumab and a taxane. Patients in TH3RESA were more heavily pretreated than those in EMILIA. “In TH3RESA, [ado-trastuzumab emtansine] demonstrated improved

the lead author of the late-breaking presentation, Hans Wildiers, MD, PhD, of University Hospitals Leuven in Leuven, Belgium. He added that ado-trastuzumab emtansine should become the new standard of care for second-line treatment. “Once HER2-positive breast cancer recurs and metastasizes, there are few treatment options that show any clear benefit for women who have probably undergone several previous treatments for the disease. These results confirm and extend the usefulness of [adotrastuzumab emtansine] for the treatment of women with advanced HER2positive disease. This is good news for these women,” said Cornelis van de Velde, MD, current President of the European Cancer Organization (ECCO) and moderator of a press conference where these findings were discussed. Ado-trastuzumab emtansine is an antibody-drug conjugate currently FDA-approved for metastatic breast cancer previously treated with a taxane and trastuzumab.

EXPERT POINT OF VIEW

ormal discussant Clifford Hudis, MD, ASCO President and Chief of the Breast Cancer Service at Memorial Sloan-Kettering Cancer Center in New York, commented that the findings were not surprising. “The results of TH3RESA nicely reflect the EMILIA trial and are consistent with those of anti-HER2 therapies. These antibody-based therapies have revolutionized the treatment of a subset of breast cancer patients.” Clifford Hudis, MD He said that ado-trastuzumab emtansine should be considered in HER2-positive disease as second-, third- or fourth-line treatment. Remaining issues are the optimal sequencing of HER2-directed therapies and the best role for ado-trastuzumab emtansine, he added. He also said that there might be biomarkers (not yet identified) for subsets of patients with a preferential response to ado-trastuzumab emtansine. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

Wildiers said this difference was both statistically and clinically significant. A subgroup analysis showed a con-

TH3RESA Trial

Hans Wildiers, MD, PhD

safety and efficacy compared with the physician’s choice of chemotherapy. [Ado-trastuzumab emtansine] achieved a significant improvement in progression-free survival, and the effect was clear and consistent across subgroups. These data affirm the results of EMILIA, demonstrating a consistent progression-free survival benefit of [ado-trastuzumab emtansine] in patients with previously treated HER2positive advanced breast cancer,” said

The study included 602 patients with advanced breast cancer previously treated with at least two previous HER2-directed therapies. Patients were randomly assigned in a 2:1 ratio to adotrastuzumab emtansine or physician’s choice of chemotherapy (83% received trastuzumab-based regimens and 17% received chemotherapy). Treatment was continued until disease progression, when patients could remain on or cross over to ado-trastuzumab emtansine. Final progression-free survival results were as follows: median progression-free survival of 6.2 months for the ado-trastuzumab emtansine–treated group vs 3.3 months in the control arm, a highly significant difference in favor of ado-trastuzumab emtansine, nearly doubling progression-free survival compared with controls (P < .0001). Dr.

Ado-Trastuzumab Emtansine in Metastatic Breast Cancer ■■ Ado-trastuzumab emtansine extended progression-free survival in

advanced, heavily pretreated HER2-positive breast cancer, compared with chemotherapy.

■■ These results are similar to those of the EMILIA trial, which was conducted in

less heavily pretreated patients with HER2-positive metastatic breast cancer.

Cornelis van de Velde, MD

sistent near-doubling of progressionfree survival with ado-trastuzumab emtansine regardless of age, geographic area, race, performance status, tumor characteristics, and visceral disease. The first interim analysis of overall survival showed median survival of 14.9 months in the control arm; median overall survival was not yet reached in the ado-trastuzumab emtansine arm at the time of analysis. Although this suggests that there may be a survival advantage for ado-trastuzumab emtansine, long-term confirmation is needed. Final survival results are expected in 2015.

Reassuring Safety Profile The safety of ado-trastuzumab emtansine was reassuring and similar to what was reported in the EMILIA trial. Adverse events of grade 3 or higher were more frequent in the control arm:

43.5% vs 32.3% in the ado-trastuzumab emtansine arm. Adverse events of any grade were reported by 94% of those who received ado-trastuzumab emtansine vs 89% in the control arm. Adverse events leading to discontinuation of therapy occurred in 6.7% of the ado-trastuzumab emtansine group vs 10.9% of controls. The rate of cardiac events was low in both arms: left-ventricular ejection fraction < 50 was reported in 1.5% and 1.1%, respectively. Lower rates of diarrhea, neutropenia, and febrile neutropenia were reported in the ado-trastuzumab emtansine arm, but a slight increase was observed in severe thrombocytopenia (4.4% vs 1.8%, respectively) and hemorrhage (2.2% vs 0.5%). According to Dr. Wildiers, an ongoing phase III trial is evaluating use of ado-trastuzumab emtansine as first-line therapy in advanced HER2positive breast cancer, and results are expected next year. The benefit of treatment with ado-trastuzumab emtansine after disease progression will also be studied. n Disclosure: Dr. Wildiers has received lecture fees from Roche. Dr. van de Velde reported no potential conflicts of interest.

Reference 1. Wildiers H, Kim SB, GonzalezMartin A, et al: T-DM1 for HER2-positive metastatic breast cancer. 2013 European Cancer Congress. Abstract 15. Presented September 28, 2013.

The ASCO Post | NOVEMBER 15, 2013

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European Cancer Congress Gynecologic Oncology

Cediranib Achieves ‘Groundbreaking’ Results in Relapsed Ovarian Cancer By Alice Goodman

he investigational oral vascular endothelial growth factor (VEGF) inhibitor cediranib extended progression-free survival when given with platinum-based chemotherapy and improved overall survival when given as maintenance therapy in patients with recurrent ovarian cancer. Experts are hopeful that these encouraging results of the ICON6 trial will trigger a resurrection for development of this agent. Cediranib plus platinum-based chemotherapy followed by maintenance cediranib prolonged progression-free survival by 3.2 months and overall survival by 2.7 months. “These are groundbreaking data. This is the first trial to demonstrate a significant improvement in progression-free survival and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer,” stated lead

Ipilimumab in Melanoma continued from page 1

In both groups, the benefit of the drug appeared to plateau after about 3 years. Beyond 7 years, no deaths were reported, and median 7-year overall survival was 17%. The longest recorded survival was 9.9 years. This survival plateau was observed regardless of dose (3 or 10 mg/kg), previous treatment, or the continued use of ipilimumab as maintenance, he said. Treatment-naive patients had a me-

Jonathan Ledermann, BSc, MD, FRCP

author Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology at the UCL Cancer Institute, University College London. He presented the results at a Presidential Session during the 2013 European Cancer Congress in Amsterdam.1

Development Discontinued At a press conference, Dr. Ledermann explained that AstraZen-

sor of Surgical Oncology at Leiden University Medical Center, Leiden, The Netherlands, who was present at the press conference.

Study Details ICON6 is the first trial to investigate an oral VEGF receptor tyrosine kinase inhibitor combined with chemotherapy and given as maintenance in recurrent ovarian cancer. The study had a complex design. Ovarian cancer patients (N = 456) with a relapse-free interval greater than 6 months following first-line chemotherapy were randomly assigned to platinum-based chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus cediranib followed by placebo maintenance, or chemotherapy plus cediranib followed by cediranib maintenance. Treatment was continued until disease progression. continued on page 5

“Around the inflexion point of 3 years, there seems to be a flattening of the tail of the curve,” Dr. Hodi noted. “Going forward up to 10 years, with lots of censoring, we see a group of patients maintaining a survival advantage long term.”

■■ In an analysis of 1,861 patients treated in 12 phase II and III trials, median

Metastatic Melanoma as Chronic Disease?

■■ In both analyses, a plateau effect emerged at 3 years, and patients who

Alexander Eggermont, MD, General Director of the Institut Gustave Roussy Comprehensive Cancer Center in France, who is Past President of the European Cancer Organization,

This pooled analysis clearly demonstrates that ipilimumab can lead to long-lasting tumor control in metastatic melanoma patients. —Alexander Eggermont, MD

dian overall survival of 13.5 months, vs 10.7 months for previously treated patients, most of whom did not receive a BRAF inhibitor. Three-year survival rates were 26% and 20%, respectively.

eca had discontinued development of cediranib after disappointing phase III results in colorectal cancer, lung cancer, and glioblastoma. The company’s cediranib team was not at the meeting, but a spokesperson for the company subsequently indicated that the results of this study would be reviewed in more detail and a decision about the possible resurrection of cediranib would be made. Thus, it remains unclear as to whether cediranib will re-enter development for U.S. Food and Drug Administration (FDA) approval in ovarian cancer. “These results are important for women with recurrent ovarian cancer. These patients have few treatment options available that can make a significant difference to progression and overall survival,” said European CanCer Organisation (ECCO) President Cornelis van der Velde, MD, Profes-

commented on the findings. “This pooled analysis clearly demonstrates that ipilimumab can lead to long-lasting tumor control in metastatic melanoma patients. With a response rate

Update on Ipilimumab in Melanoma overall survival was 11.4 months and the 3-year overall survival rate was 22%.

■■ In the 5-year survival analysis of the phase III trial of ipilimumab plus

dacarbazine, 5-year survival was 18.2% with iplimumab/dacarbazine vs 8.8% with dacarbazine alone. survived to this point were likely to be alive at 5 and 7 years.

of only 10% to 15%, one can achieve more than 3 to 10 years of survival in 17% to 25% of patients who have received only a few doses of ipilimumab. Thus, patients apparently can keep residual tumors under control for a long time when the immune system is properly ‘reset,’ and the concept of ‘clinical cures’ becomes a reality.” Dr. Eggermont and Dr. Hodi agreed that when novel antibodies targeting the programmed death 1 protein and its ligand (anti–PD-1/ PD-L1) become available, metastatic melanoma could become a chronic illness and potentially “curable” in some patients. “A few years ago, I could never imagine using the ‘C’ word, or see patients living long term,” Dr. Hodi commented. “What we are showing

is a great paradigm shift. At least we are turning this disease into a chronic illness. Possibly, in a subset [of patients], we are beginning to consider that this could be a cure. I remain optimistically conservative on that point, but we are headed in the right direction.” n

Disclosure: Dr. Eggermont participates in scientific advisory boards for BristolMyers Squibb, MSD, GlaxoSmithKline, and MedImmune.

Reference 1. Schadendorf D, Hodi FS, Robert C, et al: Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. 2013 European Cancer Congress. Abstract LBA24. Presented September 28, 2013.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 5

European Cancer Congress Cediranib in Ovarian Cancer continued from page 4

Median progression-free survival was 8.7 months in the chemotherapy/ placebo comparator arm (no cediranib) and 11.1 months in the cediranib-maintenance arm (P = .00001). A restricted means analysis showed a 3.2-month difference favoring cediranib (9.4 vs 12.5 months). Dr. Ledermann clarified the rationale for a restricted means analysis of study results. “The hazard ratio is not constant over time. Although you can undertake a standard log-rank analysis, the restricted means analysis takes into account the changing proportionality of the two curves over time,” he explained. A secondary restrictive means analysis compared the arm receiving chemotherapy/cediranib plus placebo maintenace vs the arm receiving chemotherapy/cedi-

ranib plus cediranib maintenance. This analysis showed a 1.3-month difference in progression-free survival favoring cediranib maintenance. The log-rank analysis showed a trend toward improved diseasefree survival, with some benefit from adding cediranib to chemotherapy and a greater benefit from continuing cediranib as maintenance. “The study provides strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy,” Dr. Ledermann said.

Other Findings Median overall survival was 20.3 months in the chemotherapy-alone arm and 26.3 months in the cediranib maintenance arm (P = .042). In a restricted means analysis, overall survival was 17.6 and 20.3 months, respectively.

Cediranib in Ovarian Cancer ■■ Cediranib, an oral VEGF inhibitor, prolonged survival in patients who had relapsed after first-line chemotherapy for ovarian cancer.

■■ These encouraging results were achieved with cediranib given concurrently with platinum-based chemotherapy and then as maintenance therapy.

■■ Phase III studies of cediranib in other cancer types have been disappointing, leading to the decision to stop development; the manufacturer may be reconsidering that decision after these results.

EXPERT POINT OF VIEW

ress conference moderator Cora N. Sternberg, MD, Chief of Medical Oncology at San Camillo and Forlanini Hospitals, Rome, called the 2- to 3-month improvement in overall survival “worthwhile, and clinically meaningful.” She said this should be viewed in the context of manageable toxicity. “Cediranib is a tyrosine kinase inhibitor that has a different mechanism of action from bevacizumab [Avastin]. I can envision using cediranib in a patient who becomes resistant to bevacizumab,” she comCora N. Sternberg, MD mented. “Cediranib is not a licensed drug, and won’t be available unless the manufacturer decides to continue with its development. With a positive study like this, AstraZeneca may rethink the situation,” she said. n Disclosure: Dr. Sternberg reported no potential conflicts of interest.

Adverse events that were significantly more frequent in the maintenance arm were hypertension, diarrhea, hypothyroidism, hoarseness, hemorrhage, proteinuria, and fatigue. Most of these were manageable with dose reductions or interruptions in therapy. The addition of cediranib did not compromise the ability to undergo chemotherapy; around 80% of patients completed the full six cycles, and most patients stayed on maintenance cediranib until disease progression, Dr. Ledermann told listeners.

“These results suggest cediranib will have a role in the treatment of recurrent ovarian cancer,” Dr. Ledermann said. n

Disclosure: Dr. Ledermann received grant support from AstraZeneca for this trial. Most of the funding was from Cancer Research UK.

Reference 1. Ledermann JA, Perren TJ, Raja FA, et al: Randomized double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum-sensitive ovarian cancer: Results of the ICON6 trial. European Cancer Congress. Abstract 10. Presented September 30, 2013. Gynecologic Oncology

Trebananib Improves Progression-Free Survival in Recurrent Ovarian Cancer By Alice Goodman

rebananib, an investigational antiangiogenesis inhibitor with a different mechanism of action than

Bradley J. Monk, MD, FACOG, FACS

bevacizumab (Avastin), significantly improved progression-free survival in recurrent platinum-resistant and partially platinum-sensitive ovarian cancer in the phase III TRINOVA-1 trial. The addition of trebananib to paclitaxel prolonged the time to disease progression or death by 52% compared with paclitaxel plus placebo (P < .001),

said Bradley J. Monk, MD, FACOG, FACS, of Creighton University School of Medicine and The University of Arizona Cancer Center, Phoenix, at the recent European Cancer Congress in Amsterdam.1 “Angiogenesis is a valid target in ovarian cancer. A long list of studies shows that antiangiogenesis agents can prolong progression-free survival in the platinum-sensitive space. However, no increase in overall survival has been seen with this approach,” he said. Anti–vascular endothelial growth

factor (VEGF) therapy with bevacizumab and pazopanib (Votrient) “creates a constellation of adverse events,” Dr. Monk continued. “The idea of the TRINOVA series of clinical trials is to target non-VEGF angiogenesis factors—angiopoeitin-1 and angiopoetin-2—with trebananib and determine efficacy and side effects with this non-VEGF approach,” he explained. Previous studies had suggested that inhibition of angiopoietin-1 and -2 with trebananib can delay progression of tumors or shrink them, he noted.

TRINOVA-1: Trebananib in Ovarian Cancer ■■ A non–VEGF inhibitor approach extended progression-free survival in

patients with recurrent epithelial ovarian cancer, and this benefit was seen in all subgroups.

■■ Trebananib, an inhibitor of angiopoeitin-1 and -2, will be studied further in ovarian cancer.

■■ This novel agent does not cause the adverse events associated with VEGF inhibition.

Study Design and Results The phase III TRINOVA-1 trial enrolled 919 women with recurrent epithelial ovararian cancer and randomly assigned them to treatment with trebananib at 15 mg/kg IV every 4 weeks plus weekly paclitaxel or placebo plus weekly paclitaxel. Treatment continued until disease progression, toxicity, or withdrawal of consent. Patients were stratified according to progression-free interval, measurable disease, and geographic region. At baseline, patients had received up to three prior cytotoxic regimens and had a progression-free interval of less than 12 months from the last treatment. About 40% of patients experienced treatment failure on one prior regimen, 40% on two, and 20% on three. “This was a rigorous, closely audited clinical trial, with 919 patients from 179 sites in 32 countries. Today, I will present primary progression-free continued on page 6

The ASCO Post | NOVEMBER 15, 2013

PAGE 6

European Cancer Congress Gynecologic Oncology

Two Trials Explore the Evolving Role of Bevacizumab in Ovarian Cancer By Alice Goodman

he optimal use of bevacizumab (Avastin) in ovarian cancer appears to be in high-risk subgroups and in patients with platinum-resistant ovarian cancer, according to results of two phase III trials presented at the 2013 European Cancer Congress (ECC) in Amsterdam. AURELIA investigated the safety and efficacy of bevacizumab in a range of chemotherapies in patients with platinum-resistant ovarian cancer,1 and ICON7 looked at the effect of bevacizumab on survival in women with newly diagnosed ovarian cancer.2

AURELIA AURELIA met its primary endpoint, significantly improving progression-free survival from 3.4 to 6.7 months with the additional of bevacizumab in patients with platinum-resistant ovarian cancer. Also, bevacizumab improved median overall survival from 13.3 to 16.6 months compared with chemotherapy alone (including paclitaxel, topotecan, and liposomal doxorubicin), but the survival benefit did not reach statistical significance. “No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in

Trebananib in Ovarian Cancer continued from page 5

survival and interim overall survival results, and next year, the final overall survival,” Dr. Monk told listeners. At a median follow-up of 10 months, median progression-free survival was 7.2 months in the trebananib group and 5.4 months for placebo (hazard ratio = 0.66, 95% confidence interval = 0.56–0.76, P < .001). A prespecified subgroup analysis found that trebananib improved progression-free survival in all subgroups. Overall response rate was 38% with trebananib vs 30% with placebo. Dr. Monk noted that most responses were partial.

Adverse Events The rate of adverse events of any grade was similar between the two treatment arms: 96% for trebananib and 97% for placebo, suggesting that trebananib does not increase toxicity when added to paclitaxel. The major toxicity of trebananib was edema, which occurred in 57% vs 26% of the two arms, respectively. Very few grade

platinum-resistant ovarian cancer is typically around 12 months,” said lead author Petronella O. Witteveen, MD, PhD, of University Medical Centre, Utrecht, The Netherlands. “AURELIA is the first phase III study to evaluate the addition of bevacizumab in platinum-resistant disease [defined as progression within 6 months of last platinum-containing therapy],” she added. The study randomly assigned 361 patients to bevacizumab plus investigator’s choice of chemotherapy vs chemotherapy alone and patients were treated until progression, unacceptable toxicity, or consent withdrawal. At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab

monotherapy, but bevacizumab was not continued in the bevacizumab-plus-chemotherapy arm after progression. The two arms were well balanced for demographic and disease characteristics. About 25% had a progression-free interval of less than 3 months. “At baseline, these were very sick patients,” Dr. Witteveen said. Bevacizumab almost doubled progression-free survival from a median of 3.4 months to 6.7 months (P < .001). Median overall survival was 13.3 months with chemotherapy only vs 16.6 months with bevacizumab, a difference that was not statistically s ignificant. The study was limited because it was not powered to detect a statistically sig-

Bevacizumab for High-Risk Ovarian Cancer ■■ The phase III AURELIA trial found a clinically meaningful but not statistically significant 3month survival difference when bevacizumab was given to high-risk patients with platinum-resistant ovarian cancer.

■■ An exploratory analysis suggested that weekly paclitaxel is a better partner for bevacizumab than liposomal doxorubicin or topotecan, but this remains to be established.

■■ The phase III ICON7 trial showed that bevacizumab improved survival by 4.8 months in poor-prognosis patients.

3 or higher adverse events were reported with trebananib. “The adverse event profile of antiangiopoietin therapy is not the same as with VEGF inhibitors,” Dr. Monk said. No increase in VEGF-associated side effects (ie, hypertension, proteinuria, wound healing complica-

and neurotoxicity was more common among trebananib recipients, which appears to be related to a greater number of paclitaxel cycles in that arm, he said.

Other Major Results The interim overall survival analysis showed a difference of approxi-

EXPERT POINT OF VIEW

ormal discussant of the TRINOVA-1 presentation, Antonio Casado, MD, Hospital Universitario San Carlos, Madrid, said that the study showed a clinically meaningful benefit with the addition of trebananib in this pretreated group of patients with recurrent epithelial ovarian cancer. Also, the drug had a good side-effect profile. Moving forward, if future trials of trebananib support these results and the drug is approved, the question will be how to combine it and sequence it with currently available therapies, he noted. “Weekly paclitaxel and trebananib could be an option in patients who show disease progression within 12 months after one to three previous lines of therapy,” Dr. Casado said. n Disclosure: Dr. Casado reported no potential conflicts of interest.

tions, or arterial thrombotic events) was seen with trebananib. Neutropenia and anemia were more common among placebo recipients,

mately 2 months favoring trebananib (19 vs 17.3 months, respectively), but Dr. Monk cautioned that this is with only half (n = 313) of the expected

nificant difference in overall survival, and also due to the planned nonrandomized crossover to bevacizumab in the chemotherapy arm, Dr. Witteveen noted. Seventy-two patients did cross over to bevacizumab and received a median of 4.5 cycles of therapy.

Subgroup Analysis In an exploratory subgroup analysis of overall survival, weekly paclitaxel was the winner when combined with bevacizumab. In the cohort treated with liposomal doxorubicin, median overall survival was 13.7 months in those randomized to bevacizumab plus chemotherapy vs 14.1 months with chemotherapy only. For the topotecan-treated cohort, median progression-free survival was 13.8 vs 13.3 months, respectively. However, in the weekly paclitaxel cohort, median overall survival was 22.4 months for bevacizumab vs 13.2 months in controls, representing a 35% relative improvement favoring bevacizumab. “The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Dr. Witteveen said. continued on page 11

survival events occurring. TRINOVA-1 incorporated patientreported outcomes using three different quality-of-life questionnaires: Functional Assessment of Cancer Therapy– Ovarian (FACT-O), the FACT ovarian cancer subscale (OCS), and the EuroQol Group’s EQ-5D. On these measures, no quality-of-life differences were reported between the two treatment arms. Amgen is moving forward with a full development program for trebananib, Dr. Monk noted. n

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

Reference 1. Monk BJ, Poveda A, Vergote I, et al: A phase III, randomized, doubleblind trial of weekly paclitaxel plus the angiopoeitin 1 and 2 inhibitor, trebananib, or placebo in women with recurrent ovarian cancer: TRINOVA-1. European Cancer Congress. Abstract 41. Presented October 1, 2013.

STRENGTHEN HER DEFENSE

FDA-approved HER2* dimerization inhibitor (HDI) for the first-line treatment of HER2+ metastatic breast cancer (MBC)1,2

Indication

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

Boxed WARNING: Embryo-Fetal Toxicity

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. *HER2 = human epidermal growth factor receptor.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly improve progression-free survival PERJETA-based regimen extended median progression-free survival (PFS) to 18.5 months (from 12.4 months)1 6.1-Month Improvement in Median IRF-assessed PFS1* Placebo + Herceptin + docetaxel

100

PERJETA + Herceptin + docetaxel

HR=0.62† 95% CI [0.51-0.75] P<0.0001

80 70

18.5

PFS (%)

MONTHS

12.4

MONTHS

30 20 10 0

P+H+D Pl+H+D

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk

• At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

IRF = independent review facility; CI = confidence interval; HR = hazard ratio. *At the time of the final PFS analysis, OS was not mature and first interim OS analysis results did not meet the prespecified stopping boundary for statistical significance.1 † Stratified by prior treatment status and geographic region.1 The CLEOPATRA trial was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of patients with HER2+ locally recurrent, unresectable or metastatic breast cancer (HER2+ status was defined as IHC 3+ or FISH amplification ratio ≥2.0 as determined at a central laboratory) (N=808); patients were randomized in a 1:1 ratio to either PERJETA + Herceptin + docetaxel (n=402) or placebo + Herceptin + docetaxel (n=406).1

Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information Left Ventricular Dysfunction

• In the randomized trial, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis

• PERJETA has been associated with infusion and hypersensitivity reactions • On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In the randomized trial, the overall frequency of hypersensitivity reactions/ anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebotreated group

Significantly prolong overall survival 34% reduction in risk of death with PERJETA1 Second Interim Overall Survival (OS) Results1 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR=0.66 95% CI [0.52-0.84] P=0.0008‡

OS (%)

MEDIAN NOT YET REACHED

60 50

37.6

20 10 0

P+H+D PI+H+D

402 406

387 383

371 350

342 324

317 285

25 30 MONTHS 230 143 198 128

• More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at the time of the second interim analysis, thereby indicating that the median OS for this arm has not yet been reached1 • At the time of analysis, there were 113 (28.1%) and 154 (37.9%) deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin + docetaxel arm, respectively1

MONTHS

• Median follow-up was 30 months (1 year following the first interim analysis) for both the PERJETAbased regimen and the placebo + Herceptin + docetaxel arms (Kaplan-Meier estimate)1-3

84 67

33 22

9 4

0 0

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

Patients at risk

OS = overall survival. ‡ The HR and P-value for the second interim analysis of OS crossed the predefined efficacy stopping boundary (HR≤0.739, P≤0.0138).1

• Consistent PFS and OS benefit demonstrated across several HER2+ MBC patient subgroups1,3 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])1 • The incidence of Grade 3-4 hypersensitivity reactions/anaphylaxis was 2% in the PERJETA-treated group and 2.5% in the placebo-treated group according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) (version 3). Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression, defined as 3+ IHC by Dako HercepTest™ or FISH amplification ratio ≥2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC • Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

PER0001010503

Printed in USA.

06/13

Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. April 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 3. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.

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

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

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

Grades 3-4 %

Frequency rate % All Grades %

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

Grades 3-4 %

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

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

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

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

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

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

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European Cancer Congress Bevacizumab in Ovarian Cancer continued from page 6

An updated safety analysis did not reveal any new safety concerns from the previous safety analysis in 2012, she said. The main grade 3 or higher toxicities in the bevacizumab arm were hypertension (7.8%) and proteinuria (2.2%).

ICON7 In the ICON7 trial, the previously reported primary analysis of progressionfree survival demonstrated the benefit of bevacizumab added to standard chemotherapy in newly diagnosed ovarian cancer: 19 vs 17.3 months (P = .0041).3 In the final survival analysis presented at the ECC, median overall survival was 58 months in the study for both arms. However, poor-prognosis patients experienced a 4.8-month prolongation of survival (from 34.5 to 39.3 months) if they received bevacizumab. “The survival benefit in the overall trial of 0.9 months [using a restricted means analysis] is not clinically meaningful. However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit M. Oza, MD, of Princess Margaret Cancer Center, University of Toronto, Canada. The study was conducted at 263 sites around the world and randomly assigned 1,528 women to six cycles of every-3-week carboplatin/paclitaxel vs carboplatin/paclitaxel plus bevacizu mab for five or six cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. One-third of the women were considered high risk (stage III with > 1 cm residual disease,

stage IV, and nondebulked). Patients were prestratified according to stage, extent of debulking, and time of therapy.

Key Findings At a median follow-up of 49 months, progression-free survival was not significantly different between the two arms, similar to the first interim analysis presented previously. Because nonproportional hazards were detected, the final overall survival analysis was conducted using restricted mean survival time, and the difference between the two arms was 0.9 months, which was not statistically or clinically meaningful, Dr. Oza said. In a predefined high-risk subgroup of patients, the overall survival curves for the two arms separated, and the bevacizumab arm did better throughout the study, with a 4.8-month improvement over the control arm. Dr. Oza said this difference was “highly clinically meaningful, with a significant interaction between treatment and survival in high-risk patients.” Bevacizumab showed a significant effect according to stage and amount of residual disease, with a greater impact on higher stage and greater burden of disease, he added. n

Disclosure: Drs. Witteveen and Oza reported no potential conflicts of interest.

References 1. Witteveen P, Lortholary A, Fehm T, et al: Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy with or without bevacizumab for platinum-resistant recurrent ovarian cancer. European Cancer Congress. Abstract 5. Presented September 29, 2013. 2. Oza AM, Perren TJ, Swart AM, et al:

EXPERT POINT OF VIEW

ormal discussant of the AURELIA and ICON7 presentations, Rebecca Kristeleit, MD, University College London Hospital, London, said that a consistent message in both trials was the benefit of bevacizumab (Avastin) in high-risk disease. “Angiogenesis seems to be a particular driver of advanced disease, enabling growth and metastasis in the peritoneal space. The rationale for adding bevacizumab to chemotherapy is to accomplish a twofold normalization of vasculature, to starve the tumor,” she explained.

Specific Considerations ICON7 showed that in the high-risk subgroup, bevacizumab was of benefit. This included women with residual or stage IV disease, and those who had not undergone surgery. But in stage III patients with no residual disease, no benefit was seen with the addition of bevacizumab. “The [progression-free and overall survival differences] are clinically meaningful and statistically significant [in the high-risk patients],” Dr. Kristeleit stated. “There is no survival benefit in any of the other subgroups.” “However, bevacizumab doesn’t improve the cure rate. A remaining question is whether maintenance therapy will improve survival, she said. Turning to AURELIA, she said, “The bottom line is that the [progressionfree survival] doubled in this hard-to-treat ovarian cancer group where there is significant clinical need. The best survival results in the weekly paclitaxel group were seen in an exploratory analysis, and the true benefit of bevacizumab is difficult to tease out.” The study suggests that patients relapsing within 3 months of platinum therapy may not have the same benefit from the addition of bevacizumab, she pointed out.

‘Practice-Changing’ Studies Dr. Kristeleit called AURELIA and ICON7 “practice-changing.” She continued, “Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer. This combination has the most favorable clinical and cost-benefit ratio…. And first-line therapy with bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high-risk ovarian cancer.” n Disclosure: Dr. Kristeleit reported no potential conflicts of interest.

ICON7: Final overall survival results in the GCIG phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. European Cancer Congress.

Abstract 6. Presented September 29, 2013. 3. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011.

Don’t Miss These Important Reports in This Issue of The ASCO Post Ira Byock, MD, on End-of-Life Care see page 76

Eric Lis, MD, on Vertebral Compression Fracture see page 90

Jimmie C. Holland, MD, on Advancing Psychosocial Oncology Care see page 94

Victor G. Vogel, MD, on Breast Cancer Risk see page 96

David Kissane, MD, on The Power of Human Attachment see page 140

Richard J. Boxer, MD, FACS, on Good Care see page 145

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | NOVEMBER 15, 2013

PAGE 12

Announcements

Institute of Medicine Elects New Members, Foreign Associates

he Institute of Medicine (IOM) recently announced the names of 70 new members and 10 foreign associates during its 43rd Annual Meeting. “It is an honor to welcome our highly distinguished colleagues to the Institute of Medicine,” said

IOM President Harvey V. Fineberg. “These individuals have inspired us through their achievements in research, teaching, clinical work, and other contributions to the medical field. Their knowledge and skills will deeply enrich the IOM.”

Diversity of Talent New members are elected by current active members through a selective process that recognizes individuals who have made major contributions to the advancement of the medical sciences, health care, and public health. A diver-

sity of talent among IOM’s membership is assured by the Institute’s charter, which stipulates that at least one-quarter of the membership is selected from outside the health professions, for example, from such fields as the law, engineering, social sciences, and the humanities. With their election, members make a commitment to volunteer their service on IOM committees, boards, and other activities. Projects during the past year include have included studies of the benefits of including physical activity in the school environment, improved delivery of cancer care, the international problem of illegitimate and substandard medications, and more.

2013 Members Newly elected members of the Institute of Medicine are: • Janis L. Abkowitz, MD, University of Washington, Seattle • Frederick R. Appelbaum, MD, Fred Hutchinson Cancer Research Center; Seattle Cancer Care Alliance, Seattle

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Janis L. Abkowitz, MD

Frederick R. Appelbaum, MD

• Katrina Alison Armstrong, MD, Massachusetts General Hospital; Harvard Medical School, Boston • Diana W. Bianchi, MD, Tufts University School of Medicine, Boston • Jeffrey A. Bluestone, PhD, University of California, San Francisco • Charles L. Bosk, PhD, University of Pennsylvania, Philadelphia • Mary Bartlett Bunge, PhD, Miller School of Medicine, University of Miami, Miami continued on page 78

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European Cancer Congress Important News Briefs: New Data Reported in Breast, Renal Cell, Head and Neck, and Lung Cancer By Caroline Helwick and Alice Goodman

he 2013 European Cancer Congress (ECC), held September 27 to October 1 in Amsterdam, was jointly sponsored by the European Society of Medical Oncology, the European Cancer Organization, and the European Society of Radiation Oncology. With the Congress theme being “Reinforcing Multidisciplinarity,” ECC 2013 featured 3,176 scientific abstracts, 121 late-breaking abstracts, and hundreds of lectures and special programs. The ASCO Post has covered key presentations with longer news articles, but here we bring our readers short summaries of other abstracts of interest.

cizumab as first-line therapy also had no impact on overall survival, which was 52 months in each arm, but overall response rates were almost doubled (41% vs 22%; P < .001). “Taking into account the higher toxicity with bevacizumab in addition to endocrine therapy, the overall risk-benefit analysis remains unfavorable. The study of this combination by the [Cancer and Leukemia Group B (CALGB)] should be further informative, said Sibylle Loibl, MD, Associate Professor of Gynecology at the University of Frankfurt, Germany, who presented the study.

Zoledronic Acid in Early Breast Cancer

Dovitinib for Renal Cell Carcinoma

In the phase III NEOZOTAC trial conducted in 247 early breast cancer patients, the addition of bisphosphonates to neoadjuvant chemotherapy (docetaxel, doxorubicin, cyclophosphamide) did not enhance the rates of pathologic complete response or clinical response, reported Ayoub Charehbili, of Leiden University Medical Center in The Netherlands, and colleagues.1 Rates of pathologic complete response were 18% with chemotherapy alone and 18% with chemotherapy plus zoledronic acid. In premenopausal and perimenopausal women, pathologic complete response rates for chemotherapy alone and chemotherapy plus zoledronic acid were 22% and 19%, respectively, and in postmenopausal women, they were 10% and 17%, respectively. While neither of these differences was statistically significant, the investigators felt more research is needed in postmenopausal women. Survival data were not yet mature.

The investigational oral multitargeted tyrosine kinase inhibitor dovitinib had disappointing results as third-line therapy in renal cell carcinoma, failing to meet the primary endpoint of progression-free survival vs sorafenib (Nexavar), according to an interim analysis of an open-label phase III trial.3 Patients enrolled in the trial had shown disease progression despite

Bevacizumab Plus Endocrine Therapy for Advanced Breast Cancer The LEA study failed to demonstrate a statistically significant increase in progression-free survival with the addition of bevacizumab (Avastin) to endocrine therapy as first-line treatment for advanced breast cancer.2 Median progression-free survival was 14.4 months for endocrine therapy alone and 19.3 months for endocrine therapy plus bevacizumab (P = .126) No differences according to subgroups were observed. Adding beva-

Robert J. Motzer, MD

prior vascular endothelial growth factor (VEGF)/mammalian target of rapamycin (mTOR)-targeted therapies. The “positives” of the trial are acceptable safety with dovitinib, and that it is a landmark trial for future third-line studies in renal cell carcinoma. Lead author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, said that more effective drugs are needed for patients whose disease progresses after treatment with VEGF-targeted therapies and mTOR inhibitors. The phase III GOLD trial compared dovitinib vs sorafenib, a drug approved for second-line treatment of renal cell carcinoma. Patients en-

Notable Findings From the European Cancer Congress 2013 ■■ In the phase III NEOZOTAC trial in 247 early breast cancer patients, the addition of bisphosphonates to neoadjuvant chemotherapy failed to enhance pathologic complete response or clinical response rates.

■■ The LEA study failed to demonstrate a statistically significant increase in

progression-free survival with the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer.

■■ The investigational agent dovitinib had disappointing results as third-line therapy in renal cell carcinoma, failing to meet the primary endpoint of progression-free survival vs sorafenib in an open-label phase III trial.

■■ The mTOR inhibitor everolimus showed clinical efficacy for the initial

treatment of advanced papillary renal cell carcinoma, according to phase II results of the RAPTOR trial.

rolled in the trial had metastatic renal cell carcinoma and received one prior VEGF-targeted therapy and one prior mTOR inhibitor. All patients had shown disease progression within 6 months of their last targeted therapy. As of March 2011, 570 patients were enrolled; 284 were randomly assigned to dovitinib and 286 to sorafenib. The interim data were from a cutoff of April 2013. At baseline, about 23% were classified as poor risk according to MSKCC criteria and between 35% and 42% had bone metastasis. Sunitinib (Sutent) was used as prior VEGF therapy in 90% of patients, and everolimus (Afinitor) was the predominant prior mTOR inhibitor (> 85% of patients). At the time of analysis, 495 patients were off study, mainly due to progressive disease. The primary endpoint of progression-free survival by central review was not met. Median progression-free survival was 3.7 months for dovitinib vs 3.6 months for sorafenib, a nonsignificant difference. Median progression-free survival by investigator assessment was 3.9 months for both arms. Subgroup analysis of progression-free survival

showed no significant difference between the two arms. Median overall survival was 11.1 months for dovitinib and 11 months for sorafenib. Nausea, diarrhea, and vomiting were the most common adverse events with dovitinib. Hypertension, hand/foot syndrome, and alopecia were more common in the sorafenib group. Formal discussant of this trial, James Larkin, PhD, FRCP, Consultant Medical Oncologist at The Royal Marsden Hospital, London, said the study confirms that sorafenib is a relevant benchmark for new therapies in this setting. However, predictive markers for response are greatly needed.

Everolimus in Papillary Renal Cell Carcinoma The mTOR inhibitor everolimus showed clinical efficacy for the initial treatment of advanced papillary renal cell carcinoma, according to the phase II results of the RAPTOR trial presented by Bernard J. Escudier, MD, Head of the Immunotherapy Unit at the Institut Gustave Roussy, Villejuif, France.4 RAPTOR is the continued on page 16

Erratum

n the October 15, 2013 issue of The ASCO Post, production instructions were inadvertently placed on an advertisement for Tafinlar® (page 4) and printed in the final version of the advertisement. Harborside Press, publisher of The ASCO Post, regrets this error and accepts full responsibility for its occurrence. The correct version of the Tafinlar® advertisement is printed in this issue of The ASCO Post on pages 14-17. n

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European Cancer Congress Important News Briefs continued from page 13

first prospective study that investigated the impact of a targeted agent, everolimus, in patients with papillary renal cell carcinoma; it is approved for patients who progress after treatment with sunitinib or sorafenib. Papillary carcinomas make up 10% to 15% of

Bernard J. Escudier, MD

renal cell cancers and can develop as individual or multiple tumors, appearing either in the same kidney or in both kidneys. In the open-label study, 92 treatment-naive patients received everolimus 10 mg/day. The 6-month progression-free survival was 58.7% in the per-protocol analysis, and 34.9%

by central review. Progression-free survival was 7.8 months and 3.7 months, respectively. At least half of the patients were alive at 20 months.

Recurrence Score in Rectal Cancer In patients with rectal cancer treated with surgery, the 12-gene Onco-

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European Cancer Congress type DX recurrence score assay may accurately predict risk of recurrence, Marlies S. Reimers, MD, a PhD student in the Department of Surgery at Leiden University in The Netherlands, reported at the meeting.5 The 308 stage II and III patients from the Dutch total mesorectal excision trial had been treated with total

Marlies S. Reimers, MD

mesorectal excision surgery alone, without neoadjuvant or adjuvant treatment. Recurrence score was determined for 297 patients. At a median follow-up of 11 years, recurrence score predicted the risk of recurrence (P = .011), the risk of distant recurrence (P = .030), and rectal cancer–specific survival (P = .007).

The effect of the recurrence score was most prominent in stage II rectal cancer and attenuated with more advanced stages. In stage II patients, the 5-year recurrence risk ranged from 12% in the low recurrence score group to 53% in the high recurrence score group; 5-year rectal cancer–specific mortality ranged from 5% to 37%, respectively. The investigators concluded that the recurrence score may be especially clinically useful in patients with stage II rectal cancer, by identifying high-risk patients who could benefit from adjuvant chemotherapy, and excluding low-risk patients.

Altered Fractionation for Head and Neck Cancer Compared with standard radiation, the use of altered-fractionation radiotherapy increased overall survival in patients with locally advanced head and neck cancers in a meta-analysis presented by Pierre Blanchard, MD, a radiation oncologist from the Institut Gustave Roussy, Villejuif, France.6

Pierre Blanchard, MD

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“The improvement in survival is marked for patients in the hyperfractionated regimen, with an absolute benefit of 8.1% at 5 years,” he reported. Dr. Blanchard and colleagues examined randomized trials comparing standard radiation therapy with altered-fractionation radiotherapy with or without concomitant chemotherapy in patients with local head and neck squamous cell carcinomas. Fractionation was defined as either standard (5 fractions per week for 7 weeks) or altered therapy, which could have been either hyperfractionated (10 fractions per week for 7 weeks resulting in a higher dose); accelerated (same dose given over 6 weeks); or very accelerated (low dose given in about 3 weeks). The researchers collected data from 31 trials representing more than 11,500 patients. After 7 years of follow-up, the higher dose intensity of altered-fractionation radiotherapy improved outcomes. continued on page 18

The ASCO Post | NOVEMBER 15, 2013

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European Cancer Congress Important News Briefs continued from page 17

“The hyperfractionated [regimen] is the most effective in terms of overall survival. Indeed, in this group of trials the risk of death is reduced by 18% by the use of hyperfractionated radiotherapy, with 41% of patients alive at 5 years compared to 33% in the [standard-fractionation radiotherapy] group. While the acute side effects of [altered-fractionation radiotherapy] are increased compared to those experienced by patients on [standard-fractionation radiotherapy], the late side effects are comparable and, overall, side effects

ing growth factor] (TGF)-beta to evade the immune system. Activated T- and B-cells are refractory to TGFbeta inhibition,” explained lead author Giuseppe Giaccone, MD, PhD, Associate Director of Clinical Research at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC (formerly of the National Cancer Institute). The trial was conducted in eight countries at 73 clinical sites and enrolled 532 patients (42 with stage IIIA and 490 with stage IIIB/IV) who had not shown disease progression on front-line therapy. At 4 to 17 weeks following chemotherapy, patients were randomly assigned in a 1:1 ratio to double-blind therapy with the vaccine

Notable Findings From the European Cancer Congress 2013 ■■ In patients with rectal cancer treated with surgery, the 12-gene Oncotype DX recurrence score assay may accurately predict risk of recurrence.

■■ Compared with standard radiation, the use of altered fractionation

radiotherapy increased overall survival in patients with locally advanced head and neck cancers.

■■ An investigational tumor cell vaccine (belagenpumatucel-L) failed to

improve survival vs placebo when used as maintenance therapy in a phase III study of patients with advanced NSCLC.

■■ An analysis of data from two large randomized trials found that the most

efficient use of annual lung cancer CT screening is in people aged 55 to 80 with at least 30 pack-years of smoking and who quit within the past 15 years.

are more than compensated for by the significant increase in survival in the [altered-fractionation radiotherapy] group,” Dr. Blanchard said.

Lung Cancer Vaccine as Maintenance Immunotherapy with an investigational tumor cell vaccine (belagenpumatucel-L [Lucanix]) failed to im-

Giuseppe Giaccone, MD, PhD

prove survival vs placebo when used as maintenance therapy in a phase III study of patients with advanced non– small cell lung cancer (NSCLC) without disease progression (responding or stable disease) after chemotherapy.7 “Most tumors use [transform-

or placebo as maintenance therapy. The vaccine is composed of four different allogeneic NSCLC cell lines genetically modified to block TGFbeta. The cells are irradiated and cryopreserved until the vaccine is used. The vaccine was given as 18 monthly injections followed by two quarterly injections. At 6 months of follow-up, overall survival was 20.3 months in the vaccine arm vs 17 months in the placebo arm, which was much higher than anticipated for placebo. Median overall survival is typically about 10.4 months for patients with stage IV disease given a chemotherapy doublet, Dr. Giaccone said. In this study, there were patients with stage IIIA and IIIB disease who did better, he added. An exploratory subgroup analysis showed that patients enrolled within 12 weeks of chemotherapy had a trend toward improved survival in the vaccine arm. “In several subgroups of patients randomized within 12 weeks, the results were positive enough to warrant another study,” Dr. Giaccone noted.

The rate of serious adverse events was low, with only five patients experiencing one of these events. The most common adverse events were local reactions, including injection site reaction, erythema, induration, rash, and local effects.

Patient Selection for Lung Cancer CT Screening According to a late-breaking abstract, the most efficient use of annual lung cancer computed tomography (CT) screening is in people between the ages of 55 and 80 with at least 30 pack-years of smoking and who quit within 15 years, reported Harry J. de Koning, MD, PhD, Professor of Epidemiology at Erasmus University Medical Center, Rotterdam, The Netherlands.8 Dr. de Koning and colleagues modeled a hypothetical cohort of 100,000 people based on the U.S. National Lung Screening Trial (NLST), which showed a 20% reduction in mortality with CT screening of high-risk populations. “If you go above that strategy, you exceed the harms, with more radiation exposure, more overdiagnosis and overtreatment, and higher cost,” he said. Dr. de Koning and his co-investigators used five different models to estimate the harms and benefits in the study population assuming they were born in 1950 and followed from ages 45 to 90. They evaluated 576 possible scenarios and reported on the 26 considered most efficient using the NLST scenario. In the study, triennial screening programs reduced lung cancer mortality by 5% to 6%, biennial screening programs by 7% to 10%, and annual screening programs by 11% to 21%. If screening were limited to the group they identified (aged 55–80; 30 packyears; quitting within the past 15 years), 19.3% of the cohort would be screened at least once; 287,000 CT screens would be obtained; and 1971 screen-detected cases would be found, 50% of them detected at an early and treatable stage. This would lead to a 14% reduction in lung cancer mortality (avoiding 520 deaths), and 5,500 life-years gained. The conclusion was that 550 screens are needed to avoid one death. These benefits must be balanced against extending screening to groups with less stringent criteria, which would result in 330,000 CT exams, 66,000 false-positive results, and an estimated overdiagnosis rate of 4% (190

lung cancers), as well as 24 deaths due to radiation exposure. n

Disclosure: Drs. Loibl, Charehbili, Larkin, and Reimers reported no potential conflicts of interest. Dr. Escudier has served in a consulting or advisory role for AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Dr. Motzer has had a consultant or advisory role with Pfizer and has received research funding from Astellas Pharma, AVEO, GlaxoSmithKline, Novartis, and Pfizer.

References 1. Charehbili A, Van de Ven S, Liefers GJ, et al: Clinical and pathological response after neoadjuvant chemotherapy with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer. 2013 European Cancer Congress. Abstract 1858. Presented September 29, 2013. 2. Loibl S, De la Haba J, von Minckwitz G, et al: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer. Final analysis of the LEA study. 2013 European Cancer Congress. Abstract 1851. Presented September 28, 2013. 3. Motzer R, Szczylik C, Vogelzang NJ, et al: Phase 3 trial of dovitinib vs sorafenib in patients with metastatic renal cell carcinoma after 1 prior VEGFpathway targeted and 1 prior mTOR inhibitor therapy. 2013 European Cancer Congress. Presented September 29, 2013. Abstract LBA 34. 4. Escudier B, Bracarda S, Maroto JP, et al: Open-label phase II trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. 2013 European Cancer Congress. Abstract 2706. Presented September 29, 2013. 5. Reimers MS, Kuppen PJK, Lee M, et al: Validation of the 12-gene colon cancer recurrence score assay as a predictor of recurrence risk in stage II and III rectal cancer patients. 2013 European Cancer Congress. Abstract LBA1. Presented September 28, 2012. 6. Blanchard P, Lacas B, Bourhis J, et al: Meta-analysis of radiotherapy in head and neck carcinomas: An update. 2013 European Cancer Congress. Abstract LBA26. Presented September 28, 2013. 7. Giaccone G, Bazhenova L, Nemunaitis J, et al: A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer. 2013 European Cancer Congress. Abstract LBA 2. Presented September 28, 2013. 8. De Koning HJ, Plevritis SK, Mexa R, et al: Benefits and harms of computed lung cancer screening programs for high risk populations—using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide. 2013 European Cancer Congress. Abstract 14. Presented September 30, 2013.

Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

To learn more about this study, please visit www.ClinicalTrials.gov.

The ASCO Post | NOVEMBER 15, 2013

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JCO Spotlight Gastrointestinal Oncology

Impact of Deficient DNA Mismatch Repair on Disease-Free Survival in Stage III Colon Cancer By Matthew Stenger

n an analysis reported in the Journal of Clinical Oncology, Frank A. Sinicrope, MD, of the Mayo Clinic and North Central Cancer Treatment Group (NCCTG), and colleagues investigated the association of deficient

(NCCTG) N0147 trial. Prospectively collected tumors were analyzed for DNA mismatch repair protein expression and mutations in BRAF V600E (exon 15) and KRAS (codons 12 and 13), and the association of biomark-

study initiation, the trial was amended to restrict the population to those patients with wild-type KRAS tumors. BRAF V600E and KRAS mutations were found to be mutually exclusive. The number of cancers located in

[The investigators] found that patients with proximal mismatch repair--deficient tumors had favorable outcome, whereas those with distal or N2 mismatch repair--deficient tumors had poor outcome.

Frank A. Sinicrope, MD

DNA mismatch repair with prognosis in patients with stage III colon cancer treated with adjuvant FOLFOX (fluorouracil [5-FU], leucovorin, and oxaliplatin) chemotherapy.1 They found that patients with proximal mismatch repair–deficient tumors had favorable outcome, whereas those with distal or N2 mismatch repair–deficient tumors had poor outcome.

Study Details The study population consisted of resected, stage III colon carcinomas from 2,686 patients randomly assigned to FOLFOX alone or combined with the anti-EGFR antibody with or without cetuximab (Erbitux) in the North Central Cancer Treatment Group

ers with disease-free survival was determined. In this trial, the addition of cetuximab to FOLFOX failed to improve disease-free survival overall or in patients with wild-type KRAS tumors. In the full study cohort, deficient DNA mismatch repair was detected in 314 (12%) of 2,580 tumors, and mutations in BRAF V600E and KRAS were detected in 14% and 28% of tumors, respectively. The study required centralized KRAS analysis, and after

the proximal or distal colon was equal in the study population. Patients with proximal vs distal tumors were significantly more likely to be older (median age, 61 vs 56 years, P < .001), female (50% vs 45%, P = .02), and to have tumors with high-grade histology (33% vs 18%, P < .001) and higher T stage (T1 or 2 in 12% vs 18%, T3 in 75% vs 72%, and T4 in 13% vs 10%, P < .001 for trend). Proximal vs distal cancers were significantly more likely to ex-

Mismatch Repair Deficiency in Colon Cancer ■■ The prognostic impact of mismatch repair depended on tumor site. ■■ Among mismatch repair-deficient cancers, proximal tumors had favorable outcome and distal or N2 tumors had poor outcome. ■■ BRAF and KRAS mutations were independently associated with adverse outcome.

hibit deficient DNA mismatch repair deficiency (21% vs 3%, P < .001) and to have somatic mutations in BRAF V600E (23% vs 4%, P < .001) or KRAS (33% vs 23%, P < .001).

Mismatch Repair and Key Mutations Deficient DNA mismatch repair (vs proficient mismatch repair) was significantly associated with older age (median, 62 vs 58 years, P < .001), female sex (59% vs 46%, P < .001), proximal site (88% vs 45%, P < .001), high-grade histology (53% vs 22%, P < .001), and higher T stage (P = .008 for trend). The proportion of patients with N2 vs N1 nodal classification did not differ (40% vs 42%). As with deficient mismatch repair, mutated BRAF V600E was significantly associated with older age, female sex, proximal site, high-grade histology, and higher T stage. In contrast to mismatch repair deficiency, BRAF V600E mutations were significantly more common in N2 vs N1 tumors. KRAS mutations were significantly associated with proximal site, low-grade histology, and N1 stage. Mismatch Repair and Tumor Site Of the tumors with deficient mismatch repair in the NCCTG trial population, 49.3% and 10.6% had BRAF V600E and KRAS mutations, respectively. Deficient vs proficient mismatch repair status was not progcontinued on page 24

In Mismatch Repair–Deficient Colon Cancer, Side Matters By Leonard B. Saltz, MD

n general, we have come to think of mismatch repair–deficient colon cancer as having a more favorable prognosis, being less likely to metastasize to regional nodes or distant sites, and being resistant to fluoropyrimidines. Much of our data, however, come from trials combining stage II and III patients, and treating them predominantly with fluoropyrimidines alone. In their recent manuscript, reviewed in this issue of The ASCO Post,

Dr. Saltz is Chief of the Gastrointestinal Oncology Service in the Department of Medicine at Memorial Sloan-Kettering Cancer Center, New York.

Sinicrope et al evaluated the impact of mismatch repair deficiency and other potential prognostic indicators in the North Central Cancer Treatment Group (NCCTG) N0147 trial, which treated stage III colon cancer patients with FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab (Erbitux). Since cetuximab was not active in this situation, both arms were combined for these molecular analyses. The findings, while instructive, are more complex than expected.

Location and Mutation In the overall analysis, mismatch repair status did not correlate with

prognosis. In a deeper analysis, however, mismatch repair status became prognostic when looked at by the side of the colon in which the tumor arose. Within the right, or proximal colon, mismatch repair–deficient tumors had a more favorable disease-free survival, while in the left-sided, or distal portions of the colon, mismatch repair– deficient tumors not only did not have a better prognosis, but rather, trended strongly toward a worse prognosis than mismatch repair–proficient tumors from the same region. Further complicating matters, the site of tumor was itself independently prognostic, with distal, or left-sided tumors, hav-

ing a better prognosis than proximal, or right-sided, tumors regardless of mismatch repair status. In addition, mutation in either KRAS or BRAF independently conferred a worse disease-free survival prognosis in mismatch repair–proficient tumors. This effect was not seen in mismatch repair–deficient tumors; however, the numbers begin to get small at this point, and the possibility of an interaction cannot be reliably excluded on the basis of these data. The degree of nodal involvement was also independently prognostic in both mismatch repair–proficient continued on page 26

KADCYLA®: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

Indication

KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see the following pages for additional important safety information and brief summary of full prescribing information, including Boxed WARNINGS.

The next era of treatment KADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker1-3 In preclinical studies:

Trastuzumab (monoclonal antibody) Binds to HER2 at subdomain IV to suppress downstream signaling

DM1* (cytotoxic maytansinoid) Inhibits tubulin polymerization to induce cell-cycle arrest and cell death

MCC* (stable linker) Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

• Maintains the HER2 suppression and anticancer activities of trastuzumab1 • Delivers cytotoxic DM1 to target HER2-expressing cells1 — Many normal cells express HER24 — Some cancer cells overexpress up to 200 times more HER2 than normal cells4

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Additional Important Safety Information

Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had Left Ventricular Dysfunction (LVD) trastuzumab permanently discontinued due to infusion-related reactions • Patients treated with KADCYLA are at increased risk of developing (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLArecommended for these patients. In EMILIA, the overall frequency of IRRs treated group and in 3.3% in the comparator group. Permanently in patients treated with KADCYLA was 1.4% discontinue KADCYLA if LVEF has not improved or has declined • KADCYLA treatment should be interrupted in patients with severe further IRR and permanently discontinued in the event of a life-threatening Pregnancy Registry IRR. Patients should be closely monitored for IRR reactions, especially • Advise patients to contact their healthcare provider immediately if during the first infusion they suspect they may be pregnant. Encourage women who may Thrombocytopenia be exposed to KADCYLA during pregnancy to enroll in the MotHER • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in Pregnancy Registry by contacting 1-800-690-6720 the KADCYLA-treated group and 0.4% in the comparator group (overall Pulmonary Toxicity incidence 31.2% and 3.3%, respectively) • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate been reported in clinical trials with KADCYLA. In EMILIA, the overall Neurotoxicity frequency of pneumonitis was 1.2% • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% • Treatment with KADCYLA should be permanently discontinued in in the KADCYLA-treated group and 0.2% in the comparator group (overall patients diagnosed with ILD or pneumonitis incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral © 2013 Genentech USA, Inc. All rights reserved. TDM0001944700 Printed in USA. (07/13) neuropathy until resolution to ≤ Grade 2

Superior efficacy with a single agent 1 NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS) 100

30.9 months

Proportion surviving (%)

90 80

HR=0.682 95% CI: 0.548, 0.849 P=0.0006

70 60 50

KADCYLA (n=495) No. of events: 149

25.1 months

40 30 20

lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months 485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS. References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012; 367:1783-1791 and Supplementary Appendix. 4. Hicks DG, Kulkarni S. Review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For more information on KADCYLA, visit KADCYLA.com.

The ASCO Post | NOVEMBER 15, 2013

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JCO Spotlight

DNA Mismatch Repair continued from page 20

nostic overall for disease-free survival (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.64–1.07, P = .14) after adjustment for clinical variables, BRAF V600E, and KRAS status. However, significant interactions were found between mismatch

repair status and primary tumor site (P = .009 for interaction) and lymph node category (N1 vs N2, P = .014 for interaction) for disease-free survival. Importantly, disease-free survival was significantly increased among mismatch repair–deficient proximal tumors (adjusted HR = 0.71; 95% CI =0.53–0.94, P = .018) but not mismatch repair–defi-

cient distal tumors (adjusted HR = 1.71; 95% CI = 0.99–2.95, P = .056). Diseasefree survival was significantly worse for mismatch repair–deficient tumors with N2 vs N1 status (adjusted HR = 3.49, P < .001); a similar butS:6.875” weaker association was observed among mismatch repair– proficient tumors (adjusted HR = 2.05, P < .001).

KADCYLA® (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA®, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

Validation in an Independent Study Cohort An independent cohort of 1,264 patients with stage III colon cancer randomly assigned to receive 5-FU/ leucovorin or 5-FU/leucovorin plus irinotecan in the phase III Cancer and Leukemia Group B 89803 adjuvant trial was used for validation. No difand 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

B:17

T:15

7.5”

5.5”

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JCO Spotlight

ferences in survival were observed between the treatment groups in this trial. A significant interaction between mismatch repair status and tumor site for disease-free survival (P = .037 for interaction) was also observed in the validation cohort after adjustment for clinical factors, but not BRAF V600E or KRAS status given that mutation Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

2.0

9.0

4.3

Blood and Lymphatic System Disorders

data were available in only 64% of patients in the validation cohort. Among patients in the validation cohort with proximal cancers, deficient mismatch repair was significantly associated S:6.875” with improved diseasefree survival (HR = 0.59; 95% CI = 0.41–0.86, P = .0039) after adjusting for N category, T stage, histologic

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Increased bilirubin

Increased AST

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Neutropenia

6.7

Anemia

14.3

4.1

10.5

2.5

Increased ALT

Thrombocytopenia

31.2

14.5

3.3

0.4

Decreased platelet count

1.8

0.2

3.3

0.4

3.3

2.5

Cardiac Disorders Left ventricular dysfunction Eye Disorders Lacrimation increased Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

Gastrointestinal Disorders Dyspepsia

9.2

11.5

0.4

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5

General Disorders and Administration 8.2

0.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

Decreased potassium

8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.

8.5 Geriatric Use Of 495 patients who were randomized to KADCYLA in the randomized 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients response to KADCYLA. ≥ 65 years old (n=138 across both treatment arms) the hazard ratios A total of 836 patients from six clinical studies were tested at for progression-free survival (PFS) and Overall Survival (OS) were multiple time points for anti-therapeutic antibody (ATA) responses 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post- Population pharmacokinetic analysis indicates that age does not dose time points. The presence of KADCYLA in patient serum at have a clinically meaningful effect on the pharmacokinetics of the time of ATA sampling may interfere with the ability of this assay ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. 8.6 Females of Reproductive Potential KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective Immunogenicity data are highly dependent on the sensitivity and contraception while receiving KADCYLA and for 6 months following specificity of the test methods used. Additionally, the observed the last dose of KADCYLA. incidence of a positive result in a test method may be influenced If KADCYLA is administered during pregnancy or if the patient by several factors, including sample handling, timing of sample becomes pregnant while receiving KADCYLA, immediately report collection, drug interference, concomitant medication and the exposure to the Genentech Adverse Event Line at 1-888-835-2555. underlying disease. Therefore, comparison of the incidence of Encourage women who may be exposed during pregnancy to enroll antibodies to KADCYLA with the incidence of antibodies to other in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see products may be misleading. Clinical significance of anti-KADCYLA Patient Counseling Information (17)]. antibodies is not yet known. 8.7 Renal Impairment No dedicated renal impairment trial for KADCYLA has been 7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have conducted. Based on the population pharmacokinetics, as well been conducted. In vitro studies indicate that DM1, the cytotoxic as analysis of Grade 3 or greater adverse drug reactions and dose component of KADCYLA, is metabolized mainly by CYP3A4 and modifications, dose adjustments of KADCYLA are not needed in to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, adjustment can be recommended for patients with severe renal telithromycin, and voriconazole) with KADCYLA should be avoided impairment (CLcr less than 30 mL/min) because of the limited data due to the potential for an increase in DM1 exposure and toxicity. available [see Clinical Pharmacology (12.3)]. Consider an alternate medication with no or minimal potential to 8.8 Hepatic Impairment inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is In vitro studies in human liver microsomes indicates that DM1 is unavoidable, consider delaying KADCYLA treatment until the strong metabolized by CYP3A4/5. The influence of hepatic impairment on CYP3A4 inhibitors have cleared from the circulation (approximately the pharmacokinetics of ado-trastuzumab emtansine conjugate has 3 elimination half-lives of the inhibitors) when possible. If a strong not been determined. CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical reactions. trials, overdose of KADCYLA has been reported at approximately 8 USE IN SPECIFIC POPULATIONS two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal 8.1 Pregnancy case, the patient incorrectly received KADCYLA at 6 mg/kg and died Pregnancy Category D [see Warnings and Precautions (5.3)] approximately 3 weeks following the overdose; a cause of death and Risk Summary a causal relationship to KADCYLA were not established. KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of 17 PATIENT COUNSELING INFORMATION KADCYLA in pregnant women. No reproductive and developmental • Inform patients of the possibility of severe liver injury and advise toxicology studies have been conducted with ado-trastuzumab patients to immediately seek medical attention if they experience emtansine. Nevertheless, two components of KADCYLA symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (trastuzumab and DM1) are known or suspected to cause fetal harm (especially RUQ abdominal pain), jaundice, dark urine, generalized or death when administered to a pregnant woman. If KADCYLA is pruritus, anorexia, etc. [see Warnings and Precautions (5.1)]. to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

administered during pregnancy, or if a patient becomes pregnant • Advise patients to contact a health care professional immediately while receiving KADCYLA, apprise the patient of the potential for any of the following: new onset or worsening shortness of breath, hazard to the fetus. Patients should be advised to use effective cough, swelling of the ankles/legs, palpitations, weight gain of contraception during treatment with KADCYLA and for 6 months more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)]. following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient • Advise pregnant women and females of reproductive potential that becomes pregnant while receiving KADCYLA, immediately report KADCYLA exposure can result in fetal harm, including embryo-fetal exposure to the Genentech Adverse Event Line at 1-888-835-2555. death or birth defects [see Warnings and Precautions (5.3), Use in Encourage women who may be exposed during pregnancy to enroll Specific Populations (8.1, 8.6)]. in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see • Advise females of reproductive potential to use effective Patient Counseling Information (17)]. contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA [See Warnings and Precautions (5.3) and Human Data Use in Specific Populations (8.1, 8.6)]. In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some • Advise nursing mothers treated with KADCYLA to discontinue associated with fatal pulmonary hypoplasia, skeletal abnormalities nursing or discontinue KADCYLA, taking into account the importance and neonatal death. These case reports described oligohydramnios of the drug to the mother [see Use in Specific Populations (8.3)]. in pregnant women who received trastuzumab either alone or in • Encourage women who are exposed to KADCYLA during pregnancy combination with chemotherapy. In some case reports, amniotic to enroll in the MotHER Pregnancy Registry by contacting fluid index increased after trastuzumab was stopped. In one 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in case, trastuzumab therapy resumed after the amniotic fluid index Specific Populations (8.1, 8.6)]. improved, and oligohydramnios recurred. KADCYLA® (ado-trastuzumab emtansine) Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No: 1048

In the NCCTG cohort, mutations in BRAF V600E (HR = 1.37; 95% CI = 1.08–1.70, P = .009) or mutations in KRAS (HR = 1.44; 95% CI = 1.21–1.70, P < .001) were independently associated with significantly worse disease-free survival. Diseasefree survival among patients with mismatch repair–deficient tumors did not differ significantly according to mutant vs wild-type BRAF V600E (adjusted HR = 1.58; P = .12) or mutant vs wild-type KRAS. Among the larger number of patients with mismatch repair–proficient tumors, mutated BRAF V600E was associated with significantly worse disease-free survival (adjusted HR = 1.32, P = .044), as was mutated KRAS (adjusted HR = 1.45, P < .001). However, neither the mismatch repair by BRAF V600E status (adjusted P = .93) nor the mismatch repair by KRAS status (adjusted P = .38) interaction tests were statistically significant. The investigators concluded: [T]he prognostic impact of [deficient DNA mismatch repair] on [diseasefree survival] was dependent on the primary tumor site in patients with stage III colon cancer, and this finding was validated in an independent cohort. Poor prognostic subgroups were observed within [mismatch repair–deficient] cancers that included distal site and N2 disease, which may have contributed to the nonsignificant overall impact of [deficient DNA mismatch repair] on [disease-free survival]. Mutations in BRAF V600E or KRAS were each independently associated with reduced [disease-free survival] and may therefore provide clinically useful prognostic information in FOLFOX-treated patients. n B:11.5”

7.6

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)].

BRAF V600E and KRAS Status

T:10.5”

7.1

Chills

the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

tus observed in the NCCTG cohort was not confirmed in the validation cohort (adjusted P = .7010).

S:9.875”

Peripheral edema

Decreased hemoglobin Decreased neutrophils

grade, age, sex, and study arm. Among distal cancers, disease-free survival did not differ significantly by mismatch repair status (adjusted HR = 1.58; 95% CI = 0.72–3.46, P = .2817), although only 14 of 378 patients had distal mismatch repair–deficient tumors. The significant interaction between mismatch repair and nodal sta-

Disclosure: The study was supported by National Cancer Institute and National Institutes of Health grants, with support for correlative studies also provided by BristolMyers Squibb, ImClone Systems, SanofiAventis, and Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Sinicrope FA, Mahoney MR, Smyrk TC, et al: Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 31:3664-3672, 2013. Commentary on page 26

The ASCO Post | NOVEMBER 15, 2013

PAGE 26

JCO Spotlight

Mismatch Repair– Deficient Colon Cancer

It is important to recognize that these interesting data, while informing us about who is more likely to have a favorable outcome, do not yet help us figure out who is or is not likely to have an improved outcome as the result of one intervention or another.

continued from page 20

and mismatch repair–deficient tumors, with N2 tumors having a worse prognosis than N1 tumors.

Underlying Physiology Why should location within the colon carry such strong prognostic implications? The answer is not clear, but it may be instructive to recall that the distal portion of the large intestine, from the cloaca through the distal third of the transverse colon, is embryologically derived from the hindgut, which is drained by the inferior mesenteric vein, whereas the proximal colon, from the cecum through the proximal twothirds of the transverse colon, is derived from the midgut, and is drained by the superior mesenteric vein. To what degree these differences in embryologic origin and/or vascular drainage contribute to the prognostic implications of the tumor location is not known at this point. However, it is reasonable to speculate that these issues may contribute to the differences observed.

Practical Implications The more immediate question, however, is how can we utilize this in-

—Leonard B. Saltz, MD

formation today? From a clinical trials perspective, these prognostic data can be used to either stratify patients prospectively in new trials, or to evaluate for potential imbalances that may either explain or invalidate apparent differences in already-accrued trials. From a current patient care perspective, however, it is not yet possible to reliably bring these data into the decision-making process, since these data are prognostic and not predictive. Prognostic data tell us who has a better or worse chance of a successful outcome, but they do not tell us whether we are able to influence that outcome. In fact, by definition, we cannot influence the outcome, or

the information would be predictive, rather than prognostic. We cannot choose which side of the colon our patient’s tumor will arise in, nor can we influence the mismatch repair or other mutational status of our patient’s tumor. Predictive data, which would tell us who is or is not likely to benefit from a treatment or intervention, are not derivable from the current report, since all patients effectively received the same treatment.

Actionable Markers Needed At present, oxaliplatin plus a fluoropyrimidine remains the recommended adjuvant therapy for all patients with stage III colon cancer

in the absence of medical contraindications. While it is reasonable to conjecture that some of the prognostic subgroups may either benefit more or fail to benefit from a particular maneuver, such as chemotherapy or oxaliplatin-based chemotherapy, we simply do not know yet if this is the case. It is therefore important to recognize that these interesting data, while informing us about who is more likely to have a favorable outcome, do not yet help us figure out who is or is not likely to have an improved outcome as the result of one intervention or another. It would be highly desirable to have data that define subgroups of stage III patients whose prognoses do not improve with oxaliplatin, so that these patients could be spared the unnecessary toxicity, or to define subgroups who would likely benefit from irinotecan, cetuximab, or other agents. We are not there yet, and these current data should not be misconstrued as such, but analyses of this type in other trials will hopefully provide us with actionable predictive markers in the near future. n Disclosure: Dr. Saltz is a consultant for Roche, Genentech, Bristol-Myers Squibb, Sanofi, and Pfizer.

One Dose of HPV 16/18 Vaccine Produces Durable Response, Study Finds By Jo Cavallo

esults from the Costa Rica HPV 16/18 Vaccine Trial indicate that 4-year efficacy against 12-month HPV 16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle vaccine (Cervarix). The findings suggest that vaccination schedules of two or even one HPV vaccine dose could simplify the logistics and reduce the cost of vaccination in the developing world, where more than 85% of cervical cancers occur. The study results were published in Cancer Prevention Research.1

Study Method Mahboobeh Safaeian, PhD, an Investigator in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and colleagues analyzed data from the Na-

tional Cancer Institute–funded phase III Costa Rica HPV 16/18 Vaccine Trial trial to look for the presence of an immune response to the HPV 16/18 vaccine, which was measured by antibody levels. About 20% of the women in the study received fewer than three doses of the vaccine, not by design. Blood samples were drawn from 78, 192, and 120 women who received one, two, and three doses of the vaccine, respectively. The researchers then compared the results with data from 113 women who did not receive the vaccine, but had antibodies against the viruses in their blood because they were infected with HPV in the past.

Findings The researchers found that 100% of the women in all three groups had antibodies against HPV 16 and 18 in

their blood for up to 4 years. In addition, antibody levels were comparable for women receiving two doses 6 months apart and those receiving the full three-dose regimen. Although antibody levels among women who had received one dose of the vaccine were lower than among those women who had received three doses, the levels appeared stable, suggesting that these are lasting responses. “The findings suggest that antibody titers induced by two or three vaccine doses may be substantially higher than needed for long-term protection,” wrote the researchers. The study also found that the levels of antibodies in women from the one- and two-dose groups were 24 times higher than the levels of antibodies in women who did not receive the vaccine, but had prior HPV infection.

“We hope to expand our study to include a longer follow-up because with this vaccine, and probably any other vaccine, you want the protection to last long-term, and we are definitely interested in showing what happens over the next 4 years and even 10 years,” said Dr. Safaeian. n

Disclosure: Dr. Safaeian reported no potential conflicts of interest. The trial was sponsored by the NCI with funding support from the National Institutes of Health Office of Research on Women’s Health, and the Ministry of Health of Costa Rica. GlaxoSmithKline provided the vaccine for the study.

Reference 1. Safaeian M, Porras C, Pan Y, et al: Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica vaccine trial. Cancer Prev Res 6:12421250, 2013.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 27

JCO Spotlight Gastrointestinal Oncology

Long-Term Colorectal Cancer Incidence and Mortality After Lower Endoscopy By Matthew Stenger

olonoscopy and sigmoidoscopy have been shown to provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against proximal colon cancer, remain undefined. A study of long-term colorectal cancer incidence and mortality after lower endoscopy reported in The New England Jour ishihara, nal of Medicine by Reiko N PhD, of Dana-Farber Cancer Institute and Harvard Medical School, and colleagues found that both colonoscopy and sigmoidoscopy for any indication

In the entire population, multivariate hazard ratios (HRs) for colorectal cancer for participants who had undergone endoscopy for any indication vs those not undergoing endoscopy were 0.57 (95% confidence interval [CI] = 0.45–0.72) after removal of adenomatous polyps, 0.60 (95% CI = 0.53–0.68) after negative sigmoidoscopy, and 0.44 (95% CI = 0.380.52) after negative colonoscopy. The findings were consistent among men and women and for all disease stages at presentation.

Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have [CpG island methylator phenotype] and microsatellite instability. —Reiko Nishihara, PhD, and colleagues

were associated with a reduced incidence of overall colorectal cancer and distal colorectum cancer, with only colonoscopy being associated with a reduction in the incidence of proximal colon cancer.1 Screening colonoscopy and sigmoidoscopy were both associated with reduced overall colorectal cancer mortality and mortality from distal colorectum cancer, with only colonoscopy being associated with reduced mortality from proximal colon cancer.

Study Details The study examined the association of use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal cancer incidence (through June 2010) and mortality (through June 2012) among participants in the Nurses’ Health Study and the Health Professionals Follow-up Study. Among 88,902 participants, including 31,736 men and 57,166 women, a total of 1,815 incident cases of colorectal cancer (714 in men and 1,101 in women) and 474 deaths (187 in men and 287 in women) from colorectal cancer were identified during 22 years of followup, representing a total of 1,738,396 person-years.

For distal colorectal cancer, hazard ratios were 0.40 (95% CI = 0.27–0.59) after polypectomy, 0.44 (95% CI = 0.36–0.53) after negative sigmoidoscopy, and 0.24 (95% CI = 0.18–0.32) after negative colonoscopy. Only negative colonoscopy was associated with significantly reduced risk of proximal colon cancer (HR = 0.73, 95% CI = 0.57–0.92). Findings with regard to colorectal cancer incidence were similar for screening endoscopy.

Colonoscopy Interval Compared with no endoscopy, multivariate hazard ratios for colorectal cancer according to time since last negative colonoscopy were 0.35 (95% CI = 0.28–0.45) for an interval of ≤ 3.0 years, 0.40 (95% CI = 0.31–0.52) for 3.1 to 5.0 years, 0.52 (95% CI = 0.38– 0.70) for 5.1 to 10.0 years, and 0.26 (95% CI = 0.12–0.59) for 10.1 to 15.0

years. Hazard ratios for the interval of 5.1 to 15.0 years were 0.60 (95% CI = 0.38–0.94) for proximal colon cancer and 0.35 (95% CI = 0.22–0.54) for distal colorectal cancer. Compared with no endoscopy, participants who had undergone endoscopy with removal of adenomatous polyps had a reduced incidence of colorectal cancer with surveillance intervals of ≤ 3.0 years (multivariate HR = 0.48, 95% CI = 0.33–0.69) and 3.1 to 5.0 years (HR = 0.49, 95% CI = 0.33–0.73). Results were similar for adenomas in the proximal colon and those in the distal colorectum. For participants with high-risk adenoma, the risk reduction was smaller and of shorter duration, with a hazard ratio of 0.70 (95% CI = 0.43–1.14) for the surveillance interval of 3.1 to 5.0 years. For colonoscopies performed at least 4 years apart, compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.43 (95% CI = 0.35–0.51) after one negative colonoscopy, 0.32 (95% CI = 0.22– 0.48) after two, and 0.23 (95% CI = 0.08–0.67) after three.

Subgroups Colonoscopy was associated with similar significant reductions in incidence of colorectal cancer across age, body mass index, smoking status, and aspirin use subgroups. Among participants with a family history of colorectal cancer, there was no significant reduction at more than 5 years after colonoscopy (multivariate HR = 0.91, 95% CI = 0.55–1.52), with the reduction at more than 5 years remaining significant in those without a family history (HR = 0.43, 95% CI = 0.32– 0.58; P = .04 for interaction).

Molecular Characteristics A total of 62 cancers diagnosed within 5 years after colonoscopy had

Impact of Endoscopy on Colorectal Cancer ■■ Colonoscopy and sigmoidoscopy for any indication were associated with

a reduced incidence of overall colorectal cancer and distal colorectum cancer, with only colonoscopy being associated with a (modest) reduction in the incidence of proximal colon cancer.

■■ Screening colonoscopy and sigmoidoscopy were both associated with

reduced overall colorectal cancer mortality and mortality from distal colorectal cancer, with only colonoscopy being associated with reduced mortality from proximal colon cancer.

available molecular data. Compared with cancers diagnosed in participants more than 5 years after colonoscopy or in participants with no endoscopy, these cancers were more likely to have CpG island methylator phenotype (multivariate odds ratio [OR] = 2.19, 95% CI = 1.14–4.21), microsatellite instability (OR = 2.10, 95% CI = 1.10–4.02), and an increased LINE-1 methylation level (OR = 3.21 for each 30% increment, 95% CI = 1.29–8.00). BRAF, KRAS, and PIK3CA mutations were not significantly associated with cancer diagnosed within 5 years after colonoscopy.

Screening Endoscopy and Mortality Compared with no screening endoscopy, colorectal cancer mortality was significantly reduced by screening sigmoidoscopy (multivariate HR = 0.59, 95% CI = 0.45–0.76) and screening colonoscopy (HR = 0.32, 95% CI = 0.24–0.45). Screening sigmoidoscopy was associated with reduced mortality from only distal colorectum cancer (HR = 0.31, 95% CI = 0.20–0.49), whereas screening colonoscopy was associated with reduced mortality from both distal colorectal cancer (HR = 0.18, 95% CI = 0.10–0.31) and proximal colon cancer (HR = 0.47, 95% CI = 0.29– 0.76). The investigators concluded: Colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have [CpG island methylator phenotype] and microsatellite instability. n

Disclosure: The study was funded by the National Institutes of Health and others.

Reference 1. Nishihara R, Wu K, Lochhead P, et al: Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 369:1095-1105, 2013.

The ASCO Post | NOVEMBER 15, 2013

PAGE 28

FDA Update

FDA Approves First Extended-Release, Single-Entity Hydrocodone Product

he U.S. Food and Drug Administration (FDA) today approved hydrocodone bitartrate extended-release capsules (Zohydro ER) for the management of pain severe enough to require daily, around-the-clock, long-term treatment and for which alternative treatment options are inadequate. The drug, a Schedule II controlled substance under the Controlled Substances Act, is the first FDA-approved single-entity (not combined with an analgesic such as acetaminophen) and extendedrelease hydrocodone product. The new product is in the class of extended-release/long-acting opioid analgesics. Due to the risks of addiction, abuse, and misuse

counseling practices. Hydrocodone bitartrate is the first opioid to be labeled in this manner. The FDA is requiring postmarketing studies of hydrocodone bitartrate to assess the known serious risks of misuse, abuse, hyperalgesia,

addiction, overdose, and death associated with long term use beyond 12 weeks. These studies will also be required for other extended-release/ long-acting opioid analgesics. The safety of hydrocodone bitartrate is based on clinical studies

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

46% 1-YEAR survival rate*

with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, hydrocodone bitartrate should be reserved for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Hydrocodone bitartrate is not approved for asneeded pain relief. The most common side effects of hydrocodone bitartrate are constipation, nausea, drowsiness, fatigue, headache, dizziness, dry mouth, vomiting, and pruritus. New Safety Measures The approved labeling for hydrocodone bitartrate conforms to updated labeling requirements for all extended-release/long-acting opioid analgesics announced by the FDA on September 10, 2013. The new class labeling and stronger warnings will more clearly describe the risks and safety concerns associated with extended-release/ long-acting opioid analgesics, along with the appropriate use of these medications. These warnings are expected to improve the safety of all such medicines by encouraging more appropriate prescribing, patient monitoring, and patient

of more than 1,100 people living with chronic pain, and the efficacy is based on a clinical study that enrolled over 500 patients with chronic low back pain and showed significant improvement in chronic pain compared to placebo. n

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 | NOVEMBER 15, 2013

PAGE 29

FDA Update

Sale of Ponatinib Suspended Due to Risk of Life-Threatening Blood Clots

he U.S. Food and Drug Administration (FDA) has asked the manufacturer of the tyrosine kinase inhibitor ponatinib (Iclusig) to suspend marketing and sales of the drug because of the risk of life-threatening blood clots and severe narrowing of

blood vessels. Ariad Pharmaceuticals has agreed to suspend marketing and sales while the safety of the drug continues to be evaluated.

Serious Adverse Events Ponatinib is indicated for the treat-

ment of patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia of Philadelphia chromosome–positive acute lymphoblastic leukemia, who are no longer benefiting from previous treatment or who did not tolerate treatment.

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.RedefineTreatmentGoals2.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. ©2013 Bristol-Myers Squibb Company. All rights reserved. 731US13BR02884-01-01 10/13

FDA’s recent investigation of ponatinib revealed an increased frequency of blood clots and narrowing of blood vessels since the drug was approved in December 2012. In phase I and II clinical trials, approximately 48% continued on page 30

The ASCO Post | NOVEMBER 15, 2013

PAGE 30

FDA Update

Ponatinib Sales Suspended continued from page 29

and 24% of patients, respectively, have experienced serious adverse vascular events, including fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart,

and brain requiring urgent surgical procedures to restore blood flow. In the phase II clinical trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively; patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these

events. High blood pressure occurred in 67% of patients, and heart failure, including fatalities, occurred in 8% of patients treated with ponatinib. In addition, serious adverse reactions involving the eyes, which lead to blindness or blurred vision, occurred in ponatinib-treated patients. In some patients, fatal and serious adverse events have occurred as early

as 2 weeks after starting ponatinib therapy. The relationship of these adverse events to ponatinib has not been determined, but the increasing rate and pattern of the events strongly suggests that many are drug-related. At this time, FDA cannot identify a dose level or exposure duration that is safe.

Important Important Safety Safety Information Information WARNING: WARNING: IMMUNE-MEDIATED IMMUNE-MEDIATED ADVERSE ADVERSE REACTIONS REACTIONS YERVOY YERVOY (ipilimumab) (ipilimumab) can can result result in in severe severe and and fatal fatal immune-mediated immune-mediated adverse adverse reactions reactions due due to to T-cell T-cell activation activation and and proliferation. proliferation. These These immune-mediated immune-mediated reactions reactions may may involve involve any any organ organ system; system; however, however, the the most most common common severe severe immune-mediated immune-mediated adverse adverse reactions reactions are are enterocolitis, enterocolitis, hepatitis, hepatitis, dermatitis dermatitis (including (including toxic toxic epidermal epidermal necrolysis), necrolysis), neuropathy, neuropathy, and and endocrinopathy. endocrinopathy. The The majority majority of of these these immune-mediated immune-mediated reactions reactions initially initially manifested manifested during during treatment; treatment; however, however, aa minority minority occurred occurred weeks weeks to to months months after after discontinuation discontinuation of of YERVOY. YERVOY. Assess Assess patients patients for for signs signs and and symptoms symptoms of of enterocolitis, enterocolitis, dermatitis, dermatitis, neuropathy, neuropathy, and and endocrinopathy endocrinopathy and and evaluate evaluate clinical clinical chemistries chemistries including including liver liver function function tests tests (LFTs) (LFTs) and and thyroid thyroid function function tests tests at at baseline baseline and and before before each each dose. dose. Permanently Permanently discontinue discontinue YERVOY YERVOY and and initiate initiate systemic systemic high-dose high-dose corticosteroid corticosteroid therapy therapy for for severe severe immune-mediated immune-mediated reactions. reactions. Recommended Recommended Dose Dose Modifications Modifications Withhold Withholddose dosefor forany anymoderate moderateimmune-mediated immune-mediatedadverse adversereactions reactionsor orfor forsymptomatic symptomatic endocrinopathy endocrinopathyuntil untilreturn returnto tobaseline, baseline,improvement improvementto tomild mildseverity, severity,or orcomplete completeresolution, resolution, and andpatient patientisisreceiving receiving<7.5 <7.5mg mgprednisone prednisoneor orequivalent equivalentper perday. day. Permanently Permanentlydiscontinue discontinueYERVOY YERVOYfor forany anyof ofthe thefollowing: following: ••Persistent Persistentmoderate moderateadverse adversereactions reactionsor orinability inabilityto toreduce reducecorticosteroid corticosteroiddose doseto to7.5 7.5mg mg prednisone prednisoneor orequivalent equivalentper perday day ••Failure Failureto tocomplete completefull fulltreatment treatmentcourse coursewithin within16 16weeks weeksfrom fromadministration administrationof offirst firstdose dose ••Severe Severeor orlife-threatening life-threateningadverse adversereactions, reactions,including includingany anyof ofthe thefollowing: following: ––Colitis Colitiswith withabdominal abdominalpain, pain,fever, fever,ileus, ileus,or orperitoneal peritonealsigns; signs;increase increasein instool stoolfrequency frequency (≥7 (≥7over overbaseline), baseline),stool stoolincontinence, incontinence,need needfor forintravenous intravenoushydration hydrationfor for>24 >24hours, hours, gastrointestinal gastrointestinalhemorrhage, hemorrhage,and andgastrointestinal gastrointestinalperforation perforation ––AST ASTor orALT ALT>5× >5×the theupper upperlimit limitof ofnormal normal(ULN) (ULN)or ortotal totalbilirubin bilirubin>3× >3×the theULN ULN ––Stevens-Johnson Stevens-Johnsonsyndrome, syndrome,toxic toxicepidermal epidermalnecrolysis, necrolysis,or orrash rashcomplicated complicatedby byfull-thickness full-thickness dermal dermalulceration ulcerationor ornecrotic, necrotic,bullous, bullous,or orhemorrhagic hemorrhagicmanifestations manifestations ––Severe Severemotor motoror orsensory sensoryneuropathy, neuropathy,Guillain-Barré Guillain-Barrésyndrome, syndrome,or ormyasthenia myastheniagravis gravis ––Severe Severeimmune-mediated immune-mediatedreactions reactionsinvolving involvingany anyorgan organsystem system ––Immune-mediated Immune-mediatedocular oculardisease diseasewhich whichisisunresponsive unresponsiveto totopical topicalimmunosuppressive immunosuppressivetherapy therapy Immune-mediated Immune-mediated Enterocolitis: Enterocolitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or orfatal fatal(diarrhea (diarrheaof of ≥7 ≥7stools stoolsabove abovebaseline, baseline,fever, fever,ileus, ileus,peritoneal peritonealsigns; signs;Grade Grade3-5) 3-5)immune-mediated immune-mediatedenterocolitis enterocolitis occurred occurredin in34 34(7%) (7%)and andmoderate moderate(diarrhea (diarrheawith withup upto to66stools stoolsabove abovebaseline, baseline,abdominal abdominalpain, pain, mucus mucusor orblood bloodin instool; stool;Grade Grade2) 2)enterocolitis enterocolitisoccurred occurredin in28 28(5%) (5%)patients patients ••Across Acrossall allYERVOY-treated YERVOY-treatedpatients patients(n=511), (n=511),55(1%) (1%)developed developedintestinal intestinalperforation, perforation,44(0.8%) (0.8%)died died as asaaresult resultof ofcomplications, complications,and and26 26(5%) (5%)were werehospitalized hospitalizedfor forsevere severeenterocolitis enterocolitis ••Infliximab Infliximabwas wasadministered administeredto to55of of62 62(8%) (8%)patients patientswith withmoderate, moderate,severe, severe,or orlife-threatening life-threatening immune-mediated immune-mediatedenterocolitis enterocolitisfollowing followinginadequate inadequateresponse responseto tocorticosteroids corticosteroids ••Monitor Monitorpatients patientsfor forsigns signsand andsymptoms symptomsof ofenterocolitis enterocolitis(such (suchas asdiarrhea, diarrhea,abdominal abdominalpain, pain, mucus mucusor orblood bloodin instool, stool,with withor orwithout withoutfever) fever)and andof ofbowel bowelperforation perforation(such (suchas asperitoneal peritonealsigns signs and andileus). ileus).In Insymptomatic symptomaticpatients, patients,rule ruleout outinfectious infectiousetiologies etiologiesand andconsider considerendoscopic endoscopic evaluation evaluationfor forpersistent persistentor orsevere severesymptoms symptoms ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere severeenterocolitis enterocolitisand andinitiate initiatesystemic systemic corticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent). equivalent).Upon Uponimprovement improvementto to≤Grade ≤Grade1, 1,initiate initiate corticosteroid corticosteroidtaper taperand andcontinue continueover overat atleast least11month. month.In Inclinical clinicaltrials, trials,rapid rapidcorticosteroid corticosteroidtapering tapering resulted resultedin inrecurrence recurrenceor orworsening worseningsymptoms symptomsof ofenterocolitis enterocolitisin insome somepatients patients ••Withhold WithholdYERVOY YERVOYfor formoderate moderateenterocolitis; enterocolitis;administer administeranti-diarrheal anti-diarrhealtreatment treatmentand, and,ififpersistent persistent for for>1 >1week, week,initiate initiatesystemic systemiccorticosteroids corticosteroids(0.5 (0.5mg/kg/day mg/kg/dayprednisone prednisoneor orequivalent) equivalent) Important Safety Information continued on following page.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 31

FDA Update

FDA Recommendations The FDA will continue to evaluate the drug to further understand its risks and to identify potential patient populations in which the benefits of the drug may outweigh the risks. Patients currently receiving ponatinib should discuss with their health-care professionals the risks

and benefits of continuing treatment with the drug. At this time, patients and healthcare professionals should follow FDA’s

new recommendations for the drug: Patients currently taking ponatinib who are not responding to the drug should immediately discontinue treatment and discuss alternative treatment options with their healthcare professionals. Patients who are currently taking ponatinib and responding to the

Important Important Safety Safety Information Information (cont’d) (cont’d) Immune-mediated Immune-mediated Hepatitis: Hepatitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY YERVOY(ipilimumab)-treated (ipilimumab)-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or or fatal fatalhepatotoxicity hepatotoxicity(AST (ASTor orALT ALTelevations elevations>5× >5×the theULN ULNor ortotal totalbilirubin bilirubinelevations elevations>3x >3xthe theULN; ULN; Grade Grade3–5) 3–5)occurred occurredin in88(2%) (2%)patients, patients,with withfatal fatalhepatic hepaticfailure failurein in0.2% 0.2%and andhospitalization hospitalizationin in0.4% 0.4% ••13 13(2.5%) (2.5%)additional additionalYERVOY-treated YERVOY-treatedpatients patientsexperienced experiencedmoderate moderatehepatotoxicity hepatotoxicitymanifested manifestedby by LFT LFTabnormalities abnormalities(AST (ASTor orALT ALTelevations elevations>2.5× >2.5×but but≤5× ≤5×the theULN ULNor ortotal totalbilirubin bilirubinelevation elevation>1.5× >1.5× but but≤3× ≤3×the theULN; ULN;Grade Grade2) 2) ••Monitor MonitorLFTs LFTs(hepatic (hepatictransaminase transaminaseand andbilirubin bilirubinlevels) levels)and andassess assesspatients patientsfor forsigns signsand and symptoms symptomsof ofhepatotoxicity hepatotoxicitybefore beforeeach eachdose doseof ofYERVOY. YERVOY.In Inpatients patientswith withhepatotoxicity, hepatotoxicity,rule ruleout out infectious infectiousor ormalignant malignantcauses causesand andincrease increasefrequency frequencyof ofLFT LFTmonitoring monitoringuntil untilresolution resolution ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withGrade Grade3-5 3-5hepatotoxicity hepatotoxicityand andadminister administersystemic systemic corticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent). equivalent).When WhenLFTs LFTsshow showsustained sustained improvement improvementor orreturn returnto tobaseline, baseline,initiate initiatecorticosteroid corticosteroidtapering taperingand andcontinue continueover over11month. month. Across Acrossthe theclinical clinicaldevelopment developmentprogram programfor forYERVOY, YERVOY,mycophenolate mycophenolatetreatment treatmenthas hasbeen been administered administeredin inpatients patientswith withpersistent persistentsevere severehepatitis hepatitisdespite despitehigh-dose high-dosecorticosteroids corticosteroids ••Withhold WithholdYERVOY YERVOYin inpatients patientswith withGrade Grade22hepatotoxicity hepatotoxicity Immune-mediated Immune-mediated Dermatitis: Dermatitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or orfatal fatal immune-mediated immune-mediateddermatitis dermatitis(e.g., (e.g.,Stevens-Johnson Stevens-Johnsonsyndrome, syndrome,toxic toxicepidermal epidermalnecrolysis, necrolysis,or orrash rash complicated complicatedby byfull fullthickness thicknessdermal dermalulceration, ulceration,or ornecrotic, necrotic,bullous, bullous,or orhemorrhagic hemorrhagicmanifestations; manifestations; Grade Grade3–5) 3–5)occurred occurredin in13 13(2.5%) (2.5%)patients patients ––11(0.2%) (0.2%)patient patientdied diedas asaaresult resultof oftoxic toxicepidermal epidermalnecrolysis necrolysis ––11additional additionalpatient patientrequired requiredhospitalization hospitalizationfor forsevere severedermatitis dermatitis ••There Therewere were63 63(12%) (12%)YERVOY-treated YERVOY-treatedpatients patientswith withmoderate moderate(Grade (Grade2) 2)dermatitis dermatitis ••Monitor Monitorpatients patientsfor forsigns signsand andsymptoms symptomsof ofdermatitis dermatitissuch suchas asrash rashand andpruritus. pruritus.Unless Unlessan an alternate alternateetiology etiologyhas hasbeen beenidentified, identified,signs signsor orsymptoms symptomsof ofdermatitis dermatitisshould shouldbe beconsidered considered immune-mediated immune-mediated ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere, severe,life-threatening, life-threatening,or orfatal fatalimmune-mediated immune-mediated dermatitis dermatitis(Grade (Grade3-5). 3-5).Administer Administersystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor or equivalent). equivalent).When Whendermatitis dermatitisisiscontrolled, controlled,corticosteroid corticosteroidtapering taperingshould shouldoccur occurover overaaperiod periodof ofat at least least11month. month.Withhold WithholdYERVOY YERVOYin inpatients patientswith withmoderate moderateto tosevere severesigns signsand andsymptoms symptoms ••Treat Treatmild mildto tomoderate moderatedermatitis dermatitis(e.g., (e.g.,localized localizedrash rashand andpruritus) pruritus)symptomatically. symptomatically.Administer Administer topical topicalor orsystemic systemiccorticosteroids corticosteroidsififthere thereisisno noimprovement improvementwithin within11week week Immune-mediated Immune-mediated Neuropathies: Neuropathies: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,11case caseof offatal fatalGuillain-Barré Guillain-Barrésyndrome syndrome and and11case caseof ofsevere severe(Grade (Grade3) 3)peripheral peripheralmotor motorneuropathy neuropathywere werereported reported ••Across Acrossthe theclinical clinicaldevelopment developmentprogram programof ofYERVOY, YERVOY,myasthenia myastheniagravis gravisand andadditional additionalcases casesof of Guillain-Barré Guillain-Barrésyndrome syndromehave havebeen beenreported reported ••Monitor Monitorfor forsymptoms symptomsof ofmotor motoror orsensory sensoryneuropathy neuropathysuch suchas asunilateral unilateralor orbilateral bilateralweakness, weakness, sensory sensoryalterations, alterations,or orparesthesia. paresthesia.Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere severe neuropathy neuropathy(interfering (interferingwith withdaily dailyactivities) activities)such suchas asGuillain-Barré–like Guillain-Barré–likesyndromes syndromes ••Institute Institutemedical medicalintervention interventionas asappropriate appropriatefor formanagement managementof ofsevere severeneuropathy. neuropathy.Consider Consider initiation initiationof ofsystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent) equivalent)for forsevere severe neuropathies. neuropathies.Withhold WithholdYERVOY YERVOYin inpatients patientswith withmoderate moderateneuropathy neuropathy(not (notinterfering interferingwith with daily dailyactivities) activities) Immune-mediated Immune-mediated Endocrinopathies: Endocrinopathies: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe severeto tolife-threatening life-threateningimmuneimmunemediated mediatedendocrinopathies endocrinopathies(requiring (requiringhospitalization, hospitalization,urgent urgentmedical medicalintervention, intervention,or orinterfering interferingwith with activities activitiesof ofdaily dailyliving; living;Grade Grade3-4) 3-4)occurred occurredin in99(1.8%) (1.8%)patients patients Important ImportantSafety SafetyInformation Informationcontinued continuedon onfollowing followingpage. page.

drug and whose health-care professionals determine that the potential benefits outweigh the risks should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA’s safety investigation continues. continued on page 34

The ASCO Post | NOVEMBER 15, 2013

PAGE 32

FDA Update

Ponatinib Sales Suspended continued from page 29

Health-care professionals should not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Upon the determination of their health-care professional, these patients can be con-

sidered for treatment under an IND or expanded access registry program. Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System. n See comments from Brian J. Druker, MD on page 48.

Sale of Ponatinib Suspended ■■ The FDA asked Ariad Pharmaceuticals to suspend sales and marketing of

its drug ponatinib (Iclusig) while the FDA further investigates the possible increased risk of life-threatening blood clots and severe narrowing of blood vessels in patients taking the drug.

Important ImportantSafety SafetyInformation Information(cont’d) (cont’d) Immune-mediated Immune-mediatedEndocrinopathies Endocrinopathies(cont’d): (cont’d): ––All All99patients patientshad hadhypopituitarism, hypopituitarism,and andsome somehad hadadditional additionalconcomitant concomitantendocrinopathies endocrinopathiessuch such asasadrenal adrenalinsufficiency, insufficiency,hypogonadism, hypogonadism,and andhypothyroidism hypothyroidism ––66ofofthe the99patients patientswere werehospitalized hospitalizedfor forsevere severeendocrinopathies endocrinopathies ••Moderate Moderateendocrinopathy endocrinopathy(requiring (requiringhormone hormonereplacement replacementorormedical medicalintervention; intervention;Grade Grade2)2) occurred occurredinin12 12(2.3%) (2.3%)YERVOY YERVOY(ipilimumab)-treated (ipilimumab)-treatedpatients patientsand andconsisted consistedofofhypothyroidism, hypothyroidism, adrenal adrenalinsufficiency, insufficiency,hypopituitarism, hypopituitarism,and and11case caseeach eachofofhyperthyroidism hyperthyroidismand andCushing’s Cushing’ssyndrome syndrome ••Median Mediantime timetotoonset onsetofofmoderate moderatetotosevere severeimmune-mediated immune-mediatedendocrinopathy endocrinopathywas was11 11weeks weeksand and ranged rangedup uptoto19.3 19.3weeks weeksafter afterthe theinitiation initiationofofYERVOY YERVOY ••Monitor Monitorpatients patientsfor forclinical clinicalsigns signsand andsymptoms symptomsofofhypophysitis, hypophysitis,adrenal adrenalinsufficiency insufficiency(including (including adrenal adrenalcrisis), crisis),and andhyperhyper-ororhypothyroidism hypothyroidism ––Patients Patientsmay maypresent presentwith withfatigue, fatigue,headache, headache,mental mentalstatus statuschanges, changes,abdominal abdominalpain, pain,unusual unusual bowel bowelhabits, habits,and andhypotension, hypotension,orornonspecific nonspecificsymptoms symptomswhich whichmay mayresemble resembleother othercauses causessuch such asasbrain brainmetastasis metastasisororunderlying underlyingdisease. disease.Unless Unlessan analternate alternateetiology etiologyhas hasbeen beenidentified, identified,signs signs ororsymptoms symptomsshould shouldbe beconsidered consideredimmune-mediated immune-mediated ––Monitor Monitorthyroid thyroidfunction functiontests testsand andclinical clinicalchemistries chemistriesatatthe thestart startofoftreatment, treatment,before beforeeach eachdose, dose, and andasasclinically clinicallyindicated indicatedbased basedon onsymptoms. symptoms.InInaalimited limitednumber numberofofpatients, patients,hypophysitis hypophysitiswas was diagnosed diagnosedby byimaging imagingstudies studiesthrough throughenlargement enlargementofofthe thepituitary pituitarygland gland ••Withhold WithholdYERVOY YERVOYininsymptomatic symptomaticpatients. patients.Initiate Initiatesystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayofof prednisone prednisoneororequivalent) equivalent)and andinitiate initiateappropriate appropriatehormone hormonereplacement replacementtherapy. therapy.Long-term Long-term hormone hormonereplacement replacementtherapy therapymay maybe benecessary necessary Other OtherImmune-mediated Immune-mediatedAdverse AdverseReactions, Reactions,Including IncludingOcular OcularManifestations: Manifestations: ••InInthe thepivotal pivotalPhase Phase33study studyininYERVOY-treated YERVOY-treatedpatients, patients,clinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsseen seeninin<1% <1%were: were:nephritis, nephritis,pneumonitis, pneumonitis,meningitis, meningitis,pericarditis, pericarditis,uveitis, uveitis,iritis, iritis, and andhemolytic hemolyticanemia anemia ••Across Acrossthe theclinical clinicaldevelopment developmentprogram programfor forYERVOY, YERVOY,likely likelyimmune-mediated immune-mediatedadverse adversereactions reactions also alsoreported reportedwith with<1% <1%incidence incidencewere: were:myocarditis, myocarditis,angiopathy, angiopathy,temporal temporalarteritis, arteritis,vasculitis, vasculitis, polymyalgia polymyalgiarheumatica, rheumatica,conjunctivitis, conjunctivitis,blepharitis, blepharitis,episcleritis, episcleritis,scleritis, scleritis,leukocytoclastic leukocytoclasticvasculitis, vasculitis, erythema erythemamultiforme, multiforme,psoriasis, psoriasis,pancreatitis, pancreatitis,arthritis, arthritis,autoimmune autoimmunethyroiditis, thyroiditis,sarcoidosis, sarcoidosis, neurosensory neurosensoryhypoacusis, hypoacusis,autoimmune autoimmunecentral centralneuropathy neuropathy(encephalitis), (encephalitis),myositis, myositis,polymyositis, polymyositis, and andocular ocularmyositis myositis ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYfor forclinically clinicallysignificant significantororsevere severeimmune-mediated immune-mediatedadverse adverse reactions. reactions.Initiate Initiatesystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayofofprednisone prednisoneororequivalent) equivalent)for forsevere severe immune-mediated immune-mediatedadverse adversereactions reactions ••Administer Administercorticosteroid corticosteroideye eyedrops dropsfor foruveitis, uveitis,iritis, iritis,ororepiscleritis. episcleritis.Permanently Permanentlydiscontinue discontinue YERVOY YERVOYfor forimmune-mediated immune-mediatedocular oculardisease diseaseunresponsive unresponsivetotolocal localimmunosuppressive immunosuppressivetherapy therapy Pregnancy Pregnancy&&Nursing: Nursing: ••YERVOY YERVOYisisclassified classifiedasaspregnancy pregnancycategory categoryC.C.There Thereare areno noadequate adequateand andwell-controlled well-controlledstudies studies ofofYERVOY YERVOYininpregnant pregnantwomen. women.Use UseYERVOY YERVOYduring duringpregnancy pregnancyonly onlyififthe thepotential potentialbenefit benefitjustifies justifies the thepotential potentialrisk risktotothe thefetus fetus ••Human HumanIgG1 IgG1isisknown knowntotocross crossthe theplacental placentalbarrier barrierand andYERVOY YERVOYisisan anIgG1; IgG1;therefore, therefore,YERVOY YERVOY has hasthe thepotential potentialtotobe betransmitted transmittedfrom fromthe themother mothertotothe thedeveloping developingfetus fetus ••ItItisisnot notknown knownwhether whetherYERVOY YERVOYisissecreted secretedininhuman humanmilk. milk.Because Becausemany manydrugs drugsare aresecreted secretedinin human humanmilk milkand andbecause becauseofofthe thepotential potentialfor forserious seriousadverse adversereactions reactionsininnursing nursinginfants infantsfrom from YERVOY, YERVOY,aadecision decisionshould shouldbe bemade madewhether whethertotodiscontinue discontinuenursing nursingorortotodiscontinue discontinueYERVOY YERVOY Common CommonAdverse AdverseReactions: Reactions: ••The Themost mostcommon commonadverse adversereactions reactions(≥5%) (≥5%)ininpatients patientswho whoreceived receivedYERVOY YERVOYatat33mg/kg mg/kgwere were fatigue fatigue(41%), (41%),diarrhea diarrhea(32%), (32%),pruritus pruritus(31%), (31%),rash rash(29%), (29%),and andcolitis colitis(8%) (8%) Please Pleasesee seebrief briefsummary summaryofofFull FullPrescribing PrescribingInformation, Information,including includingBoxed BoxedWARNING WARNINGregarding regardingimmune-mediated immune-mediatedside sideeffects, effects,ononfollowing followingpages. pages. References: References:1. 1.Hodi HodiFS,FS,O’Day O’DaySJ,SJ,McDermott McDermottDF,DF,etetal.al.Improved Improvedsurvival survivalwith withipilimumab ipilimumabin inpatients patientswith withmetastatic metastaticmelanoma. melanoma.N NEngl EnglJ Med. J Med.2010;363(8):711-723. 2010;363(8):711-723. YERVOYpackage packageinsert. insert.Princeton, Princeton,NJ:NJ:Bristol-Myers Bristol-MyersSquibb SquibbCompany. Company.3.3.Data Dataononfile. file.YERV YERV008. 008.Bristol-Myers Bristol-MyersSquibb SquibbCompany. Company.Princeton, Princeton,NJ.NJ.April April2011. 2011. 2.2.YERVOY

ASCOPost.com | NOVEMBER 15, 2013

PAGE 33

FDA Update

FDA Grants Priority Review to Ramucirumab as a Potential Single-Agent Treatment for Advanced Gastric Cancer

he FDA has assigned Priority Review to the regulatory submission for ramucirumab as a single-agent treatment for advanced gastric cancer following disease progression after initial chemotherapy.

Ramucirumab is a human monoclonal antibody that specifically blocks the vascular endothelial growth factor receptor 2 and inhibits downstream signaling involved in angiogenesis.

® (ipilimumab) ® (ipilimumab) YERVOY YERVOY Injection, Injection, forfor intravenous intravenous infusion infusion

Brief Brief Summary Summary of Prescribing of Prescribing Information. Information. ForFor complete complete prescribing prescribing information information consult consult official official package package insert. insert. WARNING: WARNING: IMMUNE-MEDIATED IMMUNE-MEDIATED ADVERSE ADVERSE REACTIONS REACTIONS YERVOY YERVOY (ipilimumab) (ipilimumab) cancan result result in in severe severe andand fatal fatal immune-mediated immune-mediated adverse adverse reactions reactions duedue to to T-cell T-cell activation activation andand proliferation. proliferation. These These immune-mediated immune-mediated reactions reactions may may involve involve anyany organ organ system; system; however, however, thethe most most common common severe severe immune-mediated immune-mediated adverse adverse reactions reactions areare enterocolitis, enterocolitis, hepatitis, hepatitis, dermatitis dermatitis (including (including toxic toxic epidermal epidermal necrolysis), necrolysis), neuropathy, neuropathy, andand endocrinopathy. endocrinopathy. TheThe majority majority of of these these immune-mediated immune-mediated reactions reactions initially initially manifested manifested during during treatment; treatment; however, however, a a minority minority occurred occurred weeks weeks to to months months after after discontinuation discontinuation of of YERVOY. YERVOY. Permanently Permanently discontinue discontinue YERVOY YERVOY andand initiate initiate systemic systemic high-dose high-dose corticosteroid corticosteroid therapy therapy forfor severe severe immune-mediated immune-mediated reactions. reactions. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in in FullFull Prescribing Prescribing Information.] Information.] Assess Assesspatients patientsforforsigns signsandandsymptoms symptomsof ofenterocolitis, enterocolitis,dermatitis, dermatitis,neuropathy, neuropathy,andand endocrinopathy endocrinopathy andand evaluate evaluate clinical clinical chemistries chemistries including including liver liver function function tests tests andand thyroid thyroid function function tests tests at at baseline baseline andand before before each each dose. dose. [See [See Warnings Warnings andand Precautions.] Precautions.] INDICATIONS INDICATIONS AND AND USAGE USAGE YERVOY YERVOY (ipilimumab) (ipilimumab) is indicated is indicated forfor thethe treatment treatment of unresectable of unresectable or metastatic or metastatic melanoma. melanoma. CONTRAINDICATIONS CONTRAINDICATIONS None. None. WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS YERVOY YERVOY cancan result result in severe in severe andand fatal fatal immune-mediated immune-mediated reactions reactions duedue to T-cell to T-cell activation activation andand proliferation. proliferation. [See [See Boxed Boxed Warning.] Warning.] Immune-mediated Immune-mediated Enterocolitis Enterocolitis In In Study Study 1, 1, severe, severe, life-threatening, life-threatening, or or fatal fatal (diarrhea (diarrhea of of 7 or 7 or more more stools stools above above baseline, baseline, fever, fever, ileus, ileus, peritoneal peritoneal signs; signs; Grade Grade 3–5) 3–5) immune-mediated immune-mediated enterocolitis enterocolitis occurred occurred in 34 in 34 (7%) (7%) YERVOY-treated YERVOY-treated patients, patients, andand moderate moderate (diarrhea (diarrhea with with up up to 6tostools 6 stools above above baseline, baseline, abdominal abdominal pain, pain, mucus mucus or blood or blood in stool; in stool; Grade Grade 2) enterocolitis 2) enterocolitis occurred occurred in 28 in 28 (5%) (5%) YERVOY-treated YERVOY-treated patients. patients. Across Across all all YERVOY-treated YERVOY-treated patients patients (n=511), (n=511), 5 (1%) 5 (1%) patients patients developed developed intestinal intestinal perforation, perforation, 4 (0.8%) 4 (0.8%) patients patients died died as as a result a result of complications, of complications, andand 2626 (5%) (5%) patients patients were were hospitalized hospitalized forfor severe severe enterocolitis. enterocolitis. TheThe median median time time to to onset onset was was 7.47.4 weeks weeks (range: (range: 1.6–13.4) 1.6–13.4) andand 6.36.3 weeks weeks (range: (range: 0.3–18.9) 0.3–18.9) after after thethe initiation initiation of YERVOY of YERVOY forfor patients patients with with Grade Grade 3–53–5 enterocolitis enterocolitis andand with with Grade Grade 2 enterocolitis, 2 enterocolitis, respectively. respectively. Twenty-nine Twenty-nine patients patients (85%) (85%) with with Grade Grade 3–53–5 enterocolitis enterocolitis were were treated treated with with high-dose high-dose (≥40 (≥40 mgmg prednisone prednisone equivalent equivalent perper day) day) corticosteroids, corticosteroids, with with a median a median dose dose of of 8080 mg/day mg/day of of prednisone prednisone or or equivalent; equivalent; thethe median median duration duration of treatment of treatment was was 2.32.3 weeks weeks (ranging (ranging up up to 13.9 to 13.9 weeks) weeks) followed followed by by corticosteroid corticosteroid taper. taper. Of Of thethe 2828 patients patients with with moderate moderate enterocolitis, enterocolitis, 46% 46% were were notnot treated treated with with systemic systemic corticosteroids, corticosteroids, 29% 29% were were treated treated with with <40 <40 mgmg prednisone prednisone or or equivalent equivalent perper dayday forfor a median a median duration duration of of 5.15.1 weeks, weeks, andand 25% 25% were were treated treated with with high-dose high-dose corticosteroids corticosteroids forfor a median a median duration duration of 10 of 10 days days prior prior to corticosteroid to corticosteroid taper. taper. Infliximab Infliximab was was administered administered to 5to of5 the of the 6262 patients patients (8%) (8%) with with moderate, moderate, severe, severe, or or life-threatening life-threatening immune-mediated immune-mediated enterocolitis enterocolitis following following inadequate inadequate response response to corticosteroids. to corticosteroids. Of Of thethe 3434 patients patients with with Grade Grade 3–53–5 enterocolitis, enterocolitis, 74% 74% experienced experienced complete complete resolution, resolution, 3%3% experienced experienced improvement improvement to to Grade Grade 2 severity, 2 severity, andand 24% 24% diddid notnot improve. improve. Among Among thethe 2828 patients patients with with Grade Grade 2 2 enterocolitis, enterocolitis, 79% 79% experienced experienced complete complete resolution, resolution, 11% 11% improved, improved, andand 11% 11% diddid notnot improve. improve. Monitor Monitor patients patients forfor signs signs andand symptoms symptoms of of enterocolitis enterocolitis (such (such as as diarrhea, diarrhea, abdominal abdominal pain, pain, mucus mucus or or blood blood in in stool, stool, with with or or without without fever) fever) andand of of bowel bowel perforation perforation (such (such as as peritoneal peritoneal signs signs andand ileus). ileus). In In symptomatic symptomatic patients, patients, rulerule outout infectious infectious etiologies etiologies andand consider consider endoscopic endoscopic evaluation evaluation forfor persistent persistent or or severe severe symptoms. symptoms. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with severe severe enterocolitis enterocolitis andand initiate initiate systemic systemic corticosteroids corticosteroids at at a dose a dose of 1of to1 2to mg/kg/day 2 mg/kg/day of prednisone of prednisone or or equivalent. equivalent. Upon Upon improvement improvement to Grade to Grade 1 or 1 or less, less, initiate initiate corticosteroid corticosteroid taper taper andand continue continue to to taper taper over over at at least least 1 month. 1 month. In In clinical clinical trials, trials, rapid rapid corticosteroid corticosteroid tapering tapering resulted resulted in recurrence in recurrence or worsening or worsening symptoms symptoms of enterocolitis of enterocolitis in some in some patients. patients. Withhold Withhold YERVOY YERVOY dosing dosing forfor moderate moderate enterocolitis; enterocolitis; administer administer anti-diarrheal anti-diarrheal treatment treatment and, and, if persistent if persistent forfor more more than than 1 week, 1 week, initiate initiate systemic systemic corticosteroids corticosteroids at aatdose a dose of 0.5 of 0.5 mg/kg/day mg/kg/day prednisone prednisone or equivalent. or equivalent. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Hepatitis Hepatitis In Study In Study 1, severe, 1, severe, life-threatening, life-threatening, or or fatal fatal hepatotoxicity hepatotoxicity (AST (AST or ALT or ALT elevations elevations of more of more than than 5 times 5 times thethe upper upper limit limit of normal of normal or or total total bilirubin bilirubin elevations elevations more more than than 3 times 3 times thethe upper upper limit limit of normal; of normal; Grade Grade 3–5) 3–5) occurred occurred in 8in(2%) 8 (2%) YERVOY-treated YERVOY-treated patients, patients, with with fatal fatal hepatic hepatic failure failure in 0.2% in 0.2% andand hospitalization hospitalization in 0.4% in 0.4% of of YERVOY-treated YERVOY-treated patients. patients. AnAn additional additional 1313 (2.5%) (2.5%) patients patients experienced experienced moderate moderate hepatotoxicity hepatotoxicity manifested manifested by by liver liver function function testtest abnormalities abnormalities (AST (AST or ALT or ALT elevations elevations of more of more than than 2.52.5 times times butbut notnot more more than than 5 times 5 times thethe upper upper limit limit of normal of normal or or total total bilirubin bilirubin elevation elevation of more of more than than 1.51.5 times times butbut notnot more more than than 3 times 3 times thethe upper upper limit limit of normal; of normal; Grade Grade 2).2). TheThe underlying underlying pathology pathology was was notnot ascertained ascertained in all in all patients patients butbut in some in some instances instances included included immune-mediated immune-mediated hepatitis. hepatitis. There There were were insufficient insufficient numbers numbers of patients of patients with with biopsybiopsyproven proven hepatitis hepatitis to characterize to characterize thethe clinical clinical course course of this of this event. event. Monitor Monitor liver liver function function tests tests (hepatic (hepatic transaminase transaminase andand bilirubin bilirubin levels) levels) andand assess assess patients patients forfor signs signs andand symptoms symptoms of hepatotoxicity of hepatotoxicity before before each each dose dose of YERVOY. of YERVOY. In patients In patients with with hepatotoxicity, hepatotoxicity, rulerule outout infectious infectious or malignant or malignant causes causes andand increase increase frequency frequency of liver of liver function function testtest monitoring monitoring until until resolution. resolution. Permanently Permanently discontinue discontinue YERVOY YERVOY in in patients patients with with Grade Grade 3–53–5 hepatotoxicity hepatotoxicity andand administer administer systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent. equivalent. When When liver liver function function tests tests show show sustained sustained improvement improvement or or return return to to baseline, baseline, initiate initiate corticosteroid corticosteroid tapering tapering andand continue continue to to taper taper over over 1 month. 1 month. Across Across thethe clinical clinical development development program program forfor YERVOY, YERVOY, mycophenolate mycophenolate treatment treatment hashas been been administered administered in patients in patients who who have have persistent persistent severe severe hepatitis hepatitis despite despite high-dose high-dose corticosteroids. corticosteroids. Withhold Withhold YERVOY YERVOY in patients in patients with with Grade Grade 2 hepatotoxicity. 2 hepatotoxicity. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Dermatitis Dermatitis In Study In Study 1, severe, 1, severe, life-threatening, life-threatening, or fatal or fatal immune-mediated immune-mediated dermatitis dermatitis (eg,(eg, Stevens-Johnson Stevens-Johnson syndrome, syndrome, toxic toxic epidermal epidermal necrolysis, necrolysis, or or rash rash complicated complicated by by fullfull thickness thickness dermal dermal ulceration, ulceration, or or necrotic, necrotic, bullous, bullous, or or hemorrhagic hemorrhagic manifestations; manifestations; Grade Grade 3–5) 3–5) occurred occurred in in 1313 (2.5%) (2.5%) YERVOY-treated YERVOY-treated patients. patients. OneOne (0.2%) (0.2%) patient patient died died as as a result a result of toxic of toxic epidermal epidermal necrolysis necrolysis andand oneone additional additional patient patient required required hospitalization hospitalization forfor severe severe dermatitis. dermatitis. There There were were 6363 (12%) (12%) patients patients with with moderate moderate (Grade (Grade 2) dermatitis. 2) dermatitis.

Yrv0513pbs_731US13PBS02301wip2.indd Yrv0513pbs_731US13PBS02301wip2.indd1 1

The biologics license application for ramucirumab was based on data from REGARD, a global, randomized, double-blind phase III study of ramucirumab plus best supportive care vs placebo

plus best supportive care as a treatment in patients with advanced gastric cancer (including adenocarcinomas of the gastroesophageal junction) following progression after initial chemotherapy. n

TheThe median median time time to to onset onset of of moderate, moderate, severe, severe, or or life-threatening life-threatening immune-mediated immune-mediated dermatitis dermatitis was was 3.13.1 weeks weeks andand ranged ranged up up to 17.3 to 17.3 weeks weeks from from thethe initiation initiation of YERVOY of YERVOY (ipilimumab). (ipilimumab). Seven Seven (54%) (54%) YERVOY-treated YERVOY-treated patients patients with with severe severe dermatitis dermatitis received received high-dose high-dose corticosteroids corticosteroids (median (median dose dose 6060 mgmg prednisone/day prednisone/day or or equivalent) equivalent) forfor up up to 14.9 to 14.9 weeks weeks followed followed by by corticosteroid corticosteroid taper. taper. Of Of these these 7 patients, 7 patients, 6 had 6 had complete complete resolution; resolution; time time to resolution to resolution ranged ranged up up to 15.6 to 15.6 weeks. weeks. Of Of thethe 6363 patients patients with with moderate moderate dermatitis, dermatitis, 2525 (40%) (40%) were were treated treated with with systemic systemic corticosteroids corticosteroids (median (median of of 6060 mg/day mg/day of of prednisone prednisone or or equivalent) equivalent) forfor a median a median of of 2.12.1 weeks, weeks, 7 (11%) 7 (11%) were were treated treated with with only only topical topical corticosteroids, corticosteroids, andand 3131 (49%) (49%) diddid notnot receive receive systemic systemic or or topical topical corticosteroids. corticosteroids. Forty-four Forty-four (70%) (70%) patients patients with with moderate moderate dermatitis dermatitis were were reported reported to to have have complete complete resolution, resolution, 7 (11%) 7 (11%) improved improved to to mild mild (Grade (Grade 1) severity, 1) severity, andand 1212 (19%) (19%) hadhad no no reported reported improvement. improvement. Monitor Monitor patients patients forfor signs signs andand symptoms symptoms of of dermatitis dermatitis such such as as rash rash andand pruritus. pruritus. Unless Unless an an alternate alternate etiology etiology hashas been been identified, identified, signs signs or symptoms or symptoms of dermatitis of dermatitis should should be be considered considered immune-mediated. immune-mediated. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with Stevens-Johnson Stevens-Johnson syndrome, syndrome, toxic toxic epidermal epidermal necrolysis, necrolysis, or rash or rash complicated complicated by by fullfull thickness thickness dermal dermal ulceration, ulceration, or necrotic, or necrotic, bullous, bullous, or hemorrhagic or hemorrhagic manifestations. manifestations. Administer Administer systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent. equivalent. When When dermatitis dermatitis is controlled, is controlled, corticosteroid corticosteroid tapering tapering should should occur occur over over a period a period of of at at least least 1 month. 1 month. Withhold Withhold YERVOY YERVOY dosing dosing in patients in patients with with moderate moderate to severe to severe signs signs andand symptoms. symptoms. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] ForFor mild mild to to moderate moderate dermatitis, dermatitis, such such as as localized localized rash rash andand pruritus, pruritus, treat treat symptomatically. symptomatically. Administer Administer topical topical or systemic or systemic corticosteroids corticosteroids if there if there is no is no improvement improvement of symptoms of symptoms within within 1 week. 1 week. Immune-mediated Immune-mediated Neuropathies Neuropathies In In Study Study 1, 1, 1 case 1 case of of fatal fatal Guillain-Barré Guillain-Barré syndrome syndrome andand 1 case 1 case of of severe severe (Grade (Grade 3) 3) peripheral peripheral motor motor neuropathy neuropathy were were reported. reported. Across Across thethe clinical clinical development development program program of of YERVOY, YERVOY, myasthenia myasthenia gravis gravis andand additional additional cases cases of Guillain-Barré of Guillain-Barré syndrome syndrome have have been been reported. reported. Monitor Monitor forfor symptoms symptoms of of motor motor or or sensory sensory neuropathy neuropathy such such as as unilateral unilateral or or bilateral bilateral weakness, weakness, sensory sensory alterations, alterations, or paresthesia. or paresthesia. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with severe severe neuropathy neuropathy (interfering (interfering with with daily daily activities) activities) such such as as Guillain-Barré-like Guillain-Barré-like syndromes. syndromes. Institute Institute medical medical intervention intervention as as appropriate appropriate forfor management management of of severe severe neuropathy. neuropathy. Consider Consider initiation initiation of of systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day prednisone prednisone or or equivalent equivalent forfor severe severe neuropathies. neuropathies. Withhold Withhold YERVOY YERVOY dosing dosing in patients in patients with with moderate moderate neuropathy neuropathy (not(not interfering interfering with with daily daily activities). activities). [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in in FullFull Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Endocrinopathies Endocrinopathies In InStudy Study1, 1,severe severeto tolife-threatening life-threateningimmune-mediated immune-mediatedendocrinopathies endocrinopathies(requiring (requiringhospitalization, hospitalization, urgent urgent medical medical intervention, intervention, or or interfering interfering with with activities activities of of daily daily living; living; Grade Grade 3–4) 3–4) occurred occurred in 9in (1.8%) 9 (1.8%) YERVOY-treated YERVOY-treatedpatients. patients. All All9 9patients patientshadhadhypopituitarism hypopituitarismandandsome somehadhadadditional additionalconcomitant concomitant endocrinopathies endocrinopathies such such as as adrenal adrenal insufficiency, insufficiency, hypogonadism, hypogonadism, andand hypothyroidism. hypothyroidism. SixSix of of thethe 9 patients 9 patients were were hospitalized hospitalized forfor severe severe endocrinopathies. endocrinopathies. Moderate Moderate endocrinopathy endocrinopathy (requiring (requiring hormone hormone replacement replacement or or medical medical intervention; intervention; Grade Grade 2) occurred 2) occurred in 12 in 12 (2.3%) (2.3%) patients patients andand consisted consisted of hypothyroidism, of hypothyroidism, adrenal adrenal insufficiency, insufficiency, hypopituitarism, hypopituitarism, andand 1 case 1 case each each of of hyperthyroidism hyperthyroidism andand Cushing’s Cushing’s syndrome. syndrome. TheThe median median time time to to onset onset of of moderate moderate to to severe severe immune-mediated immune-mediated endocrinopathy endocrinopathy was was 1111 weeks weeks andand ranged ranged up up to to 19.3 19.3 weeks weeks after after thethe initiation initiation of YERVOY. of YERVOY. Of Of thethe 2121 patients patients with with moderate moderate to to life-threatening life-threatening endocrinopathy, endocrinopathy, 1717 patients patients required required long-term long-term hormone hormone replacement replacement therapy therapy including, including, most most commonly, commonly, adrenal adrenal hormones hormones (n=10) (n=10) andand thyroid thyroid hormones hormones (n=13). (n=13). Monitor Monitor patients patients forfor clinical clinical signs signs andand symptoms symptoms of of hypophysitis, hypophysitis, adrenal adrenal insufficiency insufficiency (including (including adrenal adrenal crisis), crisis), andand hyperhyperor 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, andand hypotension, hypotension, or or nonspecific nonspecific symptoms symptoms which which may may resemble resemble other other causes causes such such as as brain brain metastasis metastasis or or underlying underlying disease. disease. Unless Unless an an alternate alternate etiology etiology hashas been been identified, identified, signs signs or symptoms or symptoms of endocrinopathies of endocrinopathies should should be be considered considered immune-mediated. immune-mediated. Monitor Monitor thyroid thyroid function function tests tests andand clinical clinical chemistries chemistries at at thethe start start of of treatment, treatment, before before each each dose, dose, andand as as clinically clinically indicated indicated based based on on symptoms. symptoms. In aIn limited a limited number number of of patients, patients, hypophysitis hypophysitis was was diagnosed diagnosed by by imaging imaging studies studies through through enlargement enlargement of the of the pituitary pituitary gland. gland. Withhold Withhold YERVOY YERVOY dosing dosing in in symptomatic symptomatic patients. patients. Initiate Initiate systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent, equivalent, andand initiate initiate appropriate appropriate hormone hormone replacement replacement therapy. therapy. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Other Other Immune-mediated Immune-mediated Adverse Adverse Reactions, Reactions, Including Including Ocular Ocular Manifestations Manifestations TheThe following following clinically clinically significant significant immune-mediated immune-mediated adverse adverse reactions reactions were were seen seen in in lessless than than 1%1% of of YERVOY-treated YERVOY-treated patients patients in in Study Study 1: 1: nephritis, nephritis, pneumonitis, pneumonitis, meningitis, meningitis, pericarditis, pericarditis, uveitis, uveitis, iritis, iritis, andand hemolytic hemolytic anemia. anemia. Across Across thethe clinical clinical development development program program forfor YERVOY, YERVOY, thethe following following likely likely immune-mediated immune-mediated adverse adverse reactions reactions were were also also reported reported with with lessless than than 1%1% incidence: incidence: myocarditis, myocarditis, angiopathy, angiopathy, temporal temporal arteritis, arteritis, vasculitis, vasculitis,polymyalgia polymyalgiarheumatica, rheumatica,conjunctivitis, conjunctivitis,blepharitis, blepharitis,episcleritis, episcleritis,scleritis, scleritis,leukocytoclastic leukocytoclastic vasculitis, vasculitis, erythema erythemamultiforme, multiforme, psoriasis, psoriasis, pancreatitis, pancreatitis, arthritis, arthritis, autoimmune autoimmunethyroiditis, thyroiditis, sarcoidosis, sarcoidosis, neurosensory neurosensoryhypoacusis, hypoacusis, autoimmune autoimmunecentral centralneuropathy neuropathy(encephalitis), (encephalitis), myositis, myositis, polymyositis, polymyositis, andand ocular ocular myositis. myositis. Permanently Permanently discontinue discontinue YERVOY YERVOY forfor clinically clinically significant significant or or severe severe immune-mediated immune-mediated adverse adverse reactions. reactions. Initiate Initiate systemic systemic corticosteroids corticosteroids at aatdose a dose of 1ofto1 2tomg/kg/day 2 mg/kg/day prednisone prednisone or equivalent or equivalent forfor severe severe immuneimmunemediated mediated adverse adverse reactions. reactions. Administer Administer corticosteroid corticosteroid eyeeye drops drops to to patients patients who who develop develop uveitis, uveitis, iritis, iritis, or or episcleritis. episcleritis. Permanently Permanently discontinue discontinue YERVOY YERVOY forfor immune-mediated immune-mediated ocular ocular disease disease thatthat is unresponsive is unresponsive to local to local immunosuppressive immunosuppressive therapy. therapy. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] ADVERSE ADVERSE REACTIONS REACTIONS TheThe following following adverse adverse reactions reactions areare discussed discussed in greater in greater detail detail in other in other sections sections of the of the labeling. labeling. • •Immune-mediated Immune-mediated enterocolitis enterocolitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated hepatitis hepatitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated dermatitis dermatitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated neuropathies neuropathies [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated endocrinopathies endocrinopathies [see [see Warnings Warnings andand Precautions]. Precautions]. • •Other Other immune-mediated immune-mediated adverse adverse reactions, reactions, including including ocular ocular manifestations manifestations [see [see Warnings Warnings andand Precautions]. Precautions].

10/3/13 10/3/135:26 5:26 PM PM

The ASCO Post | NOVEMBER 15, 2013

PAGE 34

Expert’s Corner Thoracic Oncology

Oncogene Addiction and the Rationale for Molecular Targeted Therapy in Lung Cancer A Conversation With Fadlo R. Khuri, MD By Jo Cavallo

ver the past decade, Fadlo R. Khuri, MD, Professor and Roberto C. Goizueta Distinguished Chair

of Hematology and Medical Oncology, and Deputy Director of the Winship Cancer Institute of Emory University,

Atlanta, has focused his research and clinical career on investigating novel approaches in the treatment and pre-

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. The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. 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. Table 1:

YERVOY 3 mg/kg n=131

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

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

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:

DRUG INTERACTIONS

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.

Percentage (%) of Patientsa

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

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 with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

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.

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. Including intestinal perforation. c Underlying etiology not established. b

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

Yrv0513pbs_731US13PBS02301wip2.indd 2

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.]

vention of lung and upper aerodigestive tract cancer. His studies—for example, showing that the expression of retinoic acid receptor (RAR) and cyclooxygenase (COX)-2 indicate poor prognosis in lung cancer and prognostic factors such as death-associated protein kinase (DAPK) methylation and lack of interleukin (IL)-10 expression independently predict cancer-specific survival—have spurred a greater understanding of individualized adjuvant therapy for patients with lung cancer. Dr. Khuri’s research in the development of novel cancer drugs has also led to new opportunities to target drivers of oncogene addiction, a phenomenon that describes the use of therapies to enhance the dependency of cancer cells to certain signaling pathways, such as EGFR, ALK, ROS, and RET. Earlier this year, Dr. Khuri was recognized for his research accomplishments in lung and aerodigestive medical oncology at the American Association for Cancer Research Annual Meeting, where he received the Richard and Hinda Rosenthal Memorial Award. In July, Dr. Khuri gave a review of new developments in novel therapeutics for lung cancer at the Debates and Didactics in Hematology and Oncology conference held on Sea Island, Georgia. The ASCO Post talked with him about his presentation, the phenomenon of oncogene addiction, progress being made in lung cancer survival, and the danger of the growing popularity of electronic cigarettes.

OVERDOSAGE

Oncogene Addiction

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.

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Rev May 2013 731US13PBS02301

Please explain the phenomenon called oncogene addiction and how it provides a rationale for molecular targeted therapy. My original medical school mentor, Dr. I. Bernard Weinstein, coined the term “oncogene addiction” in 2002. It indicates that cancer cells, which develop a dependency on certain oncogenically driven pathways, become disproportionally dependent on those pathways. Examples include EGFR and ALK in lung cancer and HER2/neu in breast cancer. The classic example is BCR-ABL in chronic myelogenous leukemia. Interrupting those pathways by targeting the kinase domain mutation or blocking the oncogenic signaling in

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Expert’s Corner

some manner makes the cancer cells much more vulnerable than normal cells because the normal cells are not as “addicted” or dependent on those pathways. Targeting drivers of oncogene addiction has been an area of explosive progress in the past decade. In our view, however, most lung cancer cells are not simply addicted to one oncogenic driver mutation. At the Lung Cancer Mutation Consortium, we looked at over 1,000 lung cancer cases and identified oncogenic drivers in about 64% of those patients. Some of the driver mutations such as EGFR, ALK, ROS, or RET are targetable with novel agents. For others, like RAS, we don’t yet have great drugs or approaches for targeting them. Ultimately we should be able to target the majority of lung adenocarcinomas or squamous cell lung cancers. The challenge will be in overcoming drug resistance that emerges in tumors with those mutations. Drug resistance often develops when the tumor cell acquires a second mutation, which has been shown in some of the ALK and VEGFR data. But we are looking at survival signaling networks to see if there is a way to interrupt or reroute the whole network, using the cancer cell’s dependence on the pathway to make it even more addicted, so that a second hit along that signaling network with a targeted therapy will be devastating for the cancer, without causing serious side effects.

Resistance Mechanisms Which resistance pathways have emerged in lung cancers for first-generation targeted therapies? Some agents such as crizotinib (Xalkori) are effective at targeting MET amplification and ALK and are already in use in the clinic. We are developing agents that target the second EGFR T790 mutation. So it’s an excit-

ing time because we have developed not only drugs that can target reasonably effective approaches to the initial oncogenic driver mutation but also approaches to the second escape mechanism. There is a lot of work going on now in resistance mechanisms and the development of therapies to target them. These are advances patients didn’t have 5 or 10 years ago.

KRAS Mutations In your presentation, you said that targeting KRAS-mutant lung cancer is still a challenge. Could you expand on that? One of the major points of my presentation was about the heat shock

particularly in patients who didn’t have early progression, but people were still disappointed that it didn’t seem to specifically target KRAS-mutant lung cancers.

Immunotherapy How effective are immunotherapies such as PD-L1 in the treatment of lung cancer? Early data on immunotherapy in lung cancer show that responses are small but meaningful. What is interesting about these responses is that they are durable. Now that we have more evidence from clinical studies, we’re starting to

Ultimately we should be able to target the majority of lung adenocarcinomas or squamous cell lung cancers. The challenge will be in overcoming drug resistance that emerges. —Fadlo R. Khuri, MD

protein (Hsp)90 inhibitors and the GALAXY-1 trial, which combined the Hsp90 inhibitor ganetespib with docetaxel vs docetaxel alone for secondline therapy of lung adenocarcinoma. Although the study data were promising, overall it was a cautionary tale. I was one of the coauthors on the GALAXY-1 abstract presented at the ASCO Annual Meeting this year,2 and we had very interesting data suggesting that ganetespib plus docetaxel vs docetaxel alone seemed to show an advantage in progression-free survival. But that benefit was not specific to patients with KRAS mutations, which is where some of our original hope was, because this is a mutation for which we don’t yet have effective therapies. So here was a trial that looked positive,

understand who can have a really durable response, based on patient biomarkers. But I don’t think we have the final answer on PD-L1 because PD-L1 staining on the tumors of about 20% of responders has been negative.

Longer Remissions, No Cures More effective therapies have resulted in extended remissions for patients with advanced lung cancer. Is it now possible to cure some patients with advanced disease? So far, we have been successful in achieving longer remissions but not cures. When I started my residency, patients with lung cancer were living 3 to 4 months and chemotherapy was experimental. Now, patients with metastatic disease live 1 year longer on average. We’re not very good yet at detecting

disease early, but we are getting better. Some of the barriers to early detection include insufficient application of smoking cessation programs and of routine screening. Just as in diseases like diabetes, you want to get good control early on in lung cancer.

E-Cigarettes A recent story in The New York Times reported on the popularity of electronic cigarettes,2 which use a nicotine solution instead of tobacco and emit a smoke-like water vapor. What is your take on e-cigarettes? I’m not in favor of e-cigarette use. We need to have more complete approaches to smoking cessation programs. I’ve seen these failures, and they don’t help people stop smoking. It is also very troubling that young people are adopting the practice of e-cigarettes because, while they may seem cool and harmless, e-cigarettes could well put people on the path to picking up a cigarette again. We know that smoking tobacco impacts on cancer survival and on second primary tumor development. It causes erratic metabolism of chemotherapy as well as increasing perioperative risk in potentially curable patients. To help patients quit smoking, oncologists need to be not just documenting smoking status, but implementing smoking cessation approaches for their patients. n Disclosure: Dr. Khuri reported no potential conflicts of interest.

References 1. Ramalingam SS, Goss GD, Andric ZG, et al: A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). 2013 ASCO Annual Meeting. Abstract CRA8007. Presented June 3, 2013. 2. Kurutz S: Smoking is back, without the stigma. New York Times. August 7, 2013.

November Is

Lung Cancer Awareness Month.

See pages 13, 18, 36 and 67 for lung cancer news in The ASCO Post.

The ASCO Post | NOVEMBER 15, 2013

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15th World Conference on Lung Cancer Thoracic Oncology

Investigational ALK Inhibitor Shows Promise in Patients With Crizotinib-Refractory, ALK-Positive NSCLC

atients with non–small cell lung cancer (NSCLC) whose tumors have the ALK gene rearrangement usually respond to the drug crizotinib (Xalkori), with a median duration of response of approximately 10 months. In a study reported by Shirish Gadgeel, MD, of Karmanos Cancer Institute in Detroit, and colleagues at the International Association for the Study of Lung Cancer’s 15th World Conference on Lung Cancer, alectinib showed promising tumor activity in patients with ALK-positive NSCLC who were refractory to crizotinib. Alectinib is a potent ALK inhibitor recently granted Breakthrough Therapy designation by the FDA.1

had progressed on crizotinib and chemotherapy. The primary endpoint was dose-limiting toxicity, with secondary endpoints of efficacy, safety, and pharmacokinetic analyses. The ALK inhibitor was administered orally at doses ranging from 300 to 900 mg twicedaily until lack of clinical benefits. Researchers found promising tumor activity with alectinib. In the 37 patients who received a therapeutic dose (≥ 460 mg twice daily), alectinib demonstrated an overall response rate of 59.5%. Median progression-free survival had not been reached after over 5 months of follow-up. No doselimiting toxicities were observed up to the highest dose tested (900 mg twice-daily), and only one patient required dose modification due to grade 2 fatigue.

Phase I Study

Effect on Brain Metastases

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

In a phase I dose-escalation study, alectinib was administered to 37 patients with ALK-positive NSCLC that

In addition, alectinib showed significant shrinkage of brain metastases,2 with only 4 of the 21 patients

References 1. Gadgeel S, Ou SH, Chiappori A, et

Phase I Study of Alectinib in ALK-Positive NSCLC ■■ In the 37 patients who received a therapeutic dose of alectinib, the ALK inhibitor demonstrated an overall response rate of 59.5%.

■■ Median progression-free survival had not yet been reached after over 5 months of follow-up.

■■ Alectinib showed significant shrinkage of brain metastases in patients who were enrolled with preexisting central nervous system lesions.

who were enrolled with preexisting brain metastases having discontinued treatment due to disease progression. Activity against brain metastases was observed as early as the third week of treatment, and the investigators noted that alectinib could “potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.” n

al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013. 2. Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

Pemetrexed Improves Progression-Free Survival vs Gefitinib in Second-Line Setting for EGFR Wild-Type Nonsquamous NSCLC

oth pemetrexed (Alimta) and gefitinib (Iressa) are standard second-line treatments for advanced nonsquamous non–small cell lung cancer (NSCLC) in East Asia. In a phase II trial (CTONG 0806) reported at the International Association for the Study of Lung Cancer’s 15th World Conference on Lung Cancer, Qing Zhou, MD, of Guangdong Lung Cancer Institute in China, and colleagues evaluated the efficacy of pemetrexed vs gefitinib as second-line treatment in advanced nonsquamous NSCLC with wild-type EGFR (Abstract O15.07).

Study Details This multicenter, randomized, controlled, open-label study enrolled 157 patients with locally advanced or metastatic nonsquamous NSCLC from

February 2009 to August 2012. The patients had previously been treated with platinum-based chemotherapy and had wild-type EGFR. Patients

the gefitinib arm (hazard ratio = 0.54, 95% confidence interval = 0.40–0.75, P < .001). A significant difference between the two arms in 4-month pro-

Pemetrexed vs Gefitinib in Second-Line Treatment of NSCLC ■■ Patients in the pemetrexed arm had a median progression-free survival of 4.8 months vs 1.6 months in the gefitinib arm.

■■ A significant difference between the two arms in 4-month progression-free survival, 6-month progression-free survival, and disease-control rate was also observed.

■■ A trend toward improved overall survival was seen in the pemetrexed arm. were randomly assigned to receive oral gefitinib or intravenous pemetrexed until disease progression or unacceptable toxicity. The primary endpoint of the study was progression-free survival. The median progression-free survival for patients in the pemetrexed arm was 4.8 months vs 1.6 months in

gression-free survival (59% vs 33% for pemetrexed vs gefitinib, respectively), 6-month progression-free survival (43% vs 23%), and disease-control rate (60.5% vs 29.6%) was also observed. A trend toward improved overall survival was seen in the pemetrexed arm (12.4 vs 9.6 months). This is the first study to show sig-

nificant improvement in progressionfree survival, disease-control rate, and a trend of improving overall survival with pemetrexed compared with gefitinib in the second-line setting for patients in this population. “This study will likely change the way patients with advanced nonsquamous NSCLC are treated with second-line therapy,” said Dr. Zhou. n Disclosure: Dr. Zhou reported no potential conflicts of interest.

Reference 1. Zhou Q, Cheng Y, Zhao MF, et al: Final results of CTONG 0806: A phase II trial comparing pemetrexed with gefitinib as second-line treatment of advanced nonsquamous NSCLC patients with wild-type EGFR. Abstract O15.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013. See page 67 for more from the 15th World Conference on Lung Cancer.

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The ASCO Post | NOVEMBER 15, 2013

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JCO Spotlight Gastrointestinal Oncology

Brivanib Studied in First- and Second-Line Therapy for Advanced Hepatocellular Carcinoma By Matthew Stenger

he investigational drug brivanib is a dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, both implicated in hepatocellular carcinoma. The agent was recently evaluated in two phase III trials, one comparing first-line brivanib with sorafenib (Nexavar) in advanced hepatocellular carcinoma (BRISK-FL trial) and one comparing brivanib plus best supportive care vs placebo plus best supportive care in patients with advanced hepatocellular carcinoma in whom sorafenib therapy failed or was not tolerated (BRISK-PS trial). In BRISK-FL, brivanib did not meet the criterion for noninferiority in overall survival compared with sorafenib. In BRISK-PS, brivanib did not improve overall survival, although benefits in response rate and time to progression were observed.

status (0 in 64% and 61%), Barcelona Clinical Liver Cancer stage (eg, C in 77% and 78%), Child-Pugh class (A in 92% in both), macrovascular invasion (no in 73% of both), portal vein invasion/thrombosis (yes in 19% of both), distant metastasis (49% and 50%), regional lymph node metastasis (27% and 28%), extrahepatic spread/macrovascular invasion (63% and 62%), alpha-fetoprotein level (median, 142 and 180 ng/mL), risk factors (any in 78% and 75%, hepatitis B virus in 44% and 45%), and previous nonsystemic treatment (55%

The primary endpoint of overall survival noninferiority for brivanib vs sorafenib in the per-protocol population was not met (hazard ratio [HR] = 1.06, 95.8% confidence interval [CI] = 0.93–1.22, P = .373), based on the prespecified noninferiority margin (upper CI limit for HR ≤ 1.08). Median overall survival was 9.5 months in the brivanib group and 9.9 months in the sorafenib group. Overall survival results were similar in the intent-to-treat popula-

[The BRISK-FL] study did not meet its primary [overall survival] objective in the first-line treatment of advanced [hepatocellular carcinoma], based on a noninferiority statistical design, but it did show similar antitumor activity for brivanib and sorafenib.

BRISK-FL Trial

—Philip J. Johnson, MD, and colleagues

In the multinational phase III BRISK-FL trial, reported in the Journal of Clinical Oncology by Philip J. Johnson, MD, of the Institute of Translational Medicine, University of Liverpool, and colleagues,1 1,155 patients with advanced hepatocellular carcinoma and no prior systemic therapy were randomly assigned to oral sorafenib at 400 mg twice daily (n = 578) or oral brivanib at 800 mg once daily (n = 577). The primary endpoint was overall survival.

Study Details In total, 62% of patients were from Asia, 23% from Europe, 13% from the Americas, 0.8% from Australia, and 0.6% from Africa. The brivanib and sorafenib groups were generally well matched for age (median, 61 and 60 years), sex (84% male in both), region (eg, Asia for 60% and 64%), Eastern Cooperative Oncology Group (ECOG) performance

and 56%; liver resection in 28% and 30%, transcatheter arterial chemoembolization in 35% and 36%). A total of 1,150 patients were treated in the BRISK-FL trial (perprotocol population). At the time of the final analysis, 6% of the brivanib group and 11% of the sorafenib group remained on study. The most common reasons for study discontinuation were disease progression (46% in the brivanib group and 53% in the sorafenib group) and study drug toxicity (24% and 15%). Median duration of treatment was 3.2 months in the brivanib group and 4.1 months in the sorafenib group. Poststudy systemic treatments were received by 22% of the brivanib group and 21% of the sorafenib group, and nonsystemic treatments were received by 19% and 17%.

BRISK-FL Trial ■■ Brivanib did not meet the overall survival noninferiority criterion vs

sorafenib as first-line treatment of advanced hepatocellular carcinoma.

■■ Similar antitumor activity of the two treatments was indicated by similar time to progression and objective response rates.

■■ Brivanib had an acceptable safety profile but was less well-tolerated compared with sorafenib.

Overall Survival Noninferiority

tion (HR = 1.07, 95.8% CI = 0.94– 1.23, P = .312). Results for subgroups were consistent with those for the overall study population. On multivariate analysis, significant prognostic factors for overall survival were alpha-fetoprotein, tumor morphologic features, size of the largest nodule, Child-Pugh score, and major portal vein invasion. After adjusting for baseline factors, the effect of brivanib vs sorafenib remained unchanged (HR = 1.09, 95% CI = 0.95– 1.25).

Secondary Endpoints Median time to progression was 4.2 months in the brivanib group and 4.1 months in the sorafenib group (P = .853), objective response rate was 12% vs 9% (P = .057), and disease control rate was 66% vs 65% (P = .874). Among patients with baseline alpha-fetoprotein ≥ 200 ng/mL and at least one on-study alpha-fetoprotein assessment, alpha-fetoprotein reduction ≥ 50% from baseline was observed in 58% of brivanib patients vs 31% of sorafenib patients. Similar reductions were observed when the baseline cutoff used was the upper limit of normal or 400 ng/mL.

Adverse Events Among adverse events of any grade, hand-foot skin reaction, alopecia, rash, and pyrexia were more frequent in sorafenib patients and decreased appetite, fatigue, hypertension, nausea, vomiting, hyponatremia, headache, dysphonia, and dizziness were more frequent in brivanib patients. Diarrhea, abdominal pain, constipation, hyperbilirubinemia, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), and weight loss occurred at a similar rate in the two groups. The most frequent grade 3 or 4 adverse events were hyponatremia (23% in brivanib group vs 9% in sorafenib group), AST elevation (14% vs 17%), fatigue (15% vs 7%), hand-foot skin reaction (2% vs 15%), and hypertension (13% vs 5%). Treatment was discontinued due to adverse events in 43% of brivanib patients and 33% of sorafenib patients, with the most common reasons being fatigue (5%), hyponatremia (2%), decreased appetite (2%), hyperbilirubinemia (2%), and AST elevations (2%) in the brivanib group and hyperbilirubinemia (3%) and AST elevations (2%) in the sorafenib group. Dose reduction occurred in 49% and 50% of patients, and dose interruption occurred in 58% of both groups. The investigators concluded: “This study did not meet its primary [overall survival] objective in the first-line treatment of advanced [hepatocellular carcinoma], based on a noninferiority statistical design, but it did show similar antitumor activity for brivanib and sorafenib, based on time to progression, objective response rate, and disease control rate. Brivanib had an acceptable safety profile; however, it was less well-tolerated than sorafenib.”

BRISK-PS Trial This multinational phase III trial—the first phase III brivanib trial in patients who have already received sorafenib—enrolled 395 patients with advanced hepatocellular carcinoma whose disease progressed on/ after sorafenib or who were intolerant of sorafenib. Patients were randomly assigned (2:1) to receive oral brivanib

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JCO Spotlight

at 800 mg once daily plus best supportive care (n = 263) or placebo plus best supportive care (n = 132). The primary endpoint was overall survival. The study was reported in the Journal of Clinical Oncology by Josep M. Llovet, MD, of the Icahn School of Medicine at Mount Sinai in New York, and colleagues.2

Study Details Overall, 42% of patients were from Europe, 41% from Asia, and 17% from the Americas. The brivanib and placebo groups were generally well matched for age (median, 64 and 62 years), sex (82% and 86% male),

vs 18%), including portal vein invasion/ thrombosis (25% vs 12%), and a higher alpha-fetoprotein level (median, 204 vs 100 ng/mL). Study treatment was discontinued in 90% of brivanib patients and 92% of placebo patients, with the most common reasons being disease progression (50% and 70%) and study drug toxicity (23% and 7%). Median treatment duration was 3.1 months for brivanib and 2.5 months for placebo. After discontinuation of study treatment, 27% of the brivanib group and 35% of the placebo group received systemic therapies and 18% and 20% received nonsystemic treatments.

In patients with [hepatocellular carcinoma] who had been treated with sorafenib, brivanib did not significantly improve [overall survival in the BRISK-PS trial]. The observed benefit in the secondary outcomes … warrants further investigation. —Josep M. Llovet, MD, and colleagues

race (46% and 50% white, 48% and 45% Asian), reason for sorafenib discontinuation (progression in 86% and 88%), prior nonsystemic treatment (any in 80% and 73%; transcatheter chemoembolization in 57% and 49%, liver resection in 39% and 36%), ECOG performance status (0 in 57% and 61%), Barcelona Clinical Liver Cancer stage (C in 87% and 85%), Child-Pugh class (A in 92% and 91%), distant metastasis (65% and 64%), regional lymph node metastasis (35% and 36%), and risk factors (any in 83% and 85%, hepatitis B virus infection in 39% and 34%). The brivanib group had more patients with vascular invasion (31%

Overall Survival Outcome Overall survival was not significantly improved in the brivanib vs placebo group (HR = 0.89, 95.8% CI = 0.69–1.15, P = .331); median overall survival was 9.4 and 8.2 months, respectively. Overall survival results across prespecified subgroups were generally consistent with the primary overall survival analysis. On multivariate analysis, alphafetoprotein (< 200 ng/mL vs ≥ 200 g/mL, P < .001) and portal vein invasion (no vs yes, P < .001) were significant prognostic factors for overall survival. After adjustment for all prespecified factors, the hazard ratio for overall survival for brivanib vs

BRISK-PS Trial ■■ Brivanib plus best supportive care did not significantly improve overall

survival compared with placebo plus best supportive care in patients with advanced hepatocellular carcinoma who had already received or were intolerant of sorafenib.

■■ Brivanib treatment was associated with significant improvements in time to progression and response and disease control rates.

placebo was 0.81 (P = .1044). Post hoc analyses using poststudy treatments as a time-dependent covariate did not show an impact of poststudy treatment on overall survival.

Secondary Endpoints Time to progression was significantly longer in the brivanib group (median, 4.2 vs 2.7 months, HR = 0.56, P < .001), including after adjustment for baseline prognostic factors (HR = 0.56, 95% CI = 0.42–0.76). The objective response rate was also significantly higher with brivanib treatment (10% vs 2%, odds ratio [OR] = 5.75, P = .0030), as was disease control rate (61% vs 40%, OR = 2.38, P < .001). Among patients with baseline alpha-fetoprotein greater than the upper limit of normal, a reduction of ≥ 50% from baseline occurred in 54% of brivanib patients and 7% of placebo patients.

Adverse Events Study discontinuation due to treatment-related adverse events occurred in 23% of brivanib patients and 7% of placebo patients. The most frequent treatment-related grade 3 or 4 adverse events in the brivanib group included hypertension (17% vs 2%), fatigue (13% vs 1%), hyponatremia (11% vs 2%), and decreased appetite (10% vs 2%). The most frequent grade 3 or 4 laboratory abnormalities were hyponatremia (27% vs 14%), AST increase (27% vs 24%), and hy-

perbilirubinemia (21% vs 18%). Six deaths on study were considered by investigators as possibly related to treatment, all of which were in the brivanib arm and occurred within 30 days of the final dose. Two of the deaths were a result of encephalopathy, and one each was due to liver failure, acidosis, sudden death, and coma/cerebral edema. The investigators concluded: “In patients with [hepatocellular carcinoma] who had been treated with sorafenib, brivanib did not significantly improve [overall survival]. The observed benefit in the secondary outcomes of [time to progression] and objective response rate warrants further investigation…. The results of our trial may inform the design of future studies in this patient population.” n

Disclosure: The studies were supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit jco.ascopubs.org.

References 1. Johnson PJ, Qin S, Park J-W, et al: Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study. J Clin Oncol 31:35173524, 2013. 2. Llovet JM, Decaens T, Raoul J-L, et al: Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: Results from the randomized phase III BRISK-PS study. J Clin Oncol 31:3509-3516 2013. See commentary on page 44

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JCO Spotlight Continued from page 43

Brivanib Fails to Live Up to the Promise of Early Studies By Laura Williams Goff, MD, MS

epatocellular carcinoma is a devastating disease worldwide. Although advances in liver transplantation, surgery, and locoregional therapies have made tumor control or even cure possible for a minority of patients, the majority of patients diagnosed with hepatocellular carcinoma will develop advanced-stage disease for which systemic therapy is the only option. Unfortunately, cytotoxic chemotherapy has been largely ineffective, and the only agent shown to definitively improve survival has been sorafenib (Nexavar), which targets vascular endothelial growth factor (VEGF) among other signaling pathways.1 Still, the results are far from spectacular, with frequent intolerance to sorafenib and shortlived responses. Therefore, new treatments are desperately needed in hepatocellular carcinoma for both untreated patients as well as those with refractory disease.

Drug Development Because of the vascular nature of hepatocellular carcinoma and the efficacy of sorafenib, many of the treatments in development have focused on the VEGF pathway, its inhibitors, and its resistance pathways. Fibroblast growth factor (FGF) and its receptors have been shown to drive angiogenesis directly, as well as function as a resistance mechanism for overcoming VEGF inhibition.2,3 Brivanib is a tyrosine kinase inhibitor of both VEGF and FGF receptors and therefore a seemingly ideal candidate drug to be considered for use in hepatocellular carcinoma, either initially or in refractory disease.4 Results in preclinical models with cell lines and xenografts looked promising, and phase II studies in patients with untreated or progressive hepatocellular carcinoma after prior antiangiogenic therapy demonstrated that the majority of patients had disease Dr. Goff is Assistant Professor of Medicine, Vanderbilt-Ingram Cancer Center, Associate Program Director, Vanderbilt HematologyOncology Fellowship Program, Vanderbilt University School of Medicine, Nashville.

control with provocative survival times observed.5,6 Consequently, two large phase III studies of brivanib in hepatocellular carcinoma were launched—the BRISK-FL study in first-line therapy and the BRISK-PS study in patients whose disease progressed on or who were intolerant of sorafenib.7,8 Unfortunately, neither study met its endpoint to demonstrate activity of brivanib in hepatocellular carcinoma.

Key Results In the BRISK-FL study, previously untreated patients were randomly assigned in equal numbers to brivanib or sorafenib. The primary

sults were disappointing. Although there was an observed response rate of 10% using the modified RECIST criteria, overall survival was not significantly improved over treatment with placebo. Interestingly, the survival time for the group treated with placebo was significantly longer than that observed in other second-line studies, and the authors do cite an imbalance in the rate of vascular invasion in the brivanib group (31%) compared to placebo (18%) as a potential confounding factor. Still, a prespecified analysis controlling for all baseline factors failed to reach statistical significance for prolonging overall survival.

Optimizing VEGF blockade and overcoming resistance to blockade are clearly not enough to treat advanced hepatocellular carcinoma. An understanding of other drivers of hepatocellular carcinoma will be essential to improve outcomes. —Laura Williams Goff, MD, MS

endpoint was noninferiority of overall survival with brivanib compared to sorafenib. This was not demonstrated, although the numeric values were in line with previously observed median survival times (9.9 months for sorafenib and 9.5 months for brivanib). Probably more importantly, overall rates of adverse events were higher with brivanib, although hand-foot syndrome occurred less frequently with brivanib. Thus, brivanib was less tolerable and resulted in survival inferior to sorafenib, clearly disappointing and echoing the failure of sunitinib (Sutent) to improve upon standard first-line treatment with sorafenib.9 Patients who had been previously treated with sorafenib and were either intolerant of or showing disease progression on that drug were enrolled on the BRISK-PS study and randomly assigned 2:1 to brivanib or placebo. Again, the re-

Conclusions Optimizing VEGF blockade and overcoming resistance to blockade are clearly not enough to treat advanced hepatocellular carcinoma. Moving forward, an understanding of other drivers of hepatocellular carcinoma apart from the VEGF pathway that may be synergistic with antiangiogenic drugs will be essential to substantially improve outcomes for patients. The role of cytotoxic chemotherapy as potentially complementary to sorafenib is under investigation in the ongoing Cancer and Leukemia Group B (CALGB) 80802 study looking at sorafenib with or without doxorubicin. Other traditional chemotherapy regimens such as GEMOX (gemcitabine, oxaliplatin) and FOLFOX (leucovorin, fluorouracil, oxaliplatin) have shown interesting results. Agents such as cetuximab (Erbitux), erlotinib (Tarceva), evero-

limus (Afinitor), cabozantinib (Cometriq), tivantinib, and others that do not primarily target angiogenesis are being explored as ways to build on the benefits and limitations seen with sorafenib treatment in hepatocellular carcinoma. n Disclosure: Dr. Goff has received research funding from Bristol-Myers Squibb, OSI/ Astellas, Roche, Pfizer, Sanofi, and Amgen.

References 1. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008. 2. Bergers G, Hanahan D: Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592-603, 2008. 3. Uematsu S, Higashi T, Nouso K, et al: Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 20:583-588, 2005. 4. Huynh H, Ngo VC, Fargnoli J, et al: Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res14:61466153, 2008. 5. Finn RS, Kang YK, Mulcahy M, et al: Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 18:20902098, 2012. 6. Park JW, Finn RS, Kim JS, et al: Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 17:1973-1983, 2011. 7. Johnson PJ, Qin S, Park J-W, et al: Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISKFL study. J Clin Oncol 31:3517-3524, 2013. 8. Llovet JM, Decaens T, Raoul J-L, et al: Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 31:3509-3516, 2013; doi: 10.1200/ JCO.2012.47.3009. 9. Cheng A, Kang Y, Lin D, et al: Phase III trial of sunitinib versus sorafenib in advanced hepatocellular carcinoma. J Clin Oncol 29(suppl):Abstract 4000, 2011.

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL

WITH ZELBORAF

Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

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

Percentage surviving

80 60 Not reached

7.9

40 20 0

ZELBORAF (n=337)

6 8 OS (months)

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Significant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | NOVEMBER 15, 2013

PAGE 48

Perspective Hematologic Oncology See related news item on page 29

Brian J. Druker, MD, Discusses Ponatinib

n an interview with The ASCO Post following FDA’s recommendation that sales of ponatinib (Iclusig) be suspended, (see page 29) Brian J. Druker, MD, Direc-

tor of Oregon Health & Science University Knight Cancer Institute and JELD-WEN Chair of Leukemia Research, had concerns about obtaining the drug for those patients Safety:7"

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily. Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure. ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine. Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade All Grade Grade All All a Other Malignancies 3a Grades 3 Grades 3 Grades (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies. Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

Patients With T3151 Mutation “Right now if a patient came in

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

Brian J. Druker, MD

with a T3151 mutation, which doesn’t respond to any other medication, I don’t know that I can get that patient ponatinib. I haven’t seen any instructions or guidance about how to get access to this medication. I know that Ariad is working very hard with the FDA to come up with a plan but I haven’t seen anything yet,” said Dr. Druker.

Adverse Events In clinical trials conducted before ponatinib’s approval, serious blood clots occurred in 8% of patients taking the drug and blood clots in the veins occurred in 3% of patients. More recent data found approximately 24% of patients in the phase II clinical trial (median treatment duration, 1.3 years) and approximately 48% of patients in the phase I clinical trial (median duration, 2.7 years) experienced serious adverse vascular events. The events included life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow. “We clearly have to take the FDA review quite seriously,” said Dr. Druker. “[But] I have to say that I have lots of patients who are doing extremely well on [ponatinib]. They had no other treatment options. I hope that we will be able to continue to treat them and should be able to treat other patients in a similar circumstance who have no other decent treatment options.” n

Safety:10"

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

who may respond and have no other treatment option.

What’s Your Opinion? Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

ASCOPost.com | NOVEMBER 15, 2013

PAGE 49

Inside the Black Box Neoadjuvant Treatment of Early Breast Cancer A Conversation With FDA’s Office of Hematology and Oncology Products INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures. In this first installment, FDA Clinical Reviewers Laleh Amiri-Kordestani, MD, and Suparna Wedam, MD, discuss FDA’s recent approval of pertuzumab (Perjeta) for the neoadjuvant treatment of HER2-positive, high-risk early breast cancer. Dr. Amiri and Dr. Wedam are Medical Officers with the Breast/Gynecologic Cancer Team in the Office of Hematology and Oncology Products.

tient level, but not at a trial level. However, this analysis does not preclude the use of pathologic complete response to support an accelerated approval, because the effect sizes in the trials used in the analysis were relatively small. Once accelerated approval is granted based on pathologic complete response, confirmation of clinical benefit (eg, improvement in event-free, disease-free, or overall survival) is required in order to convert to a regular approval.

Surrogate Endpoint

n September 30, 2013, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pertuzumab (Perjeta) for the neoadjuvant treatment of HER2-positive highrisk early breast cancer. Here Dr. Amiri and Dr. Wedam respond to questions about the processes leading to pertuzumab’s accelerated approval.

Evaluating Neoadjuvant Therapy What is the rationale for neoadjuvant therapy for breast cancer? Dr. Amiri: Neoadjuvant therapy for breast cancer was first developed to help make inoperable tumors operable and to increase the rate of breast conservation. Also, neoadjuvant trials provide a unique opportunity to study modulation of tumor biomarkers and have the potential to guide and improve the design of adjuvant trials. Regimens that are given in the adjuvant setting are commonly used in the neoadjuvant setting, knowing that survival is similar whether chemotherapy is given before or after surgery.1 From a drug development perspective, using pathologic complete response rate as the primary endpoint is very appealing since it can be assessed relatively quickly. Please explain the FDA’s view on evaluating new drugs in the neoadjuvant setting. Why is the agency interested in this? Dr. Wedam: Typically, drug development is a lengthy and expensive process. Demonstration of an improvement in disease-free survival or overall survival for a new treatment for patients with early breast cancer in the adjuvant

setting requires a large trial that takes many years to complete. Thus, pharmaceutical companies first test drugs in the metastatic setting, where endpoints can be obtained faster. Despite many recent approvals in the treatment of metastatic breast cancer, the process of drug development for patients with early breast cancer— especially for high-risk or poor prognosis populations—has been slow. In the past decade, only one drug has been approved for this early breast cancer high-risk population.2 What is the FDA doing to help facilitate this process? Dr. Amiri: FDA’s accelerated approval regulations are intended to facilitate availability of drugs for treatment of a serious or life-threatening disease that provide meaningful therapeutic benefit over available therapy.3 The agency would like to expedite the process and help patients with high-risk early breast cancer gain access to promising new agents earlier.4 To help facilitate the neoadjuvant drug development pathway, the FDA has released a draft guidance titled, “Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.”5 With the collaboration of many international groups, FDA conducted a pooled-analysis of many neoadjuvant breast cancer trials.6 Pathologic complete response was shown to correlate well with long-term outcome at a pa-

The FDA facilitated a transparent, open discussion about using pathologic complete response as a surrogate endpoint to support accelerated approval for neoadjuvant treatment of early breast cancer. Can you tell us more about that? Dr. Wedam: Since this is a new pathway, we felt it was important to have as much public dialogue as possible before finalizing the Guidance. FDA in conjunction with ASCO held a workshop in March 2013 to discuss drug development for neoadjuvant treatment of breast cancer. We had a group of experts discuss issues regarding neoadjuvant therapy and the use of pathologic complete response as a surrogate endpoint. Ultimately, the experts felt that pathologic complete response was reasonably likely to predict clinical benefit and could be used to support accelerated approval of neoadjuvant therapy for use in patients with early breast cancer at high risk of relapse or death despite the best available therapies.

Key Studies Can you describe the neoadjuvant studies that were submitted to support the pertuzumab approval? Dr. Amiri: The main trial was NEOSPHERE, a randomized, multicenter, open-label trial of 417 patients with HER2-positive, operable, locally advanced, or inflammatory breast cancer who were randomly allocated to receive one of four neoadjuvant regimens prior to surgery as follows: trastuzumab (Herceptin) plus docetaxel; pertuzumab plus trastuzumab and docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel. Following surgery all patients received

FDA Clinical Reviewers

Laleh Amiri-Kordestani, MD

Suparna Wedam, MD

three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) intravenously every 3 weeks, and trastuzumab was administered intravenously every 3 weeks to complete 1 year of therapy. The study’s primary endpoint was pathologic complete response rate, defined as the absence of invasive cancer in the breast (ypT0/is). An additional neoadjuvant phase II trial (TRYPHAENA) was conducted in 225 patients with HER2-positive, locally advanced, operable, or inflammatory breast cancer and was designed primarily to assess the cardiac safety of pertuzumab in different neoadjuvant regimens. Patients were randomly allocated to receive one of three neoadjuvant regimens prior to surgery as follows: three cycles of FEC followed by three cycles of docetaxel, all in combination with pertuzumab and trastuzumab; three cycles of FEC alone followed by three cycles of docetaxel and trastuzumab in combination with pertuzumab; or six cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab. Following surgery all patients received continued on page 50

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Inside the Black Box Neoadjuvant Treatment of Early Breast Cancer continued from page 49

trastuzumab intravenously every 3 weeks to complete 1 year of therapy.

ODAC Meeting The FDA recently called a meeting of the Oncologic Drugs Advisory Committee (ODAC) to discuss pertuzumab’s use in the neoadjuvant setting. What were the main points of discussion raised by the ODAC? Dr. Wedam: Several concerns with the application already apparent to us were raised during the ODAC discussion. These concerns included the uncertainty about whether an improvement in pathologic complete response rate would translate into long-term clinical benefit, the appropriate chemotherapy regimen to use with this targeted therapy, the appropriate duration of pertuzumab treatment, and the sequencing of chemotherapy. Additional concerns included an increased rate of cardiac toxicity with pertuzumab, the small size of the NEOSPHERE trial, the lack of patients from the United States, the lack of blinded pathology review, and the lack of prespecified pathology guidelines. In the end, ODAC voted 13 to 0 with 1 abstention that pertuzumab has demonstrated a favorable risk-benefit profile for this indication. However, many members of the committee agreed with us that this should not be considered a precedent for approval of neoadjuvant treatments, but should be viewed instead as a unique situation due to the robust overall supportive data for pertuzumab. These supportive data included a statistically significant and clinically meaningful improvement in overall survival from the metastatic breast cancer trial (CLEOPATRA) and extensive safety data with over 10,000 patients exposed to the drug at this time. Committee members also stated that completion of enrollment to the confirmatory adjuvant trial (APHINITY) increased their level of comfort with an accelerated approval.

Further Concerns Several ODAC members expressed concern about how pertuzumab would be used in clinical practice, particularly since in the two neoadjuvant trials, pertuzu mab was not given with the chemotherapy regimens commonly used in the United States. Is the FDA also concerned?

Dr. Amiri: Yes, we expressed our concern with the chemotherapy regimens, at the ODAC meeting. This was a concern we also had from the beginning. The backbone chemotherapy regimen used in the main study (NEOSPHERE) is seldom used in the United States. In addition, the splitting of the chemotherapy regimen before and after surgery is not typically done when neoadjuvant therapy is given. The chemotherapy regimens in the supportive study (TRYPHAENA) were administered entirely prior to surgery; however, two of the treatment arms included FEC, which again

thracycline regimens. Both of these trials will offer more information regarding the safety, optimal treatment regimens, and duration of treatment with pertuzumab.

Labeling Decision How did you make the final decision regarding labeling given the concerns of the applicability of the chemotherapy regimens used in the trials? Dr. Amiri: We chose to include the neoadjuvant regimens from the main experimental arm in NEOSPHERE and two of the treatment regimens from TRYPHAENA. The treatment

The totality of evidence—not just the magnitude of improvement in pathologic complete response rate—led us to approve pertuzumab for the neoadjuvant indication.

significant improvement in pathologic complete response rate of 17.8% (P = .0063) was observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. Supportive evidence of unprecedented efficacy in the metastatic setting demonstrates that pertuzumab is an active drug that could potentially contribute to treatment regimens intended to cure a larger number of women with HER2-positive early-stage breast cancer. In addition, there are extensive safety data and the confirmatory adjuvant trial has fully accrued. This totality of evidence and status of the confirmatory trial are what we will be using to evaluate future applications that seek to use this approach for accelerated approval. n

Disclosure: Drs. Amiri and Wedam reported no potential conflicts of interest.

—Suparna Wedam, MD

is not commonly used in the United States. The third treatment arm in TRYPHAENA combined pertuzumab with the nonanthracycline regimen TCH, an FDA-approved regimen in widespread use in the United States. What is the agency doing to address these concerns? Dr. Wedam: In order to address these concerns, we asked the applicant to conduct a new trial as a postmarketing requirement, investigating the combination of pertuzumab with two different anthracycline-based treatment regimens in the neoadjuvant setting. The first arm is similar to the concurrent anthracycline (FEC) treatment arm in TRYPHAENA. This regimen would provide a treatment option for physicians who choose to use an anthracycline-based regimen but also would like to get HER2-targeted therapy started quickly. The second arm will include dosedense doxorubicin/cyclophosphamide followed by weekly paclitaxel (ddAC-T) with trastuzumab and pertuzumab. The ddAC-T regimen is widely used in the United States. Both treatment arms would continue trastuzumab and pertuzumab for 1 full year. Additional information will be obtained from the fully accrued adjuvant trial (APHINITY), which includes anthracycline and nonan-

regimen from NEOSPHERE isolates the effect of pertuzumab. The two treatment regimens from TRYPHAENA include TCH, which is an approved adjuvant regimen in the United States, and the sequential anthracycline (FEC) followed by docetaxel, trastuzumab, and pertuzumab regimen. The third regimen in the TRYPHAENA trial is not recommended because there are insufficient cardiac safety data to recommend concomitant administration of an anthracycline with pertuzumab at this time. Importantly, two limitations of use were added to the label. These include the statements that safety has not been established with pertuzumab in combination with a doxorubicincontaining chemotherapy regimen and that safety of pertuzumab administration for more than six cycles in early-stage breast cancer has not been established. 7

Final Approval Why did the FDA ultimately decide to approve pertuzumab for neoadjuvant treatment of early breast cancer? Dr. Wedam: The totality of evidence—not just the magnitude of improvement in pathologic complete response rate—led us to approve pertuzumab for the neoadjuvant indication. In the main neoadjuvant study, NEOSPHERE, a statistically

References 1. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst 97:188-194, 2005. 2. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005. 3. U.S. Food and Drug Administration: About the accelerated approval regulations. Available at www.fda.gov/Drugs/ DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ucm121606.htm. Accessed October 28, 2013. 4. Prowell TM, Pazdur R: Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med 366:2438-2441, 2012. 5. Guidance for Industry: Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501. pdf. Accessed October 28, 2013. 6. Cortazar P, Zhang L, Untch M, et al: Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). Cancer Res 72(24 suppl):S1S11, 2012. 7. Drug approval package, Perjeta (pertuzumab) injection. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2013/125409s051lbl.pdf. Accessed October 28, 2013.

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Announcements

Institute of Medicine Elects New Foreign Associates

Patrick Couvreur, PhD, PharMD, University of Paris-Sud, France Professor the Lord Darzi of Denham, PC, KBE, FRS, HonFREng, FMedSci, Institute of Global Health Innovation, Imperial College London Daiming Fan, MD, PhD, Chinese

he Institute of Medicine recently announced 10 foreign associates during its 43rd Annual Meeting. They are: Sir Sabaratnam Arulkumaran, PhD, DSc, FRCS, FRCOG, St. George’s University of London

Academy of Engineering, Beijing Mauricio Hernández-Ávila, MD, DrPH, National Institute of Public Health Mexico, Cuernavaca, Mexico Anne Laude, PhD, Université Paris Descartes Francis Omaswa, MBBCh,

MMed, FRCS, FCS, Kampala, Uganda Moshe Oren, PhD, Weizmann Institute, Rehovot, Israel Xiaoming Shen, MD, PhD, Xin Hua Hospital, Shanghai Georg Stingl, MD, Medical University of Vienna, Austria n

NOW RECRUITING: RESONATE -2 ™

ibrutinib Study Treatment naïve patients age ≥ 65 years

Disease: CLL / SLL

PCYC-1115-CA

PCYC-1116-CA

A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

An Open-label Extension Study in Patients Who Participated in Study PCYC-1115-CA

Chlorambucil 0.5 mg/kg orally on day 1 & 15 of each 28-day cycle for up to 12 cycles

Arm A

Randomize 1:1 (N= 272) ibrutinib (PCI-32765) 420 mg orally once daily until disease progression

Arm B

Key eligibility criteria:

• Diagnosis of CLL/SLL • Age ≥ 65 • No previous treatment

For patients who progress on PCYC-1115-CA, choice of second-line therapy can include: ibrutinib (for patients randomized to chlorambucil arm) or other anticancer therapies at the discretion of the investigator

• ECOG 0-2 • No documented 17p deletion

Key objectives : Primary

Secondary

Progression free survival

Overall survival • Hematologic improvement • Safety

For additional information on this trial please visit: www.clinicaltials.gov (NCT 01722487 / NCT 01724346) Study website: www.btktrials.com | You may contact us at medinfo@pcyc.com or 1-855-IBRUTINIB (1-855-427-8846)

The safety and efficacy of the investigational use of this product has not been determined. There is no guarantee that the investigational uses will be filed with and/or approved for marketing by any regulatory agency. CMRC-00035 07/13

The ASCO Post | NOVEMBER 15, 2013

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Opinion

Interpretation of PET Scans continued from page 1

interpretation on SUV calculations), and a lack of standardization—have made the application of PET scanning in the care of lymphoma patients less than perfect.

Lessons of the INR and PT On a recent trip to New York, one of our mothers needed an international normalization ratio (INR) for monitoring anticoagulation with warfarin. The practice of calculating the INR was introduced in the 1980s in an effort to standardize the prothrombin time (PT), which can be extremely variable as measured at different laboratories. The INR method offers a consistent result and enabled this woman’s primary care physician to balance her risk of clotting and bleeding despite being a time zone away. This is a routine experience, and clinicians have grown accustomed to ignoring the location of where a prothrombin time was performed and only paying attention to the INR. You might ask, how can we learn anything regarding lymphoma from the history of the development of the INR and its necessary but forgotten partner, the PT? Well, just go with it, and keep reading. Over the past decade, experts in the fields of radiology, nuclear medicine, and hematologic oncology have been meeting and formalizing experiences and/or studies in an attempt to standardize response evaluations in treated lymphoma patients using PET/CT. A lot has changed in a decade. We need a control not unlike what the INR does

for the PT, so that we are all speaking the same language regardless of what time zone we’re in.

Deauville Score To try to improve comparisons among different machines and centers, and to standardize the interpretation of response to PET scans in the same way that the INR has standardized the interpretation of PT measurements, a

liver. A score of 2 indicates uptake but at a lower value than in the mediastinal blood pool, 3 denotes uptake with an intensity between the mediastinal blood pool and liver, and 4 would be an uptake greater than in the liver. A score of 5 means a dramatic increase in uptake and/or new sites of involvement. Using this method, a Deauville score of 1 or 2 is accepted as a complete response to treatment and, especially for

The Deauville score represents a significant advance in interpreting response to therapy for patients treated with chemotherapy for lymphoma. It should become a standard approach for oncologists who care for these patients. —Matthew Lunning, DO, and James O. Armitage, MD

group of investigators met in Deauville, France, in 2009 and proposed a new approach. The Deauville score grades a scan from 1 to 5, with the score of 1 meaning no uptake consistent with lymphoma. All other scores are in relation to background uptake that is always present in the mediastinal blood pool and liver (see Table 1). Uptake in the mediastinal blood pool is consistently lower than in the

Table 1: Deauville 5-Point Criteria for PET Scans 1. No uptake 2. Uptake ≤ mediastinum 3. Uptake, but at lower value than in mediastinal blood pool 4. Uptake moderately more than liver uptake, at any site 5. Markedly increased uptake at any site and new site of disease Source: André M, et al: Advances in Hematology, 2011.

New from The ASCO Post

interim scans, a score of 3 is also often taken as a complete response. The beauty of the Deauville score is that we are our own control. The mediastinal blood pool SUV and liver SUV are relatively fixed values but could vary significantly between patients—not unlike how the PT can vary between hospitals as a result of heterogeneous reagents. The Deauville score also allows for premeditated risk stratification based on the objectives of using PET/CT. Excellent examples of this approach include scenarios in early- and advanced-stage lymphoma: If the strategy is to test escalation of therapy based on interim PET/CT, it might be prudent to use a higher SUV cutpoint (ie, Deauville 3), which could reduce the number of unnecessary and potentially more risky therapeutic escalations. If testing to discontinue or reduce therapy, we should again be prudent, and

a Deauville 2 cutpoint may be considered. This is where strategies based on changes in SUV may falter and lack global acceptance despite persuasive prognostic arguments.

Conclusions and Caveats We are heading in the right direction with appropriate PET/CT evaluation in currently accruing or accrued clinical trials, but outside of a clinical trial, far too many PET/CT results lack reporting of the mediastinal blood pool or liver SUVs. The ordering physician is often responsible for this lack of reporting, having failed to provide the radiologist or nuclear medicine physician with adequate information to acknowledge that this is a staging, interim, or post-treatment PET/CT. As a result, an SUV of 3.2 can leave the oncologist scratching his head and dreading the conversation with the patient that will often ensue. We should be asking for the anatomic control SUVs, not persuading a colleague to provide a second opinion for reassurance. The Deauville score offers oncologists the opportunity to confidently use the PET scan to determine a patient’s response to chemotherapy for lymphoma. However, there are some caveats. For example, the best response to chemotherapy can be determined more quickly than the best response to radiotherapy, where it can sometimes take 2 or 3 months to see a complete response. Even so, the Deauville score represents a significant advance in interpreting response to therapy for patients treated with chemotherapy for lymphoma. It should become a standard approach for oncologists who care for these patients. n

Disclosure: Dr. Lunning reported no potential conflicts of interest. Dr. Armitage has served as a consultant for GlaxoSmith Kline, Seattle Genetics, Genentech, Roche, Spectrum, and Ziopharm. He is on the Board of Directors’ of Tesaro bio, Inc.

Dr. Lunning is an assistant professor, and Dr. Armitage is Professor, Department of Internal Medicine, and Joe Shapiro Distinguished Chair of Oncology, University of Nebraska Medical Center, Omaha.

Learn more about our latest discoveries in oncology at BioOncology.com/explore

A deeper exploration — uncovering new opportunities in oncology

At Genentech BioOncology, we’re leading the fight against cancer with innovative science. We believe that great science and the right people can lead to significant advances in cancer treatment. Dedicated scientists — Our researchers are dedicated to defining the molecular basis of cancer and developing groundbreaking treatments. Gold standard clinical development — We identify biomarkers and develop companion diagnostics wherever possible, with the goal of matching each patient with the most appropriate therapy. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

The ASCO Post | NOVEMBER 15, 2013

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Health-care Policy

IOM Report

Framework for Change

continued from page 1

The IOM report puts forth a conceptual framework, or blueprint, for a strategic approach to change, at the core of which is the delivery of comprehensive, patient-centered, evidence-based, high-quality care that is accessible and affordable to all U.S. patients. The IOM’s conceptual framework leads to 10 specific goals and their associated recommendations: 1. Provide patients and family members with understandable information at key decision points on such matters as cancer prognosis, treatment benefits and harms, palliative care, psychosocial support, and costs. 2. Provide patients with end-of-life care that is consistent with their needs, values, and preferences. 3. Provide patients with high-quality cancer care that is delivered by a diverse team of professionals to ensure coordinated and comprehensive patient-centered care. 4. Require cancer care teams to have the necessary skills through training, certification, and credentials to de-

multidisciplinary IOM committee that wrote the report. Dr. Ganz is Distinguished University Professor, University of California, Los Angeles Schools of Medicine and Public Health, and Director, Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center. “Now we have the advances from the Human Genome Project and we know that breast cancer is not 2 or 3 diseases—it is 10 diseases, and lung cancer may be 15 different diseases,” she said. “We have very expensive diagnostic tests that we have to apply to every tumor in order to find the few that have specific treatable mutations,” Dr. Ganz continued. “We have targeted therapies that are very useful but are very expensive. The ability to deliver high-quality evidence-based care has been accelerated, but we have the aging of the population and looming workforce shortages placing great potential stress on the system.”

10. Improve the affordability of cancer care by leveraging existing efforts to eliminate, e.g., choosing wisely, as well as reform payment strategy and reforms fee-for-service reimbursements to new payment models and eliminates duplications of services.

Tailored Care “What we have done in developing this conceptual framework for a highquality cancer care delivery system is put the patient and patient-clinician interactions at the center. Cancer care needs to be tailored to every patient’s needs, and communication is central to that effort,” said Dr. Ganz. To ensure quality care, patients need to understand their diagnosis, prognosis, and treatment plan—which should include palliative care to alleviate symptoms such as pain, fatigue, and insomnia, and psychosocial support across the treatment continuum—and make their preferences known, according to Dr. Ganz. To accomplish the development of a higher-quality cancer care deliv-

Rising Numbers The numbers cited in the report tell the story of why the country’s cancer care system is in such a perilous state and likely to become worse unless a new approach is taken. According to the report, approximately 14 million Americans are survivors after a cancer diagnosis more than 1.6 million new cases are diagnosed each year. By 2022, the number of U.S. cancer survivors is expected to grow to 18 million and by 2030 cancer incidence is projected to climb to 2.3 million. In addition, the number of older Americans is predicted to double between 2010 and 2030, contributing to a projected 30% rise in the number of cancer survivors from 2012 to 2022, and a 45% increase in cancer incidence by 2030. The cost of cancer care, which is escalating faster than other sectors of medicine, is also soaring and expected to rise from $125 billion in 2010—up from $72 billion in 2004—to $173 billon by 2020. The rising costs are making care less affordable, according to the report, and creating disparities in patients’ access to high-quality cancer care. The increasing numbers of patients with cancer coupled with escalating costs to care for them is also resulting in a workforce shortage of oncology care professionals.

Every person with cancer should receive state-of-the-art, high-quality, and compassionate care. —Clifford A. Hudis, MD, FACP

liver high-quality care. 5. Provide evidence-based care by expanding the breadth of data collected in clinical trials through the enrollment of older adults and patients with comorbidities. 6. Expand the depth of data collected in clinical research through patientreported outcomes, patient characteristics, and health behaviors. 7. Implement health-care learning and information technology, such as ASCO’s CancerLinQ™, that enables real-time analysis of data from cancer patients to inform medical decisions. 8. Develop a national quality-reporting program for cancer care. 9. Develop a national strategy to reduce disparities in accessing cancer care, especially in underserved populations that leverages existing community interventions to improve access to affordable cancer care.

ery system, the IOM authors urge all stakeholders, including medical teams, patients and their families, researchers, payers, industry, and federal agencies to work together toward a shared goal of improving the quality of life and outcomes for people diagnosed with cancer.

ASCO Commends Report ASCO was among the 13 study sponsors of the IOM report. The Society applauded the recommendations by the committee members. “Every person with cancer should receive state-of-the-art, high-quality, and compassionate care,” said ASCO President Clifford A. Hudis, MD, FACP. “The IOM’s recommendations offer a solid framework for achieving that goal by helping us improve the quality of care today while developing evidence for safe and effective treat-

ments for tomorrow.” His statement continued: For oncologists, continuously improving the quality of cancer care is at the core of our mission. This report provides important strategies we can use now to reach this goal and ASCO already has efforts in place that will advance many of the IOM’s recommendations. The Society’s Quality Oncology Practice Initiative (QOPI®) … is the first, national program to help practices improve the quality of care they deliver. In 2011, ASCO issued recommendations to improve physicianpatient communication regarding the full range of care options for patients with advanced cancer. And now, ASCO’s Institute for Quality is developing CancerLinQ™, a groundbreaking effort to achieve the IOM’s vision of a learning health system that will revolutionize cancer care and achieve better outcomes for patients. We commend the IOM for this landmark report and will work with policymakers, patients, health IT groups, and the oncology community to implement its recommendations.

Future of Cancer Care Despite the challenges ahead, Dr. Ganz is optimistic that the goals set forth in the IOM report will result in higher quality of care for patients and a more accessible health-care system. “With every crisis, there is tremendous opportunity for growth, and I think for most of our recommendations, various stakeholders are already working on achieving these goals,” said Dr. Ganz. “What we are really saying is that this is a blueprint—a plan to give us focus—and one that we can all rally around.” n

Disclosure: Drs. Ganz and Hudis reported no potential conflicts of interest.

References 1. Levit L, Balogh L, Nass S, Ganz PA (eds): Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Washington, DC; National Academies Press, 2013. Available at www.iom. edu/qualitycancercare. Accessed October 18, 2013. 2. Hewitt M, Simone JV (eds): Ensuring Quality Cancer Care. Washington, DC; National Academy Press, 1999. Available at www.nap.edu/openbook. php?record_id=6467. Accessed October 18. 2013.

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News Technology

Technologic Innovations Are Likely to Transform Oncology Care By Susan London

ncology and medicine as a whole are likely to benefit from a variety of technologic innovations recently showcased at the third annual The Atlantic Meets the Pacific symposium, according to Peter P. Yu, MD, PresidentElect of the American Society of Clinical Oncology, and medical oncologist and Director of Cancer Research at the Palo

Peter P. Yu, MD

Alto Medical Foundation, Mountain View and Sunnyvale, California. The symposium—a joint collaboration of The Atlantic magazine and the University of California, San Diego— brings together top thought leaders in technology, the sciences, and health to discuss innovations in these fields and issues surrounding their implementation in real-world practice. It features one-on-one interviews, panel discussions, and laboratory tours. More than 300 scientists, engineers, physicians, software developers, venture capitalists, and patient advocates attended this year’s event. “Personally, I found the symposium valuable because of the exposure to people who are in the cancer space but are not physicians.… For the most part, they appear to be highly intelligent and knowledgeable about the field,” Dr. Yu commented in an interview. “I found it a validation of what we [oncologists] are thinking and doing … in the sense that it isn’t going to be as hard to explain to someone what we are doing because they are already wondering about the same questions. They don’t necessarily have our degree of insight into cancer or the possible solutions, but they understand the issues in a broad sense. So that means we can engage these folks more readily.”

Harnessing Big Data A major symposium theme was harnessing big data—the mining of vast amounts of information to solve problems and ultimately improve outcomes. “I heard a lot of generalities in

terms of molecular medicine, precision medicine, and drugs and diseases.… People have a better sense of what that means than they did, say, 5 years ago,” Dr. Yu commented. “But big data is where we were with

molecular medicine 10 year ago, where we believed in it, we could see it, but it wasn’t tangible—patients weren’t living decades longer because of that,” he continued. “So the big data people are still not sure they have their hands

around it. That makes it positive for us with CancerLinQ, because if we can offer something that’s more tangible, people will gravitate toward that.” Symposium presenters discussed continued on page 56

The ASCO Post | NOVEMBER 15, 2013

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News

Technologic Innovations continued from page 55

a variety of novel technologies that are poised to change the clinician and patient experience. “The technologies seemed to be unified by a single concept, which is unleashing the information that’s already known somewhere and bringing it to bear at

the time when it’s most relevant,” Dr. Yu observed. Examples included use of Google Glass during medical visits to streamline accessing of online information, and programs that crunch patient data to anticipate complications after chemotherapy or surgery and preemptively send out queries to patients.

Cost Issues Inevitably, a key issue attendees broached was the cost of these advances. “It may be great and cool and wonderful, but can we afford it?” Dr. Yu commented. “The answer is, we can afford it if it improves outcomes sufficiently to justify it and/or if it saves money immediately because it eliminates a problem

that we would have to spend even more money on if we don’t do this right. And it has to be now—it can’t be, well, we do this now, and 10 years from now we’ll reap the savings, because no one’s going to pay for that,” he said. “There’s a sense of energy, a sense that we need to move faster, that the world wants more from us, more quickly—and that we have to look hard at what we’re doing because we are not doing it fast enough and we’re not doing it affordably enough,” he said, summing up the atmosphere at the symposium.

Inevitable Tradeoff However, Dr. Yu acknowledged, “there’s something that’s lost by moving away from a very slow, methodical approach.… The concern I’ve heard from some oncologists is that if we only look for the big leaps forward, we will inadvertently miss the small—but what turn out to be very important— new drug or new therapy that maybe in a different setting would have proven to be a blockbuster, but in the setting we studied it in was only a small step forward. There is that risk, and I don’t think there is any way to get around it…. That’s a tradeoff that we have to decide about.” n Disclosure: Dr. Yu reported no potential conflicts of interest.

The ASCO Post

@ASCOPost

ASCOPost.com | NOVEMBER 15, 2013

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Journal Spotlight Genitourinary Oncology

No Difference in Long-Term Survival With Finasteride or Placebo in the Prostate Cancer Prevention Trial By Matthew Stenger

n the Prostate Cancer Prevention Trial (PCPT), initially reported in 2003, finasteride significantly reduced the risk of prostate cancer by 24.8% but was associated with a relative 26.9% increase in risk of high-grade disease compared with placebo. In a study reported in The New England Journal of Medicine, Ian M. Thompson, MD, of The University of Texas Health Science Center at San Antonio, and colleagues analyzed survival rates of all subjects and those with prostate cancer in the trial during up to 18 years of follow-up.1 They found that although high-grade cancer was more common in the finasteride group, there were no significant differences between the finasteride and placebo groups in rates of overall survival or survival after diagnosis of prostate cancer.

prostate cancer prevention. In the current study, investigators analyzed survival in the two study groups at 18 years after initial randomization to identify evidence of increased risk of death in the finasteride group, since such an increase might be an indicator of increased risk of highgrade cancer. Data on the incidence of

Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer.

Study Details Analyses of the PCPT have indicated that the use of finasteride improved the sensitivity of prostate-specific antigen (PSA) testing, prostate biopsy, and digital rectal examination for identification of prostate cancer and improved the sensitivity of PSA testing and prostate biopsy for detection of high-grade disease. The improved sensitivity may have reflected reduction of PSA in finasteride recipients who had benign enlargement and subsequent shrinkage of the prostate. Although analyses suggested that such detection bias accounted for at least some of the greater rate of high-grade tumors in the finasteride group, concern over the potential risk with finasteride has resulted in virtual abandonment of its use in

0.70 (P < .001). Of these cancers, 3.5% of those in the finasteride group and 3.0% of those in placebo group were assessed as high-grade cancer (Gleason score of 7–10; RR = 1.17, P = .05). Risk of low-grade cancer was reduced in the finasteride group (RR = 0.57, P < .001). In the primary 2003 report, rela-

—Ian M. Thompson, MD, and colleagues

prostate cancer among PCPT participants for an additional year after the first study report in 2003 were collected and the Social Security Death Index was searched to assess survival status through October 31, 2011.

Cancer Risk Among 18,880 men who were randomly assigned to finasteride or placebo, prostate cancer was diagnosed in 989 (10.5%) of 9,423 in the finasteride group and 1,412 (14.9%) of 9,457 in the placebo group, yielding a relative risk (RR) in the finasteride group of

Long-Term Impact of Finasteride Therapy ■■ Continued follow-up of subjects in the Prostate Cancer Prevention Trial

showed a 30% reduction in prostate cancer risk with finasteride and a 17% increase in risk for high-grade cancer.

■■ After follow-up of up to 18 years, there were no differences between

finasteride recipients and placebo recipients in overall survival or survival after prostate cancer diagnosis.

tive risks were 0.75 (P < .001) for any cancer, 0.62 (P < .001) for low-grade cancer, and 1.27 (P = .005) for highgrade cancer.

Survival Outcomes At the time of randomization, the median age of participants was 63 years. As of October 31, 2011, the median age of those still alive was 79 years. Median age at the time of prostate cancer diagnosis was 70 years in the two groups. The 15-year survival rate was 78.0% in the finasteride group and 78.2% in the placebo group (unadjusted hazard ratio [HR] 1.02, P = .46; HR adjusted for age, race, and prostate cancer diagnosis 1.03, P = .26). Factors significantly associated with death from any cause were age at randomization (HR = 1.12 as continuous variable, P < .001) and black vs non-black race (HR = 1.48, P < .001). Among men with prostate cancer, the unadjusted hazard ratio for

death in the finasteride group was 1.01 (P = .90) and the hazard ratio adjusted for cancer grade, age at diagnosis, race, and family history of prostate cancer was 0.93 (P = .45). At 10 years, survival rates for men with prostate cancer were 79.3% in the finasteride group and 79.5% in the placebo group, including rates of 83.0% vs 80.9% in those with low-grade cancer and 73.0% vs 73.6% in those with high-grade cancer. Compared with patients with highgrade cancer in the finasteride group, patients with low-grade cancer and placebo recipients were less likely to die. Hazard ratios for death after diagnosis were 0.64 (P = .001) for finasteride patients with low-grade cancer, 0.94 (P = .68) for placebo patients with high-grade cancer, and 0.73 (P = .01) for placebo patients with low-grade cancer. Age at diagnosis was a significant predictor of death after diagnosis (HR = 1.11, P < .001). Limitation of the survival analysis to patients diagnosed with prostate cancer at the time of the initial report did not change the results. The test for interaction between treatment and cancer grade was not significant (P = .32), indicating that the betweengroup difference in risk of death from high-grade cancer was not significant. The investigators concluded, “Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of followup, there was no significant betweengroup difference in the rates of overall survival or survival after the diagnosis of prostate cancer.” n

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Thompson IM Jr, Goodman PJ, Tangen CM, et al: Long-term survival of participants in the Prostate Cancer Prevention Trial. N Engl J Med 369:603-610, 2013. See Commentary on page 58

The ASCO Post | NOVEMBER 15, 2013

PAGE 58

Journal Spotlight

Continued from page 57

Finasteride for Prostate Cancer Prevention: LongTerm Results Disappointing but Reassuring By Michael L. LeFevre, MD, MSPH

ll medical care should seek to achieve one or more of three goals: to relieve suffering, to prevent future suffering, or to prolong life. Care for cancer is no exception, and minimizing suffering from cancer and prolonging life has primarily resulted from advances in treatment. Although there are a few notable exceptions, neither primary nor secondary prevention (screening) has had much impact on the morbidity and mortality of cancer.

Screening Efforts Prostate cancer is a logical target for a preventive service, and one of the few cancers for which both primary and secondary prevention seems attainable. However, results from screening efforts have been disappointing. The multicenter Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial1 conducted in the United States showed a non–statistically significant increase in prostate cancer mortality, though the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial2 showed a statistically significant absolute reduction of 0.10 prostate cancer deaths per 1,000 person-years after a median follow-up of 11 years. All-cause mortality was 19.1% in the screened group and 19.3% in the control group—a difference that was not statistically significant. Much of the morbidity resulting from prostate cancer is a consequence of the diagnosis and management of the disease, rather than the disease itself. Unfortunately, the small reduction in prostate cancer mortality that was seen in the ERSPC occurred in Dr. LeFevre is Future of Family Medicine Professor and Vice Chair, Department of Family and Community Medicine, University of Missouri, Columbia.

the context of a significant increase in the number of cancers diagnosed and treated in the screened group.

Primary Prevention Safe and effective primary prevention of any cancer has much appeal. The Prostate Cancer Prevention Trial (PCPT)3 was a landmark study that sought to reduce the morbidity and mortality of prostate cancer by use of finasteride to prevent development of

bias, then one would have anticipated a higher rate of mortality in the finasteride group. In this regard, the results were reassuring, with an overall 15-year mortality rate of 22% in the finasteride group and 21.8% in the control group. The investigators were unable to report prostate cancer-specific mortality, and as noted in the results of the ERSPC above, a small difference in prostate cancer mortality can exist in the absence of a difference in all-

Primary prevention with finasteride likely has no significant impact on mortality, but may reduce the iatrogenic harm that results from screening. We all hope science will move us forward in both areas. —Michael L. LeFevre, MD, MSPH

the disease—ie, primary prevention. Men in both the finasteride and placebo groups were regularly screened for prostate cancer. Previously published results from this trial showed that the risk of prostate cancer in the finasteride group was 24.8% lower than the placebo group, but the risk of high-grade cancer was 26.9% higher. Several biases have been identified to explain the increase in high-grade cancers,4 but concern for harm remained. In addition, the impact of the reduction in the overall incidence of prostate cancer on morbidity and mortality was uncertain. Thompson et al recently reported long-term all-cause mortality in study participants,5 and the results were both reassuring and disappointing. If the increase in high-grade cancers had been real rather than the result of diagnostic

cause mortality. On the other hand, the large overall reduction in prostate cancer incidence should have resulted in a reduction in mortality if these cancers were indeed a significant threat to the health of those diagnosed. In this regard the results were disappointing.

Conclusions Is there a role for finasteride in the primary prevention of prostate cancer? The safest conclusion is that it has no short- or long-term effect on all-cause mortality; we cannot recommend its use to prolong life. However, one of the major problems with efforts to screen for prostate cancer is overdiagnosis, the diagnosis and treatment of cancers that would never become apparent in the lifetime of the patient in the absence of screening. In a population of men being

actively screened for prostate cancer, finasteride does appear to reduce the likelihood of the diagnosis of cancer, and thus reduce the harm associated with overdiagnosis and overtreatment. This reduction has no impact on all-cause mortality. Whether it has either a positive or negative effect on prostate cancer-specific mortality remains unknown, but either way, the effect is likely very small. A safe and effective approach to both primary and secondary prevention of prostate cancer remains elusive. Screening has at most a small benefit and significant harm. Primary prevention with finasteride likely has no significant impact on mortality, but may reduce the iatrogenic harm that results from screening. We all hope science will move us forward in both areas. n Disclosure: Dr. LeFevre reported no potential conflicts of interest.

References 1. Andriole GL, Crawford ED, Grubb RL III, et al: Prostate cancer screening in the randomized prostate, lung, colorectal, and ovarian cancer screening trail: Mortality results after 13 years of follow-up. J Natl Cancer Inst 104:125-132, 2012. 2. Schröder FH, Hugosson J, Roobol MJ, et al: Prostate cancer mortality at 11 years of follow-up. N Engl J Med 366:981-990, 2012. 3. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-224, 2003. 4. Redman MW, Tangen CM, Goodman PJ, et al: Finasteride does not increase the risk of high-grade prostate cancer: A bias-adjusted modeling approach. Cancer Prev Res 1:174-181, 2008. 5. Thompson IM Jr, Goodman PJ, Tangen CM, et al: Long-term survival of participants in the Prostate Cancer Prevention Trial. N Engl J Med 369:603-610, 2013.

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

THIS IS WHAT RECURRENT GBM THERAPY CAN LOOK LIKE TODAY NovoTTFTM Therapy delivers efficacy with improved quality of life and fewer treatment-related toxicities1 •

In the Phase III clinical trial of 237 patients with recurrent GBM, the NovoTTF™-100A System demonstrated comparable overall survival (OS) to chemotherapy

•

Patients on the NovoTTF-100A System experienced fewer of the systemic adverse events associated with chemotherapy treatment

•

Most measures of quality of life (QoL), including cognitive and emotional functioning, were improved in NovoTTF-100A System-treated patients compared to chemotherapy-treated patients

Learn more about the NovoTTF-100A System at NovoTTFtherapy.com The NovoTTF-100A System is approved for the treatment of adult patients with recurrent glioblastoma. GBM=Glioblastoma Reference: 1. Instructions for use. NovoTTF-100A System. Novocure; 2012.

For full prescribing information refer to the IFU at NovoTTFtherapy.com

ASCOPost.com | NOVEMBER 15, 2013

FDA Update

Important Safety Information Indications for Use The NovoTTF™-100A System is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM), following histologically- or radiologically-confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

Contraindications Do not use the NovoTTF-100A System if you have an active implanted medical device, a skull defect (such as, missing bone with no replacement), a shunt, or bullet fragments. Examples of active electronic devices include deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts. Use of the NovoTTF-100A System together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of the NovoTTF-100A System together with skull defects, shunts, or bullet fragments has not been tested and may possibly lead to tissue damage or render the NovoTTF-100A System ineffective. Do not use the NovoTTF-100A System if you are known to be sensitive to conductive hydrogels like the gel used on electrocardiogram (ECG) stickers or transcutaneous electrical nerve stimulation (TENS) electrodes. In this case, skin contact with the gel used with the NovoTTF-100A System may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions Use the NovoTTF-100A System only after receiving training from qualified personnel, such as your doctor, a nurse, or other medical personnel who have completed a training course given by the device manufacturer (Novocure). All servicing procedures must be performed by qualified and trained personnel. Do not wet the device or transducer arrays. Do not use any parts that do not come with the NovoTTF-100A System Treatment Kit, or that were not sent to you by the device manufacturer or given to you by your doctor. The NovoTTF-100A System commonly causes skin irritation beneath the transducer arrays and in rare cases can lead to headaches, falls, fatigue, muscle twitching or blisters. Please refer to the Instructions For Use NovoTTF-100A System for complete information regarding the device’s indication, contraindications, risks and benefits.

PAGE 60

FDA Announces Strategic Plan to Prevent Drug Shortages

he U.S. Food and Drug Administration (FDA) is taking two actions to further enhance the agency’s ongoing efforts to prevent and resolve drug shortages.. The FDA has released a strategic plan called for in the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 to improve the agency’s response to imminent or existing shortages, and for longer term approaches for addressing the underlying causes of drug shortages. The plan also highlights opportunities for drug manufacturers and others to prevent drug shortages by promoting and sustaining quality manufacturing.

turing metrics to assist in the evaluation of manufacturing quality, as well as incentives for high-quality manufacturing; internal organization improvements to focus on quality; and risk-based approaches to identify early warning signals for manufacturing and quality problems.

Early Notification Early notification gives the FDA time to work with manufacturers to investigate the issue leading to the manufacturing disruption, identify other manufacturers who can make up all or part of the shortfall, and expedite inspections and reviews of submissions from manufacturers of drugs that may

The complex issue of drug shortages continues to be a high priority for the FDA, and early notification is a critical tool that helps mitigate or prevent looming shortages. —Janet Woodcock, MD

Second, the FDA issued a proposed rule requiring all manufacturers of certain medically important prescription drugs and biologic products to notify the FDA of a permanent discontinuance or a temporary interruption of manufacturing likely to disrupt their supply. The proposed rule implements the expanded early notification requirements included in FDASIA.

Strategic Plan The strategic plan, which was required by FDASIA and has been sent to Congress, describes actions the FDA will undertake to improve its current efforts to respond to early notifications of a potential shortage. These include improving the FDA’s communications about shortages, clarifying manufacturers’ roles and responsibilities by encouraging them to engage in certain practices that will reduce the likelihood of a shortage, updating the FDA’s internal procedures for responding to early notifications of potential shortages. The plan also describes efforts the FDA is considering to address the manufacturing and quality issues that are most often the root cause of drug shortages. These include broader use of manufac-

prevent or mitigate a shortage. Early notification from manufacturers about possible shortages, as required by FDASIA, has enabled the FDA to work with manufacturers to restore production of many lifesaving therapies. Since the Executive Order, there has been a 6-fold increase in notifications to the FDA. The notifications received under the existing requirements have resulted in real progress in addressing shortages. The FDA helped prevent 195 drug shortages in 2011 and 282 drug shortages in 2012, leading to a reduced number of new shortages in 2012. The expanded early notification requirements would further enhance the FDA’s ability to address issues prior to the occurrence of a shortage. “The complex issue of drug shortages continues to be a high priority for the FDA, and early notification is a critical tool that helps mitigate or prevent looming shortages,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA continues to take all steps it can within its authority, but the FDA alone cannot solve shortages. Success depends upon a commitment from all stakeholders.” n

ASCOPost.com | NOVEMBER 15, 2013

PAGE 61

In the Clinic

Pertuzumab in Neoadjuvant Treatment of HER2-Positive Early Breast Cancer By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication On September 30, 2013, pertuzumab injection (Perjeta) was granted accelerated approval for use in combination with trastuzumab (Herceptin) and docetaxel for neoadjuvant treatment of patients with HER2positive locally advanced, inflammatory, or early-stage breast cancer (either > 2 cm in diameter or nodepositive) as part of a complete treatment regimen for early breast cancer.1 The accelerated approval is based on demonstration of an improvement in pathologic complete response rate. No data are yet available showing improved event-free survival or overall survival. Continued approval for this indication is contingent upon demonstration of improvement in diseasefree survival in a confirmatory trial. The approval is based on a randomized, multicenter, open-label phase II trial in patients with HER2positive operable, locally advanced, or inflammatory breast cancer (T24d).2,3 Breast tumor samples were required to show HER2 overexpression (immunohistochemistry [IHC] 3+

OF NOTE Pertuzumab inhibits ligandinitiated intracellular signaling through two major pathways, which results in cell growth arrest and apoptosis. or fluorescence in situ hybridization [FISH] amplification ratio ≥ 2.0). A total of 417 patients were randomly assigned to receive one of four neoadjuvant regimens: trastuzumab plus docetaxel (n = 107), pertuzumab plus trastuzumab and docetaxel (n = 107), pertuzumab plus trastuzumab (n = 107), or pertuzumab plus docetaxel (n = 96). Pertuzumab (initial dose of 840 mg, followed by 420 mg), trastu-

zumab (initial dose of 8 mg/kg, followed by 6 mg/kg), and docetaxel (75 mg/m2, escalated to 100 mg/m2 at investigator discretion) were administered preoperatively by intravenous infusion every 3 weeks for a total of four cycles. Following surgery, all patients received three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) intravenously every 3 weeks, and trastuzumab was administered intravenously every 3 weeks to complete 1 year of therapy. The primary endpoint was pathologic complete response rate, defined as the absence of invasive cancer in

OF NOTE Pertuzumab carries a boxed warning for cardiomyopathy and embryo-fetal toxicity. manized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of HER2 and thus blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major pathways,

Pertuzumab for Early Breast Cancer ■■ Pertuzumab was granted accelerated approval for use in combination with

trastuzumab and docetaxel for neoadjuvant treatment of patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

■■ The recommended dose and schedule of pertuzumab is an initial dose

of 840 mg administered intravenously as a 60-minute infusion followed every 3 weeks by 420 mg administered intravenously as a 30- to 60-minute infusion.

the breast (ypT0/is). The FDA-preferred definition of pathologic complete response is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0). Demographics were well balanced among treatment groups. Median ages were 49 to 50 years, 71% of patients were Caucasian, 7% had inflammatory breast cancer, 32% had locally advanced cancer, 61% had operable cancer, 70% had clinically node-positive cancer, and 47% had hormone receptor (HR)-positive disease. Statistically significant improvements in pathologic complete response rates by both the study definition and the FDA-preferred definition (39.3% vs 21.5%, difference of 17.8%, adjusted P = .0063) were observed in patients receiving pertuzumab plus trastuzumab/docetaxel vs patients receiving trastuzumab/docetaxel. The pathologic complete response rates and magnitude of improvement with pertuzumab were lower in the subgroup of patients with HR-positive tumors (22.0% vs 12.0%) compared with patients with HR-negative tumors (54.4% vs 29.8%).

How It Works Pertuzumab is a recombinant hu-

mitogen-activated protein kinase, and phosphoinositide 3-kinase. Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity.

How It Is Given The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered intravenously as a 60-minute infusion followed every 3 weeks by 420 mg administered intravenously as a 30- to 60-minute infusion. Pertuzumab should be administered every 3 weeks for three to six cycles as part of one of the following treatment regimens for early breast cancer: four preoperative cycles of pertuzumab in combination with trastuzumab/docetaxel followed by three postoperative cycles of FEC; three preoperative cycles of FEC alone followed by three preoperative cycles of pertuzumab in combination with docetaxel/trastuzumab; or six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab. Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is

insufficient evidence to recommend continued use of pertuzumab for greater than six cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.

Safety Profile In the primary trial supporting approval, the most common adverse events (> 30%) with pertuzumab in combination with trastuzumab/ docetaxel were alopecia (65% vs 66% with trastuzumab/docetaxel), neutropenia (50.5% vs 64%), diarrhea (46% vs 34%), and nausea (39% vs 36%). The most common grade 3 or 4 adverse events (>2%) were neutropenia (45% vs 59%), febrile neutropenia (8.4% vs 6.5%), leukopenia (4.7% vs 11.2%), and diarrhea (5.6% vs 3.7%). Other significant adverse events reported with pertuzumab included left-ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, and anaphylaxis. The approval is supported by an additional randomized phase II study conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety when FEC or carboplatin is incorporated into the preoperative regimen. Pertuzumab carries a boxed warning for cardiomyopathy and embryo-fetal toxicity. The cardiomyopathy warning is based on an increased rate of leftventricular ejection fraction decline observed in neoadjuvant trials. Cardiac function should be evaluated prior to and during treatment with pertuzumcontinued on page 66

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

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

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

100%

Patients, %

80%

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

60% 40% 20% 0%

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

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

ORR 29.2% (n=33)

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

POMALYST + low-dose dex (N=113)

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

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

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

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

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

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

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

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

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

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

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

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

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

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In the Clinic

Pertuzumab in HER2- Positive Breast Cancer continued from page 61

ab. The embryo-fetal toxicity warning is based on observations of oligohydramnios, delayed renal development, and embryo-fetal death in animal studies. Patients should be advised of these risks and need for effective contracep-

tion prior to starting pertuzumab. Pertuzumab also has warnings/ precautions f or embryo-fetal toxicity, left-ventricular dysfunction, infusionrelated reactions, hypersensitivity reactions/anaphylaxis, and HER2 testing. HER2 testing should be performed using FDA-approved tests by laboratories with demonstrated proficiency. n This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

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

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

References 1. U.S. Food and Drug Administration: Pertuzumab injection. Available at www. fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm370449.htm. 2. PERJETA® (pertuzumab) injection prescribing information, Genentech, Inc, October 2013. Available at www. accessdata.fda.gov/drugsatfda_docs/

Toxicity

Dose Modification

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

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

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

label/2013/125409s051lbl.pdf. 3. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

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

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15th World Conference on Lung Cancer Thoracic Oncology

Interim Data Reported From Phase IB Study of Investigational Anti-PD-1 Immunotherapy for NSCLC

nterim data from a Phase IB trial evaluating the investigational antiPD-1 immunotherapy, MK-3475, in patients with previously treated nonsmall cell lung cancer (NSCLC) were • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

presented recently at the 15th World Conference on Lung Cancer in Sydney, Australia. Edward Garon, MD, Director of Thoracic Oncology, Jonsson Comprehensive Cancer Center at (6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

UCLA presented the findings. MK-3475 is an investigational, highly selective anti–PD-1 immunotherapy designed to restore the natural ability of the immune system to Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 continued on page 68

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15th World Conference on Lung Cancer Anti-PD-1 Immunotherapy

In the phase IB trial, a cohort of 38 patients with previously treated

NSCLC were given MK-3475 10 mg/ kg every 3 weeks. The objective response rate in patients with squamous and nonsquamous subtypes receiving MK-3475 was 24% by investigatorassessed, immune-related assessed criteria (irRC) and 21% per RECIST 1.1 criteria. The median overall survival at the time of analysis was 51 weeks with

8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

continued from page 67

enables activation of the immune system’s T cells that target cancer.

Study Details

seven of the nine responders continuing on treatment. The median response duration had not been reached at the time of analysis. The most commonly reported drugrelated adverse events (all grades) in the study were rash (21%), pruritus (18%), fatigue (16%), diarrhea (13%), and arthralgia (11%). The majority of

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

adverse events were low grade (grade 1–2), and there was one incident of grade 3 pulmonary edema.

Effect of PD-L1 Expression Status An analysis of the relationship between PD-L1 expression status and response rates in this NSCLC patient cohort was also presented. Tumor

Edward Garon, MD

samples were analyzed and classified as expressing either zero/low or high levels of PD-L1. High levels of expression according to the assay criteria were associated with response rates of 67% (95% confidence interval [CI] = 30–93) per irRC and 57% (95% CI = 18–90) per RECIST 1.1 criteria. In comparison, tumor samples expressing zero/low levels of PD-L1, according to assay criteria, were associated with response rates of 4% (95% CI = 0–21) per irRC and 9% per RECIST (95% CI = 1–29). More data are needed to better understand the relationship between PD-L1 expression and response to MK-3475. Based on these preliminary data, a phase II/III trial comparing two doses of MK-3475 vs docetaxel in patients with previously treated NSCLC who have received at least one prior treatment regimen has been initiated. n

More on

Lung Cancer See pages 34-36 for more on lung cancer in this issue of The ASCO Post

ASCOPost.com | NOVEMBER 15, 2013

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Direct from ASCO

ASCO Reconfirms Commitment to Choosing Wisely® Campaign Task Force on Value of Cancer Care Releases New ‘Top Five’ List

n collaboration with the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely® campaign, ASCO recently released a second “Top Five” opportunities list of

Lowell E. Schnipper, MD

common practices or procedures in oncology whose clinical value is not supported by available evidence and if eliminated, can improve the quality and value of patient care.

Value of Cancer Care Task Force Like the original “Top Five” list, published in 2012, the new list was developed under the leadership of ASCO’s Value of Cancer Care Task Force, a multidisciplinary group of oncologists that was formed to address the rising cost of cancer care in this country while tackling solutions to improve quality and value. “Even in an area of care like oncology, where you are dealing with a scary illness with uncertain outcomes, doing everything possible for a patient

is not always helpful,” said Lowell E. Schnipper, MD, Chair of the Value of Cancer Care Task Force. “There are plenty of things that we automatically do that may not add value to the patient.” According to Dr. Schnipper, ASCO members widely supported ASCO’s initial “Top Five” opportunities list, which called for the elimination of unnecessary chemotherapy for patients with advanced disease who were unlikely to benefit, the use of costly imaging technologies for detecting breast cancer recurrence and for the staging of early breast and prostate cancers that are unlikely to metastasize, and the use of drugs to prevent febrile neutropenia for patients at low risk for the complication. When the ABIM Foundation recently asked ASCO to participate in a second “Top Five” list, the Task Force began the work of soliciting ideas from ASCO committee members, which include clinical oncologists in the community and in academia with a wide variety of expertise. “ASCO has devoted considerable energy in focusing on value in cancer care, and identifying and rationalizing key areas where medical activity is not producing value,” said Derek Raghavan, MD, PhD, a member of ASCO’s Value of Cancer Care Task Force. “This campaign has focused on common cancers where common patterns of practice— either diagnostic tests or patterns of treatment—no lon-

New Recommendations on HER2 Testing and Colorectal Cancer Follow-up Care

he latest additions to Cancer. Net’s patient-friendly versions of ASCO’s Clinical Practice Guidelines include guidance on HER2

testing, as well as an endorsement of colorectal cancer follow-up care recommendations from Can-

cer Care Ontario. ASCO Care and Treatment Recommendations (formerly called What to Know Guides) explain what the recommendations mean for patients and provide a list of questions to ask the doctor. Patients can find these and an infographic on HER2 testing at www .cancer.net/recommendations. n © 2013. American Society of Clinical Oncology. All rights reserved.

ger provide value to patients, neither improving outcomes or prognosis, nor reducing side effects.

Top Suggestions from Experts The following was developed from a list of top suggestions from ASCO committee members, which was compiled, ranked by importance, and narrowed down to five. 1. Do not give antiemetics intended for use with a chemotherapy regimen with a high risk of causing severe nausea and vomiting to an asymptomatic patient who is starting on a regimen that has a low or moderate risk of caus-

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

ing nausea and vomiting. 2. Do not use combination chemotherapy instead of single-agent chemotherapy when treating a patient for metastatic breast cancer unless the patient needs a rapid response to relieve tumor-related symptoms. 3. Avoid using advanced imaging techniques, such as PET or PET/CT scanning, as part of routine follow-up care to monitor for cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is highlevel evidence that such imaging will continued on page 71

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

What’s Hot in

JCO

JCO.org Double-Hit Diffuse Large B-Cell Lymphoma by Jonathan W. Friedberg

Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen by Eric Van Cutsem, et al

Growing Importance of MYC/BCL2 Immunohistochemistry in Diffuse Large B-Cell Lymphomas by Michael Pfreundschuh

Immunohistochemical Double-Hit Score Is a Strong Predictor of Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone by Tina Marie Green, et al Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone by Nathalie A. Johnson, et al

The ASCO Post | NOVEMBER 15, 2013

PAGE 70

Direct from ASCO

Celebrating 30 Years of Mentorship That Makes a Difference

he Conquer Cancer Foundation (CCF) Grants and Awards Program has been instrumental in helping launch the careers of hundreds of aspiring cancer researchers around the world over the past 30 years. Since the first grant provided

time and time again by Conquer Cancer Foundation grantees, many of whom advance in their careers to the point where they are able to mentor other grantees. Such is the case with 1992 Young Investigator Award recipient Elizabeth Jaffee, MD, Professor of Oncology, and 2000 Young Investigator Award recipient Daniel Laheru, MD, Associate Professor of Oncology, both at Johns Hopkins University. “Dr. Jaffee was the perfect mentor for me because she understood Elizabeth Jaffee, MD Daniel Laheru, MD how important the Young Investigator Award was for in 1984, Conquer Cancer Foundamy current training and also for my tion–funded scientists have become future development at Johns Hopsome of the most widely recognized kins University. She is very interested and respected names in the field of in the success of others, and to me cancer research today. This is in large that is the definition of a true menpart due to the program’s emphasis tor,” said Dr. Laheru. “In addition to on mentoring and career developme, there have been other trainees in ment. her lab who have gone on to receive The importance of mentorship for Young Investigator Awards or Career a young investigator cannot be overDevelopment Awards, and I think stated. It is a sentiment expressed that is a reflection of the time she has

ASCO Resources for Transitioning to ICD-10

SCO has developed resources to educate and assist oncology practices in transitioning to the Center for Medicare and Medicaid Services (CMS) 10th Edition of its International Classification of Diseases (ICD-10) coding system. Practices are encouraged to prepare for the transition before the October 1, 2014, deadline. On that date, ICD-10 will fully replace ICD-9 and providers may no longer bill with ICD-9 codes. Therefore, it is important to take the time to educate oneself about ICD-10 and determine what impact it will have on your practice. ASCO resources are available on its online resource center

for transitioning to ICD-10, which is available at http://www.asco.org /practice-research/icd-10. In addition, CMS has developed an online ICD-10 implementation guide that provides step-by-step guidance on how to transition to ICD-10. To access the webpage, please visit http://www .cms.gov/Medicare/Coding /ICD10/index .html ?redirect= /icd10. If you have any questions regarding ICD-10, please contact ASCO via email at billingandcoding @asco.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

taken to really help the trainees understand how to put together a grant proposal.”

Funding Opportunities Twenty-six percent of Career Development Award mentors and 19% of Young Investigator Award mentors for awards granted from 2008 to 2013 are past Conquer Cancer Foundation grantees, and one-third of the mentors for the 2013 Young Investigator Award class alone are past recipients of Conquer Cancer Foundation

grants. In addition to the Career Development Award and Young Investigator Award programs, the Foundation also offers many other funding opportunities that place a strong emphasis on mentoring. Learn more about these programs and make a donation to help support the next generation of cancer researchers at ConquerCancerFoundation.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

Save the Date 2014 Gastrointestinal Cancers Symposium January 16-18, 2014

Hyatt Regency Chicago San Francisco, California

2014 Genitourinary Cancers Symposium January 30-February 1, 2014 San Francisco Marriott Marquis San Francisco, California

ASCOPost.com | NOVEMBER 15, 2013

PAGE 71

Direct from ASCO

Choosing Wisely continued from page 69

change the outcome. 4. Do not perform PSA testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live less than 10 years. 5. Do not use a targeted therapy intended for use against a specific gene mutation if a patient’s tumor does not have that specific gene mutation.

add value and improve the quality of patient care (See related news item on page 144). “Oncologists would do well to understand that the recommendations on the ASCO list will reduce cost dramatically, will save patients

unnecessary inconvenience (and, in some cases, side effects and cost), but will not adversely impact quality of life or duration of survival,” Dr. Raghavan said. “ASCO is focused on providing the best care to patients, but also on ensuring that the things

we do actually improve outcomes.” To learn more about the Top Five and ASCO’s participation in Choosing Wisely, visit asco.org/topfive. n © 2013. American Society of Clinical Oncology. All rights reserved.

WHAT IF ENGINEERING THE ANTIBODY COULD IMPROVE ADCC? Glycoengineering a monoclonal antibody may improve ADCC1-4 In preclinical studies, the modification of certain sugar molecules via glycoengineering has been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by enhancing the ability of monoclonal antibodies to activate immune effector cells. Fc Region

The recommendations on the ASCO list will reduce cost dramatically, will save patients unnecessary inconvenience ... but will not adversely impact quality of life or duration of survival.

SUGARS MAY COMPROMISE IMMUNE EFFECTOR–ANTIBODY BINDING 4

Based on preclinical models, the ability of an antibody to bind to immune effector cells may be compromised by the presence of certain sugar residues on the antibody’s Fc region.

Sugar Modification

—Derek Raghavan, MD, PhD

GLYCOENGINEERING MAY INCREASE BINDING AFFINITY 1,3,4

GLYCOENGINEERING COULD LEAD TO IMPROVED ADCC 2,5

The modification of certain sugar residues via glycoengineering may result in enhanced binding affinity to immune effector cells that activate ADCC.

Preclinical data have demonstrated that certain glycoengineered antibodies may induce a greater level of ADCC than non-glycoengineered antibodies.

Glycoengineered antibodies have been or are being studied across a panel of molecular targets5

Vetting Process Members of the Task Force with expertise in each area were asked to vet the recommendations by evaluating the literature to make sure each recommendation was evidencebased, and that, whenever possible, they were consistent with guidelines issued by professional societies like ASCO or the National Comprehensive Cancer Network. The “Top Five” list was published in the Journal of Clinical Oncology with explanations of how eliminating each practice can

Immune Effector Cell

Glycoengineered antibodies have been or are being investigated in clinical trials across multiple disease states, including cancer, inflammation, and asthma.

Target Protein Target Cell

For more information, visit ResearchBcell.com

References: 1. Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chem. 2002;277(30):26733-26740. 2. Ogorek C, Jordan I, Sandig V, von Horsten HH. Fucose-targeted glycoengineering of pharmaceutical cell lines. Methods Mol Biol. 2012;907:507-517. 3. Herbst R, Wang Y, Gallagher S, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther Ther. 2010;335(1):213222. 4. Ferrara C, Grau S, Jäger C, et al. Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA. 2011;108(31):12669-12674. 5. Beck A, Reichert JM. Marketing approval of mogamulizumab: a triumph for glyco-engineering. MAbs. 2012;4(4):419-425.

*Based on preclinical models.

The ASCO Post | NOVEMBER 15, 2013

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Direct from ASCO

ASCO Announces Inaugural Class for Quality Training Program

“F

or oncologists, continuous quality improvement is a key goal. We measure and assess the quality of care we deliver and constantly look for areas where we can do better,” said ASCO President Clifford A. Hudis, MD, FACP. “ASCO’s Quality Training Program will guide oncology care providers in establishing methods and solutions to implement these quality improvements within their practices.” ASCO issued its first clinical practice guideline in 1994 and launched the Quality Oncology Practice Initiative (QOPI®), the first national program to help practices improve the quality of care they deliver, in 2006. The Quality Training Program represents an expanded opportunity for oncologists to improve care in their practice.

About the Program The 6-month Quality Training Program will offer 5 days of face-to-face education sessions between October 2013 and March 2014 at ASCO’s headquarters. Throughout the program, each practice will undertake its own focused quality improvement project, and the practice team will immediately be able to implement what they have

Clifford A. Hudis, MD, FACP

learned. After completing the training program, participants will have an understanding of process analysis, rapid cycle improvement, quantitative and qualitative methods, and creating and managing effective teams. Practices wishing to participate submitted an application, which was rigorously reviewed by the program’s selection committee. The inaugural class includes: • The Center for Breast Health – Bethesda, Maryland • Clearview Cancer Center – Huntsville, Alabama • Cleveland Clinic Foundation Taussig Cancer Institute – Cleveland, Ohio • LSU Health Shreveport, Feist‐Weiller Cancer Center– Shreveport, Louisiana

• New York University Langone Medical Center; NYU Cancer Institute – New York, New York • Palo Alto Medical Foundation – Palo Alto, California • Regional Cancer Care Associates ‐ Central Jersey Division – East Brunswick, New Jersey • The Comprehensive Cancer Center at Rhode Island Hospital – Providence, Rhode Island • Trillium Health Partners ‐ Peel Regional Cancer Centre – Mississauga, Ontario • University of Illinois Cancer Center – Chicago, Illinois • University of Pennsylvania Health System, Abramson Cancer Center –

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

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

www.jop.ascopubs.org

Philadelphia, Pennsylvania. • Washington Cancer Institute, MedStar Washington Hospital Center – Washington, DC • West Virginia University/Mary Babb Randolph Cancer Center – Morgantown, West Virginia • Yale Cancer Center & Smilow Cancer Hospital – New Haven, Connecticut • Yolanda G. Barco Oncology Institute – Meadville, Pennsylvania To learn more about ASCO’s Quality Training Program, please visit: www.asco.org/qualitytraining. n © 2013. American Society of Clinical Oncology. All rights reserved.

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

What’s Hot in

JOP

JCO.org

ASCO Receives Additional Funding for Virtual Learning Collaborative From California HealthCare Foundation

SCO is pleased to announce grant funding from the California HealthCare Foundation to support the Virtual Learning Collaborative (VLC). This pilot project will use the VLC to improve the quality of palliative care in routine medical oncology practice. ASCO is also collaborating with the American Academy of Hospice and Palliative Medicine and Duke University, with funding from the Agency for Healthcare Research and Quality, to harness technology to foster improved palliative care in oncology. The VLC is a web-based technology platform designed to efficiently disseminate educational tools and resources to

support practice improvement. The VLC will include customized learning modules, social networking capabilities, and a toolbox of evidence-based resources to help translate the latest research into practice. The VLC will provide participants with the opportunity to learn best practices in palliative care for oncology through collaboration with their peers. For more information or to learn about application requirements please go to www.asco.org/VLC or email vlc@ asco.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

Reduction in Chemotherapy Order Errors With Computerized Physician Order Entry by Barry R. Meisenberg, et al

Potential Benefits of Treatment Summaries for Survivors’ Health and Information Needs: Results From a LIVESTRONG Survey by Ruth Rechis, et al

Skin Cancer Surveillance and Malignancies of the Skin in a Community-Dwelling Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia by Aaron S. Mansfield, et al

Financial Distress, Use of Cost-Coping Strategies, and Adherence to Prescription Medication Among Patients With Cancer by Leah L. Zullig, et al

Improving Quality of Cancer Care at Community Hospitals: Impact of the National Cancer Institute Community Cancer Centers Program Pilot by Michael T. Halpern, et al

ASCOPost.com | NOVEMBER 15, 2013

PAGE 73

Journal Spotlight Breast Cancer

Breast Cancer Index Assay Prognostic for Distant Recurrence in Estrogen Receptor–Positive, Node-Negative Breast Cancer By Matthew Stenger

n a study reported in The Lancet Oncology, Dennis C. Sgroi, MD, of Massachusetts General Hospital, and colleagues compared the ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) to predict early and late distant recurrence in patients with estrogen receptor (ER)-positive, node-negative breast cancer. The study showed that a BCI-linear model was superior to a BCI-cubic model. Further, while all tests were significantly prognostic for overall risk of recurrence and early recurrence, only the BCI-linear assay, which is comprised of two independently developed gene expression biomarkers, was significantly prognostic for late recurrence.

BCI-Linear vs BCI-Cubic The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-cubic risk groups (P < .0001), with 6.8% of patients in the low-risk group, 17.3% in the intermediate-risk group, and 22.2% in the high-risk group having distant recurrence. Multivariate analysis showed that the BCI-linear test was a stronger predictor for overall distant recurrence compared with the BCI-cubic test (interquartile hazard ratio [HR] =

[The BCI-linear assay] was the only significant prognostic test for risk of both early and late distant recurrence and … could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.

Study Details The study was performed in 665 patients with ER-positive, nodenegative disease who received either tamoxifen or anastrozole monotherapy in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, using archived tumor blocks from patients for whom the 21-gene recurrence score and IHC4 values had already been ascertained. BCI analysis was performed in matched samples with sufficient residual RNA using BCI-linear and BCI-cubic models. The prognostic ability of the BCI assay for distant recurrence over 10 years (the primary endpoint) was determined and compared with that of the 21-gene recurrence score and IHC4 for overall 10-year, early (0–5 years), and late (5–10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathologic variables, the change in the likelihood-ratio χ2 (LR-Δχ2) was calculated from Cox proportional hazards models.

Δχ2 = 29.14, P < .0001) all were significantly prognostic for early distant recurrence. Similarly, the BCI-linear (HR = 2.77, 95% CI = 1.63–4.70, LR-Δχ2 = 15.42, P < .0001), 21-gene recurrence score (HR = 1.80, 95% CI = 1.42–2.29, LR-Δχ2 = 18.48, P < .0001), and the IHC4 (HR = 2.90, 95% CI = 2.01–4.18, LR-Δχ2 = 29.14, P < .0001) were all prognostic for early distant recurrence. However, only BCI-linear was prognostic for late distant recurrence (HR = 1.95, 95% CI = 1.22–3.14, LR-Δχ2 = 7.97, P = .0048), with the 21-gene recur-

—Dennis C. Sgroi, MD

2.30 (95% confidence interval [CI] = 1.62–3.27), LR-Δχ2 = 22.69, P < .0001) and that both the 21-gene recurrence score (HR = 1.48, 95% CI = 1.22–1.78], LR-Δχ2 = 13.68, P = .0002) and IHC4 (HR = 1.69, 95% CI = 1.51–2.56], LR-Δχ2 = 22.83, P < .0001) were less predictive than the BCI-linear test. All further analyses were done using the BCI-linear model.

Prognostic for Overall, Early, and Late Recurrence In multivariate analyses, the BCI-linear assay (HR = 2.77, 95% CI = 1.63–4.70, LR-Δχ2 = 15.42, P < .0001), 21-gene recurrence score (HR = 1.80, 95% CI = 1.42–2.29, LRΔχ2 = 18.48, P < .0001), and IHC4 (HR = 2.90, 95% CI = 2.01–4.18, LR-

Prediction of Recurrence in Breast Cancer ■■ The BCI-linear assay was significantly prognostic for overall, early, and late distant recurrence, whereas the 21-gene recurrence score and IHC4 were not prognostic for late recurrence.

■■ The BCI-linear assay identified two distinct risk groups for early and late

recurrence and could help identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.

rence score (HR = 1.13, 95% CI = 0.82–1.56, LR-Δχ2 = 0.48, P = .47) and the IHC4 (HR = 1.30, 95% CI = 0.88–1.94, LR-Δχ2 = 1.59, P = .20) not achieving significance. Results were similar in the subgroup of 597 HER2-negative patients, with all three tests being significantly prognostic for overall distant recurrence and early recurrence, but only BCI-linear being prognostic for late distant recurrence.

Two Distinct Risk Groups for Early and Late Recurrence A post hoc analysis of BCI-linear in early recurrence showed that there was little difference in distant recurrence at 5 years between the BCI lowrisk and intermediate-risk groups, which together included 556 (84%) of 665 patients with a combined 5-year rate of distant recurrence of 2.6%. The BCI high-risk group, which included 109 patients (16%), had a 5-year distant recurrence rate of 18·1%. After adjustment for clinical treatment score, the hazard ratio for the highrisk group vs this low-risk grouping was 4.61 (95% CI = 2.20–9.66). An analysis of late recurrence

showed that intermediate-risk and high-risk patients had highly similar rates of recurrence, with the combined groups including 230 (39%) of 596 patients with a distant recurrence rate of 13.4% for years 5 to 10. The low-risk group included 366 patients (61%) with a recurrence rate of 3.5% for years 5 to 10. After adjustment for clinical treatment score, the hazard ratio for this high-risk grouping vs the low-risk group was 2.94 (95% CI = 1.44–6.01). The investigators noted that these modified risk groupings could allow baseline identification of a relatively small group of patients at higher risk of early recurrence who might be considered for therapy in addition to endocrine therapy and a larger group that might be regarded as adequately treated with endocrine therapy. Similarly, the finding of two distinct risk groupings for late recurrence in patients remaining disease-free on adjuvant tamoxifen or aromatase inhibitor treatment at 5 years suggests that there is a sizable group of patients at low risk who may require no further systemic therapy. The investigators concluded, “[The BCI-linear assay] was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk populations for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.” n Disclosure: The study was funded by the Avon Foundation, National Institutes of Health, Breast Cancer Foundation, U.S. Department of Defense Breast Cancer Research Program, Susan G. Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, AstraZeneca, Cancer Research UK, and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden (London).

Reference 1. Sgroi DC, Sestak I, Cuzick J, et al: Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: A prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncology 14:1067-1076, 2013.

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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. 5/13 74386-R1-V2

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The ASCO Post | NOVEMBER 15, 2013

PAGE 76

Perspective End-of-Life Care

Illness Is Personal! By Ira Byock, MD

or clinicians and health service researchers striving to improve care for people living with life-threatening conditions, September was a sobering month. The Dartmouth Atlas group released a brief report on Trends in Cancer Care Near the End of Life1 showing that while the proportion of patients with cancer who die in hospitals slightly decreased between 2003–2007 and 2010, patients in 2010 were more Dr. Byock is a palliative care physician and a Professor of Medicine at the Geisel School of Medicine at Dartmouth. He is author of The Best Care Possible: A Physician’s Quest to Transform Care Through the End of Life. www.The BestCarePossible.org.

likely to receive life-sustaining treatments, spend time in an ICU in the final month of life, or undergo chemotherapy during the last 2 weeks of life (see related news item below). Moreover, while hospice use is up, many cancer patients are receiving hospice care only at the brink of death, for the last 3 to 7 days of life. Two weeks later, the Institute of Medicine published a 360-page report on Delivering High Quality Cancer Care, which was subtitled, Charting a New Course for a System in Crisis.2 This report details ongoing patterns of excessive disease treatments coupled with insufficient attention to cancer patients’ and their families’ comfort,

social support, and well-being.

Buyer Beware Cancer care statistics and data tables are deliberately anonymous, yet the people whose stories the facts and figures represent all had names and faces, feelings and families. Anyone who has cancer—or loves someone who has it—knows that cancer is profoundly personal. From the moment the test results come back and a doctor utters the words, “I’m afraid you have cancer,” people’s worlds are shaken. Getting the best care becomes Job 1. These days, that entails finding the best doctors and cancer centers in the area, searching the Internet for treat-

ment options, and seeking second (and sometimes third and fourth) opinions. Without notice and, in most cases, without preparation, the diagnosis turns patients and their families into “consumers” of health care. (I dislike the term, but it seems apt for the choices people with cancer must make.) Becoming an effective, discriminating consumer is essential because, as the graphs and data tables show, habits of medical practice vary dramatically from one region of the country to another—and even from one medical center to another within large cities. These regional and institutional practice patterns bias the types of care people receive, without their

New Report Examines Trends in End-of-Life Care By Jo Cavallo

lthough fewer Medicare patients with cancer died in the hospital in 2010 than in the years 2003–2007, aggressive treatment continues at the end of life, according to a new report from the Dartmouth Atlas Project.1 The findings also show that a significant number of patients were likely to receive lifesustaining treatments, including intubation, a feeding tube, or cardiopulmonary resuscitation, in the final month of life, or to undergo chemotherapy during the last 2 weeks of life.

Longitudinal Analysis The report examined trends in end-of-life care for advanced cancer patients across regions, academic medical centers, and National Cancer Institute–designated cancer centers. It is the first Dartmouth Atlas report with a longitudinal analysis of the care provided to Medicare patients with advanced cancer. According to the report, although

the percentage of patients with cancer receiving hospice care during the last month of life has increased to 61.3% in 2010 from 54.6% in 2003–2007, the percentage of patients admitted to hospice care during the last 3 days of life— when it is often too late to provide much benefit—rose from 8.3% in 2003–2007 to 10.9% in 2010. The report also found that most patients with cancer who are approaching the end of their lives prefer supportive care that minimizes symptoms and the number of days spent in the hospital. “Unfortunately, the care patients receive does not always reflect their own preferences, but the prevailing styles of treatment in the regions and health-care systems where they happen to receive cancer treatment,” wrote the authors.

Hospice Services Provided Too Late In a statement, David C. Goodman, MD, MS, Professor of Pe-

End-of-Life Care in 2013 ■■ Fewer Medicare patients with cancer died in the hospital in 2010 than in 2003–2007, but a new report found that aggressive, life-sustaining treatment continues at the end of life.

■■ Most patients with cancer approaching the end of their lives prefer

supportive care that minimizes symptoms and time spent in the hospital.

■■ An ASCO provisional clinical opinion calls for the integration of palliative

care services into standard oncology practice when a person is diagnosed with advanced cancer, to improve quality of life.

David C. Goodman, MD, MS

diatrics and Health Policy at The Dartmouth Institute for Health Policy & Clinical Practice and coprincipal investigator of the Dartmouth Atlas Project, said, “Our research continues to find that patients with advanced cancer are often receiving aggressive care until their final days, when we know that most patients would prefer care directed toward a better quality of life through hospice and palliative services. The increase in patients admitted to hospice care only days before death suggests that hospice services are often provided too late to provide much benefit. Fuller discussions with patients who have advanced cancer on their prognosis and options for care can lead to a better quality of life than many receive today.”

Communication on Care Goals ASCO has been proactive in calling for an increase in physician-patient communication on treatment options and care goals immediately following a

diagnosis of advanced cancer and published a provisional clinical opinion on palliative care in 2012.2 “ASCO has long advocated for improved physician-patient communication about care preferences, especially for patients with advanced cancer,” said ASCO President Clifford A. Hudis, MD, FACP. “Over the past few years, we’ve seen data that show that patients who talk about these issues with their clinicians early in the course of treatment are more likely to receive the type of care they prefer. These important discussions lead to greater use of palliative and hospice care, and can improve a patient’s quality of life, sense of control, and satisfaction with their care and choices.”n

Disclosure: Drs. Goodman and Hudis reported no potential conflicts of interest.

References 1. Goodman DC, Morden NE, Chang C, et al: Trends in cancer care near the end of life. Lebanon, New Hampshire; The Dartmouth Insitute. September 4, 2013. Available at www. dartmouthatlas.org. Accessed October 8, 2013. 2. Smith TJ, Temin S, Alesi ER, et al: ASCO provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 77

Perspective

knowledge, and often in ways they would not want. Note to health-care consumers: Let the buyer beware. As a doctor who has helped care for people with advanced cancer for over 30 years, when my own relatives or personal friends are wrestling with treatment decisions and turn to me for advice, here is the perspective I offer. First, if you have a curable or highly treatable cancer, go for it! Get the best treatments you can and, within reason, stick with the program through predictably difficult times. Advances in oncology have made many of today’s treatments well worth the effort.

More Is Not Always Better However, if and when your cancer advances despite treatments and you find your strength, energy, appetite, and overall stamina are waning, be cautious about excessive medical care. The longstanding assumption is that the more diagnostic tests and treatments patients receive, the better off they will be. However, 2 decades of studies by Dartmouth Atlas researchers have proven that this supposition is often wrong.3 In advanced illnesses, including cancer, higher levels of medical treatments are commonly associated with more suffering but little or no extension of life. Yet when a person—someone’s mother or father, spouse, sibling, or child—is getting sicker, the desire to do something is strong. Under the influence of the more-is-better mentality, well-intentioned clinicians and loving families can inadvertently cause people to spend precious, fleeting days at the end of a long illness in hospitals and ICUs, instead of at home or other places they would rather be.

Palliative Care, Hospice Can Extend Life Don’t confuse palliative and hospice care with giving up hope of living longer. In actuality, patients with invasive cancers who receive palliative care along with cancer treatments tend to enjoy better quality of life and live longer.4,5 Similarly, cancer patients who receive hospice care tend to live longer than those who don’t.6 The reasons are not mysterious. Palliative care and hospice teams provide meticulous clinical attention to people’s pain and other symptoms, basic bodily needs (such as eating, sleeping, eliminating, washing, grooming, and getting around), as well as support for their emotional and spiritual concerns.

It’s little wonder that people with advanced cancer who receive such comprehensive whole-person care are able to feel a bit better and survive longer.

Since Cancer Is Personal, So Is Cancer Care The best care helps people live as comfortably and fully as possible through the very end of life. It supports people in the difficult but normal tasks of completing their affairs and relationships—includ-

Yet many people avoid talking about dying, as if talking about it will make death more likely. In reality, everyone knows cancer can be life-threatening. That’s why getting the best care is so important. If we don’t talk with our families and doctors about what we would want or not want, how are they to know? Published surveys can tell us what most people want as they come to the end of life, but one size does not fit all.

Published surveys can tell us what most people want as they come to the end of life, but one size does not fit all.… The right choice is one that is well considered and made by a well-informed person (and family) in collaboration with health-care professionals. —Ira Byock, MD

ing, if they wish, taking stock of their lives, telling their stories, and leaving a legacy to those they leave behind. The Institute of Medicine, American Cancer Society, and American Society of Clinical Oncology have all called for cancer care to be patientcentered and attend to the well-being of people living with cancer.7-10 Despite published clinical standards and evidence-based “best practice” treatment guidelines, progress has been slow and uneven, and much remains to be done. The solution begins with recognizing that since cancer is personal, the “best care” must be defined one person at a time. Evidence-based treatment algorithms for specific types and stages of cancer are invaluable; however, quality requires tailoring treatments and plans of care to reflect the values, preferences, and priorities of the individual living with cancer. It takes a patient with his or her chosen family members and clinicians working together to determine the optimal plan of care at each particular point in time.

Conversations Matter Even a single conversation about end-of-life preferences between cancer patients and their physicians has been shown to improve the chances that people will be comfortable and not burdened with extraordinary treatments during their final days.11,12

Some people want all possible treatments to prolong life, regardless of discomfort; others set limits on the amount of discomfort and treatments they will accept. The right choice is one that is well considered and made by a well-informed person (and family) in collaboration with health-care professionals.

Don’t Take Quality for Granted The genuinely best doctors and medical centers have made care planning conversations and shared decision-making routine. They make it easy for people to get cutting-edge cancer treatments right along with the full services of a palliative care team. Truly excellent clinicians and health systems pay conscientious attention to transitions of care, seamlessly extending care to people’s homes and support to people’s family caregivers. If you or someone you love is living with cancer, it is wise to consider your options carefully. Talk with your doctor and with the people you trust to consider what types of treatment and overall care are right for you. Check the Dartmouth Atlas website (www.dartmouthatlas.org) to learn how the region you live in and the medical centers near you compare with others. Get that second, third, or fourth opinion, including one of a palliative care specialist. After all, this is personal. There is no reason to settle for less than the best. n

References 1. Goodman DC, Morden NE, Chang C, et al: Trends in cancer care near the end of life. Lebanon, New Hampshire; The Dartmouth Insitute. September 4, 2013. Available at www.dartmouthatlas.org. Accessed October 8, 2013. 2. Institute of Medicine: Delivering high quality cancer care: Charting a new course for a system in crisis. Washington, DC; National Academies Press, 2013. 3. Wennberg JE, Fisher ES, Stukel TA, et al: Use of hospitals, physician visits, and hospice care during last six months of life among cohorts loyal to highly respected hospitals in the United States. BMJ 328:607, 2004. 4.Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010. 5. Bakitas M, Lyons KD, Hegel MT, et al: Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: The Project ENABLE II randomized controlled trial. JAMA 302:741-749, 2009. 6. Connor SR, Pyenson B, Fitch K, et al: Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symptom Manage 33:238-46, 2007. 7. Field MJ, Cassell CK: Approaching death: Improving care at the end of life. Washington, DC, National Academy Press; 1997. 8. Cancer care during the last phase of life. J Clin Oncol 16:1986-1996, 1998. 9. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012. 10. Institute of Medicine. Improving Palliative Care for Cancer: Summary and Recommendations. 2001. 11. Zhang B, Wright AA, Huskamp HA, et al: Health care costs in the last week of life: associations with end-of-life conversations. Arch Intern Med 169:480488, 2009. 12. Wright AA, Zhang B, Ray A, et al: Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA 300:1665-1673, 2008. Reprinted, with permission from Ira Byock and The Dartmouth Institute, from Trends in Cancer Care Near the End of Life: A Dartmouth Atlas of Health Care Brief. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

The ASCO Post | NOVEMBER 15, 2013

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Announcements

IOM Elects New Members continued from page 12

• Molly Cooke, MD, University of California, San Francisco • Delos M. Cosgrove III, MD, The Cleveland Clinic Foundation, Cleveland • Janet M. Currie, PhD, Princeton University, Princeton, New Jersey • Mary E. D’Alton, MD, Columbia University College of Physicians and Surgeons; New York-Presbyterian/Sloan Hospital for Women, New York • Carlos del Rio, MD, Emory University, Atlanta • David L. DeMets, PhD, University of Wisconsin, Madison • Phyllis A. Dennery, MD, University of Pennsylvania; The Children’s Hospital of Philadelphia, Philadelphia • James R. Downing, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee • Jeffrey Adam Drebin, MD, PhD, University of Pennsylvania, Philadelphia • Gideon Dreyfuss, PhD, Howard Hughes Medical Institute; University of Pennsylvania, Philadelphia • Eric R. Fearon, MD, PhD, University of Michigan, Ann Arbor • Mark Edwin Frisse, MD, MS, MBA, Vanderbilt University, Nashville, Tennessee • Judy E. Garber, MD, MPH, Dana Farber Cancer Institute; Harvard Medical School, Boston

• Jody Heymann, MD, PhD, University of California, Los Angeles • Waun Ki Hong, MD, FACP, DMSc (Hon.), The University of Texas MD Anderson Cancer Center, Houston • Brian Jack, MD, Boston University, Boston • Clifford R. Jack Jr., MD, Mayo Clinic, Rochester, Minnesota

Waun Ki Hong, MD, FACP, DMSc (Hon.)

Richard D. Kolodner, PhD

Sally Kornbluth, PhD

Simulated image based on patient with locally advanced BCC at Week 24.

Judy E. Garber, MD, MPH

• Ronald N. Germain, MD, PhD, National Institutes of Health, Bethesda, Maryland • Arline T. Geronimus, Sc.D., University of Michigan School of Public Health, Ann Arbor • Karen Glanz, PhD, MPH, University of Pennsylvania, Philadelphia • Joseph G. Gleeson, MD, Howard Hughes Medical Institute; University of California, San Diego • Susan B. Hassmiller, PhD, RN, FAAN, Robert Wood Johnson Foundation, Princeton, New Jersey

Boxed Warning And Additional Important Safety Information

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly Embryo-Fetal Death and Severe Birth Defects or through seminal fluid, to participate in the Erivedge • Erivedge capsule can cause fetal harm when pregnancy pharmacovigilance program by contacting administered to a pregnant woman based on its the Genentech Adverse Event Line at (888) 835-2555 mechanism of action Blood Donation • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months risks. Advise female patients of the need after the last dose of Erivedge for contraception during and after treatment and advise male patients of the potential risk Nursing Mothers of Erivedge exposure through semen • Inform female patients of the potential for serious • Advise patients to contact their healthcare provider adverse reactions in nursing infants from Erivedge, ERIV3D0021_F_Transformation_Print_Update_ASCO_r3.indd immediately if they suspect they 1(or, for males, their taking into account the importance of the drug to female partner) may be pregnant the mother

ASCOPost.com | NOVEMBER 15, 2013

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Announcements

• Carlos Roberto Jaén, MD, PhD, University of Texas Health Science Center at San Antonio, San Antonio • Alan M. Jette, PT, MPH, PhD, Boston University, Boston • Ashish K. Jha, MD, MPH, Harvard School of Public Health, Boston • Gary S. Kaplan, MD, FACP, FACMPE, FACPE, Virginia Mason

Health System, Seattle • Evan D. Kharasch, MD, PhD, Washington University, St. Louis • Richard D. Kolodner, PhD, Ludwig Institute for Cancer Research; University of California, San Diego • Sally Kornbluth, PhD, Duke University, Durham, North Carolina • Ann Elizabeth Kurth, PhD, Global

Institute of Public Health, New York University, New York • Nancy E. Lane, MD, UC Davis Health System, University of California, Davis • Thomas A. LaVeist, PhD, Johns Hopkins Bloomberg School of Public Health, Baltimore • Quynh Thu Xuan Le, MD, Stanford

TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL CARCINOMA ((aBCC) ERIVEDGE IS A UNIQUE ORAL THERAPY (Not actual size)

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness), some patients may not be candidates for surgery or radiation1,2 • Erivedge is an oral treatment option dosed as a 150-mg capsule once daily until disease progression or unacceptable toxicity3 • Erivedge reduced lesions in patients with aBCC1,3 Objective response rates (ORR) by IR from ERIVANCE1,3* ORR (95% CI)

laBCC (n=63)

mBCC (n=33)

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

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

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median duration of response (months) (95% CI)

Indication Erivedge® (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. *Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IR=Independent Review; laBCC=locally advanced BCC; ORR=objective response rate; CI=confidence interval; NE=not estimable; mBCC=metastatic BCC.

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) 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 Brief Summary of Prescribing Information on following page.

See what you can offer your patients with aBCC at www.Erivedge.com References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. 2004;23:389-402. 3. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 5/29/13 2:53 PM

University, Stanford, California • Brendan Lee, MD, PhD, Howard Hughes Medical Institute; Baylor College of Medicine, Houston • Warren J. Leonard, MD, National Institutes of Health, Bethesda, Maryland • Pat R. Levitt, PhD, Keck School of continued on page 80

The ASCO Post | NOVEMBER 15, 2013

PAGE 80

Announcements

IOM Elects New Members

sity, Waltham, Massachusetts • Jonna Ann Mazet, DVM, MPVM, PhD, School of Veterinary Medicine, University of California, Davis • Ruslan Medzhitov, PhD, Howard Hughes Medical Institute; Yale University School of Medicine, New Haven, Connecticut • Diane E Meier, MD, Center to Ad-

continued from page 79

Medicine, University of Southern California; Children’s Hospital Los Angeles, Los Angeles • Beverly Louise Malone, PhD, RN, FAAN, National League for Nursing, New York • Eve Marder, PhD, Brandeis Univer-

vance Palliative Care; Ichan School of Medicine, Mount Sinai, New York • Michelle M. Mello, PhD, Harvard School of Public Health, Boston • Bernadette Mazurek Melnyk, PhD, RN, FNAP, FAANP, FAAN, Ohio State University, Columbus • David J. Mooney, PhD, Harvard University, Cambridge, Massachussets

Safety:7" Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

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

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2013 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301

Safety:10"

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

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

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]

• Louis Joseph Muglia, MD, PhD, University of Cincinnati College of Medicine, Cincinnati • Joan M. O’Brien, MD, University of Pennsylvania, Philadelphia • Daniel Samuel Pine, MD, National Institutes of Health, Bethesda, Maryland • Helen Piwnica-Worms, PhD, The University of Texas MD Anderson Cancer Center, Houston • Bruce Mark Psaty, MD, PhD, University of Washington, Seattle • Danny Reinberg, PhD, Howard Hughes Medical Institute; New York University School of Medicine, New York • J. Evan Sadler, MD, PhD, Washington University School of Medicine, St. Louis • Yoel Sadovsky, MD, Magee-Womens Research Institute; University of Pittsburgh, Pittsburgh • Peter Salovey, PhD, Yale University, New Haven, Connecticut • Mark A. Schuster, MD, PhD, Boston Children’s Hospital, Boston • Nirav Ramesh Shah, MD, MPH, New York State Department of Health, Albany • George M. Shaw, MD, PhD, University of Pennsylvania, Philadelphia • Lisa Simpson, MBBCh, MPH, FAAP, AcademyHealth, Washington, DC • Pamela Sklar, MD, PhD, Icahn School of Medicine at Mount Sinai, New York • Matthew W. State, MD, PhD, University of California, San Francisco • Subra Suresh, ScD, Carnegie Mellon University, Pittsburgh • Christopher A. Walsh, MD, PhD, Howard Hughes Medical Institute; Boston Children’s Hospital; Harvard Medical School, Boston • Elizabeth (Betsy) Elder Weiner, PhD, RN-BC, FACMI, FAAN, Vanderbilt University School of Medicine, Nashville, Tennessee • James Owen Woolliscroft, MD, University of Michigan Medical School, Ann Arbor See page 51 for a list of newly elected foreign associates to the Institute of Medicine. n

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

ASCOPost.com | NOVEMBER 15, 2013

PAGE 81

JCO Spotlight Hematology

Multicenter Analysis of Outcomes of Lymphoma in Pregnancy By Matthew Stenger

ymphoma is the fourth most frequent cancer to occur in pregnant women. In a multicenter retrospective analysis reported in Journal of Clinical Oncology, Andrew M. Evens, DO, MSc, Chief of Hematology/Oncology at Tufts University Medical Center, Boston, and colleagues examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and nonHodgkin lymphoma (NHL) occurring during pregnancy.1 The findings indicate that standard, non-antimetabolite, combination chemotherapy can be administered past the first trimester with few complications.

phoma diagnosis at a median of 22 weeks (range, 6–32 weeks; P < .001), with no difference in median time of diagnosis according to lymphoma type. Antenatal treatment was started in patients at a median of 25 weeks, with 89% receiving combination chemotherapy, most commonly with standard regimens for the particular lymphoma subtypes. Treatment was started in the second trimester in 37 patients (66%). The overall response rate for the 56 patients who received antenatal therapy was 82%, including complete response in 64%; overall response rate was 71% (complete response in 50%) in NHL

When clinically indicated, standard chemotherapy regimens for lymphoma administered during the second and third trimesters were associated with minimal maternal complications or fetal detriment. —Andrew M. Evens, DO, MSc, and colleagues

Study Details The study included 90 patients from 11 academic centers who had a diagnosis of NHL (n = 50) or HL (n = 40) during pregnancy over a 13year period (1999–2011). Patients had a median age of 30 years (range, 18–44 years) and median diagnosis occurred at 24 weeks’ gestation. Advanced-stage disease was present in 52% of patients with NHL and 25% of those with HL (P = .01). Of patients with stage I to II disease, 17% of patients with NHL and 30% of patients with HL had B symptoms or bulky disease.

Treatment Details and Outcome Among the 90 patients, pregnancy was terminated in 6 (7%) to permit immediate chemotherapy. Among the other 84 patients, 28 (33%)—including 32% of NHL patients and 35% of HL patents—had therapy deferred to postpartum; these patients were diagnosed with lymphoma at a median of 30 weeks’ gestation (range, 12–38 weeks). The 56 patients (67%) who received antenatal treatment had lym-

patients and 96% (complete response in 83%) in HL patients (P = .03 for overall response rate, P = .013 for complete response).

Complications The most common complication was induction of labor, in 33% of patients. Perinatal events included premature rupture of membranes in 13% and preeclampsia in 7%. Delivery was via cesarean section in 33% of patients, with such delivery occurring in more NHL patients (44% vs 19%, P = .007). Among the 83 patients for whom timing of delivery was available, 44% had preterm deliveries with no difference based on NHL vs HL (51% vs 36%, P = .19).

Fetal Outcomes The median gestation at delivery was 37 weeks (range, 31–40 weeks). Gestation went to full term in 47 (56%) of 84 patients, with no differences according to lymphoma type or receipt of antenatal therapy. One miscarriage occurred at 19 weeks’ gestation in a 34-year-old patient with double-hit NHL following one cycle of R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and pred-

Impact of Lymphoma on Pregnancy ■■ As stated by the investigators: “Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks’ gestation, was associated with few complications and expected maternal [and fetal] survival with lymphoma occurring during pregnancy.”

■■ In mothers with NHL, radiotherapy predicted inferior progression-free

survival and poor ECOG performance status and increased lactate dehydrogenase predicted inferior overall survival. In mothers with HL, multiparous status predicted improved progression-free survival and presence of B symptoms at diagnosis predicted inferior progression-free survival.

nisone). The median birth weight was 2,668 g (range, 1,005–3,628 g). Although there was no difference in birth weight according to receipt of antenatal chemotherapy vs deferred therapy (2,670 g vs 2,665 g, P = .74), there was a trend for infants to be small for gestational age if their mothers had received antenatal therapy (41% vs 9%, P = .09). Of gestations for which information was available, 8 (11%) of 72 infants, all born to NHL patients, required admission to the neonatal intensive care unit (median stay, 12 days; range, 3–40 days), with no differences based on antenatal therapy vs deferred therapy. Microcephaly was reported in one infant following four antenatal cycles of CHOP for diffuse large B-cell lymphoma in the mother, who started treatment at 28 weeks’ gestation and delivered at 38 weeks. Grade 1 pelviectasis occurred in an infant whose mother received four antenatal cycles of R-CHOP for diffuse large B-cell lymphoma at 21 weeks’ gestation and delivered at 34 weeks due to preeclampsia. No other malformations were detected.

Maternal Outcomes At a median follow-up of 41 months (range, 6–147 months), 3-year progression-free survival and overall survival rates were 53% and 82% for NHL patients and 85% and 97% for HL patients; rates were 55% and 79% for diffuse large B-cell lymphoma patients and 37% and 90% for patients with Tcell NHL (P = .43 and P = .60, respectively). There were 8 deaths related to NHL, including 5 due to diffuse large B-cell lymphoma, 1 due to peripheral T-cell lymphoma–not otherwise specified, 1 due to Burkitt’s lymphoma, and 1 due to double-hit NHL. In NHL patients, radiotherapy

was the only predictor of inferior progression-free survival (hazard ratio [HR] = 5.19, P = .003) and Eastern Cooperative Oncology Group (ECOG) performance status of 2 to 4 (HR = 5.51, P = .001) and increased lactate dehydrogenase (HR = 9.93, P = .03) predicted inferior overall survival. For patients with diffuse large B-cell lymphoma, radiotherapy predicted inferior progression-free survival (HR = 7.72, P = .008) and poor ECOG performance status predicted worse overall survival (HR = 2.33, P = .04). For patients with HL, multiparous status predicted improved progression-free survival (HR = 0.07, P = .01), presence of B symptoms at diagnosis predicted inferior progression-free survival (HR = 10.78, P = .04), and no variables were predictive of overall survival. Dr. Evens told The ASCO Post that “When clinically indicated, standard chemotherapy regimens for lymphoma administered during the second and third trimesters were associated with minimal maternal complications or fetal detriment.” In addition, Dr. Evens indicated there were lowrisk clinical scenarios with low tumor burden or late gestational diagnosis, where therapy was safely deferred to postpartum. And in all cases, he said it is critical that care be closely coordinated with high-risk maternal-fetal medicine.n Disclosure: Dr. Evans reported no potential conflicts of interest.

Reference 1. Evens AM, Advani R, Press OW, et al: Lymphoma occurring during pregnancy: Antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol. September 16, 2013 (early release online). See Commentary on page 82

The ASCO Post | NOVEMBER 15, 2013

PAGE 82

JCO Spotlight Continued from page 81

Two Patients in One, Mom and Baby: Managing Coincident Pregnancy and Lymphoma By Joseph M. Connors, MD

he news that she is both pregnant and has been found to have a potentially lethal malignancy is one of the most emotionally wrenching events any young woman ever faces. Understandably, the patient, her partner, their families, and even their caregivers find this experience fraught with anxiety and fear. Being able to provide solid information and a sensible plan of management is a major responsibility of the woman’s oncologist. All of us who fulfill this role should be grateful for the thoroughgoing analysis provided by Dr. Andrew Evens and his colleagues in their recent publication in the Journal of Clinical Oncology,1 as reviewed in this issue of The ASCO Post. As with any retrospective collection of special cases from multiple institutions gathered over many years of experience, however, the reader must be careful not to overinterpret the validity of the results. The authors describe the clinical course of 90 pregnant patients found to have either non-Hodgkin lymphoma (NHL, n = 50) or Hodgkin lymphoma (HL, n = 40) and were able to make several very important observations. Observation #1: Pregnancies encountered coincident with lymphoma do not need to be terminated. Two patients already had lymphoma when they became pregnant. Of 11 patients diagnosed in the first trimester of pregnancy, 6 elected to terminate the pregnancy, and treatment was deferred until later in the remaining 5. This is important because major organogenesis is mostly completed during the first trimester, when treatments could be likely to cause major birth defects. After the first trimester, treatments may be tolerated and not likely to cause fetal harm. Most patients were diagnosed in the second or third trimester (79/88, 90%). The large majority (83/84, 99%) of patients who chose Dr. Connors is Clinical Director, BC Cancer Agency Centre for Lymphoid Cancer, Vancouver, British Columbia.

to keep the pregnancy successfully reached term delivery. Observation #2: Intervention is not necessary unless the lymphoma is symptomatic or of a histologic type that threatens rapid progression. Treatment was deferred until after delivery in 28 patients, primarily those with HL or indolent NHL (HL: 13/40; follicular NHL: 4/5). Deferral of treatment in asymptomatic patients does not appear to jeopardize the

patients were able to defer delivery until good fetal maturation was achieved, which was also reflected in the low rate of admission to a neonatal intensive care unit (11%). Early induction of delivery is unnecessary unless fetal distress or major complications develop, and is seldom needed. Observation #5: The infants born to women with coincident pregnancy and lymphoma do well. Although gestational age was lower than the 10th percentile in 23% of in-

The clinical team can provide guarded reassurance that treatment deferral if possible, and standard treatment if necessary, will allow successful term delivery of a normal child and likely cure of the lymphoma for most patients. —Joseph M. Connors, MD

mother or child. Thus, only 56 of the 90 patients required intervention, and neither fetal nor maternal outcomes appear to have been negatively impacted by deferral of treatment until after delivery in the 28 patients so managed. Observation #3: When treatment is required, standard regimens are acceptable. Most patients received standard regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (Rituxan) for NHL and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for HL. Appropriately, very few patients received radiation (NHL: 5, HL: 4), which should be avoided because scatter radiation reaches the uterus in significant amounts, especially during the late phases of pregnancy. Observation #4: Term delivery is both desirable and regularly achievable. Median gestation at delivery was 37 weeks with 56% of patients delivering at full term, indicating that most

fants, the median birth weight of 2,668 g was in the normal range (> 2,500 g), and neonatal intensive care was seldom needed (11%); only two (2%) fetal malformations were seen. Observation #6: The mothers do well. Although the small numbers of patients, the diverse mix of histologic types, and wide distribution of prognostic factors limit conclusions, the outcome of treatment is roughly comparable to that seen in nonpregnant women. Progression-free and overall survival rates at 3 years were 55% and 79% for diffuse large B-cell lymphoma and 85% and 97% for HL, respectively.

More importantly, no long-term follow-up of the children is provided. Firm conclusions about their well-being cannot be drawn. While the low fetal malformation rate is reassuring, none of the fetuses was exposed to treatment during the first trimester. Furthermore, no one should be complacent about the potential for late consequences in children who are exposed to highly cytotoxic chemicals during fetal development. Deferral of treatment remains the best choice for asymptomatic patients with less threatening types of lymphoma such as HL and indolent NHL. None of the patients was managed with minimal chemotherapy such as single-agent vinblastine for HL with deferral of multiagent regimens until after delivery, a strategy that has been employed with success by other authorities,2 and this approach should not be dismissed. Finally, all patients were managed by a sophisticated multidisciplinary team, an approach that should be considered mandatory for this challenging clinical situation.

Conclusion Women, their partners, and their families will continue to be frightened and anxious when pregnancy and lymphoma coincide. Armed with the information provided in this excellent study and the literature reviewed by the authors, the clinical team can provide guarded reassurance that treatment deferral if possible, and standard treatment if necessary, will allow successful term delivery of a normal child and likely cure of the lymphoma for most patients. n

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

Cautionary Remarks These results describing the outcome of coincident lymphoma and pregnancy are very encouraging. However, several cautions are necessary. First, even though this series is the largest and best reported to date, it is still small and heterogeneous. Followup of the mothers is reasonably, but not completely, mature (median, 41 months; range, 6–147 months).

References 1. Evens AM, Advani R, Press OW, et al: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol. September 16, 2013 (early release online). 2. Bachanova V, Connors JM: Hodgkin lymphoma in pregnancy. Curr Hematol Malig Rep 8:211-217, 2013.

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 e Median duration of treatment 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”

B:14.25”

S:13”

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 | NOVEMBER 15, 2013

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JCO Spotlight Radiation Oncology

Vertebral Compression Fracture Risk Increased After Spinal Stereotactic Body Radiotherapy By Matthew Stenger

n a study reported in Journal of Clinical Oncology, Arjun Sahgal, MD, of Princess Margaret Cancer Centre in Toronto, and colleagues evaluated the occurrence of vertebral compression fractures in patients undergoing spinal stereotactic body radiotherapy.1 Vertebral compression fractures occurred in 14% of spinal segments treated, and radiation dose/fraction, vertebral compression fractures at baseline, lytic tumors, and spinal deformity were associated with significantly increased risk of this adverse event.

segments treated at The University of Texas MD Anderson Cancer Center,

Study Details

Houston, 85 patients with 132 spinal segments treated at the Cleveland Clinic, and 99 patients with 189 spinal segments treated at University of Toronto. The primary outcome was the

The study included a total of 252 patients with 410 spinal segments treated with stereotactic body radiotherapy, including 68 patients with 89 spinal

development of vertebral compression fractures, defined as a new fracture or

Caution must be observed when treating with ≥ 20 Gy/fraction, in particular, for patients with lytic tumor, spinal misalignment, and a baseline vertebral compression fracture. —Arjun Sahgal, MD, and colleagues

progression of a baseline fracture. In addition to patient, treatment, and tumor factors, the Spinal Instability Neoplastic Scoring (SINS) system was used to determine predictive value

(Table 1).2 Individual SINS criteria consist of location (junctional, mobile, semirigid, and rigid spine), type of pain (mechanical, nonmechanical) vs pain-free, spinal misalignment (kyphosis/scoliosis, translation/subluxation) vs normal alignment, presence of baseline vertebral compression fractures (≥ 50% collapse, < 50% collapse) vs no collapse but > 50% of the vertebral body involved by tumor vs neither, type of lesion (lytic, mixed, sclerotic), and whether tumor involves the posterolateral elements (bilateral, unilateral) or not. The scoring system classifies patients as stable, potentially unstable (indeterminate), and unstable based on the overall score. Each treated vercontinued on page 92

High-Dose Spinal Stereotactic Body Radiotherapy Associated With Increased Risk of Vertebral Compression Fracture By Eric Lis, MD

s reviewed in this issue of The ASCO Post, Sahgal et al reported a multi-institutional analysis aimed at clarifying the risk of developing either new or progressive vertebral body compression fractures following high-dose spinal stereotactic body radiation therapy. In the period studied, they encountered 57 vertebral compression fractures out of 410 vertebrae that were treated with such therapy (14%). They report that vertebrae at risk for collapse included those with a baseline vertebral compression fracture, lytic disease, or malalignment, and that caution should be taken when treating such lesions with doses ≥ 20 Gy/fraction.

Positive Perspective I tend to look at this well-written paper in a positive light in that there were only 57 vertebral compression fractures out of the 410 segments treated, and of those 57 vertebral compression fractures, only 24 required further interventions, of which 18 had minimally invasive procedures. Dr. Lis is Director of Interventional Neuroradiology, Memorial Sloan-Kettering Cancer Center, New York.

Thus, the majority of the vertebral compression fractures encountered required no further intervention. The authors comment that highdose single-fraction stereotactic body radiotherapy (≥ 20 Gy/fraction) may

with high-dose single-fraction stereotactic body radiotherapy is to provide local control regardless of tumor histology. One can argue that dealing with the increased risk of a vertebral compression fracture is perhaps a

The risk of vertebral compression fracture associated with [spinal stereotactic body radiotherapy] is outweighed by the benefit of local tumor control…. [I]t is far easier to palliate a vertebral compression fracture without tumor progression than it is to deal with the complications associated with active tumor recurrence. —Eric Lis, MD

be exposing patients to prohibitive risks of vertebral compression fracture. I believe we are not exposing patients to prohibitive risks of vertebral compression fracture. It can be agreed upon that the ultimate goal in treating spine metastasis

small price to pay in the setting of local tumor control, knowing that most of these vertebral compression fractures might require no further intervention, and those that do can often be dealt with in a minimally invasive manner with cement augmentation

with or without percutaneous instrumentation. To put it another way, it is usually easier to handle a vertebral compression fracture in the setting of nonviable tumor treated with high-dose singlefraction stereotactic body radiotherapy (≥ 20 Gy/fraction) than it is to treat a recurrent metastasis that has been treated with < 20 Gy/fraction.

Conclusion In summary, this paper further identifies risks for vertebral compression fracture associated with spine stereotactic radiosurgery, especially regarding lesions treated with highdose single-fraction stereotactic body radiotherapy (≥ 20 Gy/fraction). I contend that the risk of vertebral compression fracture associated with such treatment is outweighed by the benefit of local tumor control and that it is far easier to palliate a vertebral compression fracture without tumor progression than it is to deal with the complications associated with active tumor recurrence—which frequently include vertebral compression fractures anyway. n

Disclosure: Dr. Lis has given educational lectures for Medtronic.

In the research of advanced cancers

What if inhibiting the PD-1 checkpoint pathway played an important role in restoring immune response to tumor cells? In a normal state, the immune system recognizes tumors and can mount an active antitumor response1,2 Antigen-presenting cell

Step 1:

Tumor releases antigen3

Active T cells

Step 2:

Antigen-presenting cells activate T cells that proliferate and migrate to the tumor. T cells then release apoptosisinducing proteins, which attack the tumor cells3,4

Tumor

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity, by converting active T cells to inactive T cells5-8

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 ligands on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack 6-9

PD-1 receptor

Inactive T cells

Bristol-Myers Squibb is researching ways to block the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands to restore T-cell activation, which may play a role in helping the body fight cancer.8,10 PD-1=programmed death 1; PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 2. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 3. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 4. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735-747. 5. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 6. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7): 3635-3643. 7. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 8. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.pd1pathway.com.

The ASCO Post | NOVEMBER 15, 2013

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JCO Spotlight

Vertebral Compression Fracture Risk continued from page 90

tebral segment was scored according to the SINS criteria. Additional factors analyzed included histologic type, paraspinal/epidural disease extension, whether any targeted therapy or bisphosphonates had been given within 2 months before stereotactic body radiotherapy, prior radiation to the treated segment, total dose prescribed, number of fractions, and whether the treated segment included other adjacent segments in the target volume (single vs multiple).

Fracture Incidence Median follow-up was 11.5 months (range, 0.03–113 months). Median and mean overall survival were 16 and 26 months, respectively. A total of 57 vertebral compression fractures were identified (14% of spinal segments), consisting of 27 new fractures (47% of fractures) and 30 fracture progressions. Median time to vertebral compression fracture was 2.46 months (range, 0.03–43.01 months), with 65% occurring within the first 4 months after stereotactic body radiotherapy. The 1- and 2-year cumulative rates of fracture were 12.35% and 13.49%, respectively. Mean age was 57 years for patients with and without fractures. Of the 57 fractures, 26 each occurred in the thoracic and lumbar spine and 5 occurred in the cervical spine. Paraspinal/epidural disease was present in 38 cases. Patients were receiving targeted systemic therapy and bisphosphonates in 31 and 14 cases, respectively, and had received prior radiation in 7 cases. There

was a single segment target in 43 cases. Radiation dose/fraction was < 8 Gy in 4 cases, 8 to 11 Gy in 13, 12 to 19 Gy in 22, 20 to 23 Gy in 6, and ≥ 24 Gy in 12. Bone lesion types were lytic in 48 cases, mixed in 6, and blastic in 3. In 47 cases, patients had normal spinal alignment, with kyphosis/scoliosis present in 9 and subluxation/translation present in 1. Vertebral body collapse was present in 30 cases, with ≥ 50% vertebral body involvement in 3 and < 50% in 27; no collapse but > 50% of vertebral body involvement with the tumor was present in 13 cases. SINS classification was stable in 13 cases, indeterminate in 42, and unstable in 2.

Table 1: Spinal Instability Neoplastic Scoring (SINS) SINS Component Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) Mobile spine (C3-C6, L2-L4) Semirigid (T3-T10) Rigid (S2-S5)

Postradiotherapy Vertebral Compression Fracture Risk ■■ Vertebral compression fracture occurred in 57 (14%) of 410 vertebral segments treated with stereotactic body radiotherapy.

■■ Nearly two-thirds of fractures occurred within 4 months after the radiotherapy.

■■ On multivariate analysis, radiation dose/fraction, baseline fracture, lytic

tumor, and spinal deformity were associated with significantly increased risk of vertebral compression fractures.

3 2 1 0

Paina Yes Occasional pain but not mechanical Pain-free lesion

3 1 0

Bone lesion 2 1 0

Lytic Mixed (lytic/blastic) Blastic Radiographic spinal alignment

Predictors of Fracture On multivariate analysis, radiation dose/fraction and baseline vertebral compression fracture, presence of a lytic tumor, and spinal deformity (3 of the 6 SINS criteria) were significant predictors of vertebral compression fracture. For baseline vertebral body collapse, compared with no vertebral compression fracture and < 50% vertebral body involvement, hazard ratios were 6.92 (P = .0189) for ≥ 50% vertebral compression fracture, 8.98 (P < .001) for < 50% vertebral compression fracture, and 4.96 (P < .001) for no vertebral compression fracture but > 50% of vertebral body involved. Compared with radiation dose/ fraction ≤ 19 Gy, hazard ratios were 5.25 (P < .001) for ≥ 24 Gy/fraction and 4.91 (P < .001) for 20 to 23 Gy/ fraction. Compared with normal spinal alignment, the hazard ratio was 2.99 (P < .001) for kyphosis/scoliosis or subluxation/translation. Compared with mixed and osteoblastic tumors,

Score

4 2 0

Subluxation/translation present De novo deformity (kyphosis/scoliosis) Normal alignment Vertebral body collapse > 50% collapse < 50% collapse No collapse with > 50% body involved None of the above

3 2 1 0

Posterolateral involvement of spinal elementsb 3 1 0

Bilateral Unilateral None of the above a

Pain improvement with recumbency and/or pain with movement/loading of spine. Facet, pedicle, or costovertebral joint fracture or replacement with tumor.

the hazard ratio was 3.53 (P = .0022) for osteolytic tumors. Paraspinal/epidural disease extension was a significant predictor on univariate but not multivariate analysis. The investigators concluded: Caution must be observed when treating with ≥ 20 Gy/fraction, in particular, for patients with lytic tumor, spinal misalignment, and a baseline vertebral compression fracture. Frequent shortterm follow-up is required, as nearly two-thirds of all vertebral compression fractures occurred within the first 4 months. We also conclude that SINS may have utility in predicting patients at high risk of [stereotactic body

radiotherapy]-induced [vertebral compression fracture]. n Disclosure: For full disclosures of all study authors, please visit jco.ascopubs.org.

References 1. Sahgal A, Atenafu EG, Chao S, et al: Vertebral compression fracture after spine stereotactic body radiotherapy: A multi-institutional analysis with a focus on radiation dose and the Spinal Instability Neoplastic Score. J Clin Oncol 31:3426-3431, 2013. 2. Fourney DR, Frangou EM, Ryken TC, et al: Spinal Instability Neoplastic Score: An analysis of reliability and validity from the Spine Oncology Study Group. J Clin Oncol 29:3072-3077, 2011.

Visit The ASCO Post website at

ASCOPost.com

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Awards

NIH Announces 15 Clinical and Translational Science Awards

ranslating basic discoveries into new treatments that tangibly improve human health requires innovative collaborations and resources, as well as a diverse, highly trained workforce. To help meet these needs, the National Institutes of Health recently announced more than $79 million in fiscal year 2013 funding to support 15 Institutional Clinical and Translational Science Awards.

• Indiana University, Indianapolis • Johns Hopkins University, Baltimore • Ohio State University, Columbus • Scripps Research Institute, La Jolla, California • Stanford University, Stanford, California • Tufts University, Boston

• University of Colorado, Denver • University of North Carolina at Chapel Hill • University of Texas Health Science Center, San Antonio • University of Texas Southwestern Medical Center, Dallas

• University of Utah, Salt Lake City To learn more about how Clinical and Translational Science Awards supported investigators are translating basic discoveries into improved health, visit http://www.ncats.nih. gov/ctsa.html. n

CTSA Program Led by the National Center for Advancing Translational Sciences, the Clinical and Translational Science Awards program catalyzes improvements across the entire spectrum of translational research through efforts to broadly develop, demonstrate and disseminate health interventions. It serves as a connector to engage key partners including other NIH institutes and centers, patient groups, communities, health-care providers, industry, and regulatory organizations. “Science and technology are progressing at an unprecedented pace, and the [Clinical and Translational Science Awards] program — which represents NIH’s largest single investment in clinical research — is helping researchers harness these innovations and deliver improved diagnostics, treatments and cures for disease,” said NIH Director Francis S. Collins, MD, PhD. “The Clinical and Translational Science Awards Consortium is leading national efforts to enhance the efficiency, quality, and safety of translational research, no matter the disease or condition,” said Director of National Center for Advancing Translational Sciences, Christopher P. Austin, MD.

Award Recipients The 2013 awards expand consortium representation to New Hampshire with an award to Dartmouth College, extending the network to 31 states and the District of Columbia. The institutions receiving 5-year awards are: • Albert Einstein College of Medicine, New York • Dartmouth College, Hanover, New Hampshire • Duke University, Durham, North Carolina • Harvard Medical School, Boston

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Future of Oncology Advancing Psychosocial Oncology Care Over the Next Decade A Conversation With Jimmie C. Holland, MD By Jo Cavallo

psychiatrist for more than 40 years, Jimmie C. Holland, MD, Attending Psychiatrist and Wayne E. Chapman Chair at Memorial SloanKettering Cancer Center and Professor of Psychiatry, Weill Medical College of Cornell University in New York, is internationally recognized as the founder of the subspecialty of psycho-oncology. Dr. Holland conducted some of the first studies on the psychological impact of a cancer diagnosis on patients and proved that interventions to combat the anxiety and depression associated with cancer can work. According to Dr. Holland’s research, one-third of patients with cancer experience clinically significant mental distress. To help oncologists evaluate their patients’ distress levels, Dr. Holland and her colleagues at the National Comprehensive Cancer Network developed a “distress thermometer,” a psychosocial distress-screening tool that measures a patient’s distress level on a 0-to-10 scale. If a patient scores 4 or higher on the distress thermometer, it is a signal that the individual should be further evaluated and referred to a mental health-care specialist and monitored closely. Based on the Institute of Medicine (IOM) report, Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs, the Commission on Cancer, which accredits centers that treat patients with cancer, mandated that by 2015 providers must have a plan in place to evaluate patients for distress and refer them to programs for help. The ASCO Post talked with Dr. Holland about integrating psychosocial care into routine cancer care, the progress being made in implementing methods to identify distress levels in patients, and advancements predicted over the next decade in the field of psycho-oncology.

Treating the Whole Patient Please talk about the importance of caring for the whole patient and integrating psychosocial care into routine cancer care. Cancer has had a particularly frightening stigma attached to it because for centuries we didn’t know the

cause of it and we didn’t have a cure. The result was that people didn’t even say the word “cancer” because it was so frightening. Patients often were not even told of their diagnosis, and doctors gave up before they started treatment, because they thought there was nothing more to be done. Those things really had an impact

unless you have integrated the psychosocial aspect into routine medical care. That was enormously helpful, and we took the report findings to the International Psycho-Oncology Society and the International Union Against Cancer, and about 60 countries have now endorsed the IOM’s recommendations.

Our main issue is the implementation of a psychosocial program in every cancer center in the country by 2015.… Once that happens, it will change the patient experience enormously. —Jimmie C. Holland, MD

on people feeling that somehow cancer is different from heart disease or other life-threatening diseases. Cancer became more than just a disease, it was a metaphor for all bad things, so it had a fearsome meaning for a long while. It wasn’t until Elisabeth Kübler Ross, MD, came around in the late 1950s and said that people with cancer want to talk about their disease, even when they have advancing disease, and doctors and nurses should be encouraging that communication, not avoiding the subject. That led to a change in the humanistic side of medicine. But the idea of treating the whole patient, both the physical and psychological ramifications of cancer, didn’t happen until more recently. It has been an uphill battle to get across the idea that you must treat the whole person—that you must have a way to incorporate treatment of both the tumor and the emotional distress patients feel into your everyday care. What was the turning point? Things significantly changed in 2007, when the IOM report was published. The central message of the report was that there are evidence-based interventions—both psychological and pharmacologic—for patients with cancer, and that you cannot say you’re doing quality cancer care today

In 2012, the Commission on Cancer (COC) mandated that in order to receive accreditation, cancer centers across the country must have a program in place by 2015 to identify distressed patients and refer them to the proper source. Are you seeing evidence that cancer centers are starting to comply with the mandate? Many centers still don’t have a distress program in place, but I think they are all concerned about meeting the deadline. We are working very hard with various organizations to provide staff education and help them implement programs.

Looking Ahead What advancements do you see in psycho-oncology over the next 5 to 10 years, and how will those advancements benefit patients? I often say we’ve always had a carrot to get people to pay attention to the psychosocial needs of patients. Now for the first time, we also have a stick—the mandate from the COC. So I think that within 5, and certainly 10 years, every center will have some type of psychosocial program. The programs will vary from place to place, depending on the number of staff and resources they have, but at least some type of psychosocial

program will be available for patients with cancer in every cancer center, whereas often there is nothing along those lines now. Once the ball starts rolling, people will see how important this program is, how grateful patients are, and that it is a big value added. Over the next decade, there probably will be more ways to find out which patients meet the criteria for distress and need some type of therapy. For example, there might be a way patients can use their electronic health record to punch in whether they are feeling distressed, and we will be able to get help to more people in that way. We would love to see a better way to diagnose and treat patients suffering from all forms of distress, including depression, anxiety, and insomnia. Part of the COC mandate is that you must triage patients to a mental health resource for monitoring or treatment. But right now it’s hard to find mental health counselors in many parts of the country, and that’s a big area we need to work on—how to triage patients to a proper resource. We need to come up with a national plan so people can find psychological help that has been vetted and that includes mental health professionals who know about cancer and its impact on patients and can offer counseling. Currently, a wide array of evidence-based interventions are available to help patients cope with their level of distress, and that will grow wider. There are several forms of counseling, mindfulness meditation, yoga, relaxation techniques, music, and dance therapy, which qualify as complementary therapies. There are also medications for more serious types of distress. So the future looks good for providing patients with more helpful options. The other area that needs attention is the shortage of mental health experts trained in the problems of having cancer. We need more opportunities to encourage and train young people in the fields of psychology and social work and then train them in the issues that affect patients with cancer. We also need to be sure that there are psychiatrists consulting with all the cancer centers, so every center has access to somebody who knows how to

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Future of Oncology prescribe psychiatric medication and can diagnose the more formal psychiatric disorders.

Survivorship Issues Will the need for psychosocial care for patients with cancer become even more important as the number of survivors grows? Yes. There are over 13 million cancer survivors in the country, but the psychological issues do not end once treatment is over. There is anxiety about the cancer coming back and

the long-term and late side effects of treatment. All of the survivorship issues are new. When I started out, for example, there were not many Hodgkin lymphoma survivors, and now, almost 100% of those patients are cured, so we have a big survivorship population. We’re learning more about the

psychosocial problems patients have, and it has opened a whole new era for us. That said, our main issue is the implementation of a psychosocial program in every cancer center in the country by 2015. That’s where we are right now. We are trying to see how we can help all these cancer centers

meet the new accreditation deadline. Once that happens, it will change the patient experience enormously, because oncologists will at least be paying attention to psychosocial issues in a way that hasn’t been true up to now. So things are changing. n

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

Contact

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Journal Spotlight Breast Cancer

Circulating Estrogens and Androgens Associated With Breast Cancer Risk in Premenopausal Women By Matthew Stenger

n a study reported in The Lancet Oncology, Timothy Key, DPhil, of Oxford University, and colleagues in the Endogenous Hormones and Breast Cancer Collaborative Group analyzed data from seven prospective studies to determine associations between sex hormones and risk of breast cancer in premenopausal women.1 They found that estradiol, calculated free estradiol, estrone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), and testosterone concentrations were positively associated with risk of breast cancer and that luteal phase progesterone and sex hormone– binding globulin were not.

stratification by study and further adjustment for cycle phase.

Estrogens and Androgens Associated With Risk The analyses included data for up to 767 women with breast cancer and 1,699 controls. Breast cancer risk was significantly associated with a doubling in concentrations of estradiol

This collaborative analysis noted a positive association between sex hormones and breast cancer risk in premenopausal women. Whether or not this association is causal is not known, but plausible biological mechanisms exist that could explain such an effect.

Study Details Individual participant data for prediagnostic sex hormone and sex hormone–binding globulin concentrations were contributed from seven prospective studies, with analyses restricted to women who were premenopausal and younger than 50 years at blood collection and to women with breast cancer diagnosed before age 50 years. Most of the women in the analysis were of white European ethnic origin. Odds ratios for breast cancer associated with hormone concentrations were calculated for cases and controls matched for age, date of blood collection, and day of cycle, with

testosterone (OR = 1.08, 95% CI = 0.97–1.21), luteal phase progesterone (OR = 1.00, 95% CI = 0.92–1.09), or sex hormone–binding globulin (OR = 1.07, 95% CI = 0.94–1.23). Further adjustment for age at menarche, age at first full-term pregnancy, number of full-term pregnancies, and body mass index had little effect on any of these odds ratios, except that the asso-

—Timothy Key, DPhil, and colleagues

(OR = 1.19, 95% confidence interval [CI] = 1.06–1.35), calculated free estradiol (OR = 1.17, 95% CI = 1.03– 1.33), estrone (OR = 1.27, 95% CI = 1.05–1.54), androstenedione (OR = 1.30, 95% CI = 1.10–1.55), DHEAS (OR = 1.17, 95% CI = 1.04–1.32), and testosterone (OR = 1.18, 95% CI = 1.03–1.35), but not calculated free

ciation with doubling of calculated free testosterone with risk became significant (OR = 1.14, 95% CI = 1.01–1.28). There was no evidence suggesting that any of the odds ratios varied by the time between blood collection and diagnosis. For estrogens and androgens, the odds ratios were larger for estrogen receptor–positive tumors than for es-

trogen receptor-negative tumors (eg, 1.25 vs 1.09 for estradiol, 1.26 vs 0.90 for estrone, 1.45 vs 1.11 for androstenedione, and 1.13 vs 1.03 for testosterone), but none of the differences was significant (all P > .19 for heterogeneity). For estradiol according to phase of the menstrual cycle, the odds ratios for a doubling in concentration were 1.25 (95% CI = 1.06–1.48) for follicular samples, 1.20 (0.81–1.79) for midcycle samples, and 1.13 (0.92–1.37) for luteal samples (P = .732 for heterogeneity).

Association of Sex Hormones With Risk Factors in Controls Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. Compared with women with a body mass index of less than 22.5 kg/m2, those with a body mass index of 30 kg/m2 or more had lower mean concentrations of estradiol (by 17%), luteal phase progesterone (by 28%), and sex hormone–binding globulin (by 46%), and body mass index was positively associated with higher mean concentrations of calculated free estradiol (by 10%), estrone (by 16%), DHEAS (by 8%), testosterone (by 7%), and calculated free testosterone (by 63%), with means adjusted for age,

Evidence-Based Opportunity to Personalize Breast Cancer Risk: The Data Are Building By Victor G. Vogel, MD, MHS

he worldwide data from prospective studies of the relationship between levels of endogenous sex hormones and breast cancer risk in postmenopausal women show multiple and complex relationships.1 Nine prospective studies (different from those reported here) of women not taking exogenous sex hormones when their blood was collected to determine hormone levels showed that the risk for breast cancer increased significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non–sex hormone binding globulin (SHBG)-bound estradiol, estrone, estrone sulfate, andro-

stenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The relative risks for women with increasing quintiles of all hormone concentrations, relative to the lowest quintile, ranged from a marginal increase in risk to more than doubling of risk, and high SHBG was associated with a decrease in breast cancer risk. Interestingly, estradiol levels are generally higher in North American women than Asian women, and urinary estrogens are higher in North American teenagers, who face higher lifetime risks for breast cancer.

Dr. Vogel is Director, Breast Medical Oncology/Research, Geisinger Health System, Danville, Pennsylvania.

Earlier Data Earlier studies among women at increased risk for osteoporotic frac-

tures who had traditional risk factors for breast cancer showed that the risk for breast cancer was more than three times greater among women with the highest concentrations of bioavailable estradiol compared with women with the lowest concentrations.2 In addition, investigators in the Women’s Health Initiative, a randomized study of hormone replacement therapy in postmenopausal women, measured total estradiol, bioavailable estradiol, estrone, and estrone sulfate in the study subjects prior to enrollment in the trial. Conjugated equine estrogens plus progestin increased all measured estrogens and SHGB after 1 year of use. The effect of combination hormonal therapy on breast cancer risk

was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. Women with lower pretreatment endogenous estrogen levels were at greater risk of breast cancer during combined hormonal therapy compared with those with higher levels.3

Complex Relationship The relationship of circulating hormone levels to the risk of breast cancer, and to the type of cancer that develops, is complex. In a case-cohort study within the Women’s Health Initiative Observational Study among postmenopausal women aged 50 to 79 years, investigators examined associations between endogenous tescontinued on page 98

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Journal Spotlight

study, and cycle phase. Concentrations of sex hormones were lower in older women than in younger women and sex hormone– binding globulin was higher in older women. Parity was inversely associated with calculated free testosterone, but was not associated with concentrations of the other sex hormones or sex hormone–binding globulin, and none of the hormones or sex hormone–binding globulin was associated with age at menarche or family history of breast cancer. Compared with never-smokers, current smokers of at least 15 cigarettes per day had increased concentrations of androstenedione (by 21%), DHEAS (by 12%), testosterone (by 12%), and calculated free testosterone (by 13%). Compared with women who did not consume alcohol, women with an alcohol intake of at least 20 g/d had increased concentrations of androstenedione (by 13%), DHEAS (by 16%), testosterone (by 23%), and calculated free testosterone (by 23%). Adjustment of the analyses by smoking for alcohol and of the analyses by alcohol for smoking had no marked effect on the results. Women who had used hormonal contraceptives had lower concentrations of estradiol (by 7%), estrone (by 7%), androstenedione (by 5%), and sex hormone–binding globulin (by

Sex Hormones and Breast Cancer Risk ■■ Estradiol, calculated

free estradiol, estrone, androstenedione, dehydroepiandrosterone sulphate, testosterone, and calculated free testosterone concentrations were positively associated with risk of breast cancer in premenopausal women, whereas luteal phase progesterone and sex hormone–binding globulin were not. The magnitude of the associations was modest.

■■ Odds ratios were higher for

estrogen receptor–positive tumors than for estrogen receptor–negative tumors, but none of the differences were significant.

■■ Analyses in control women

showed several associations of sex hormones with breast cancer risk factors.

4%) compared with those who had not. The investigators concluded: “This collaborative analysis noted a positive association between sex hormones and breast cancer risk in premenopausal women. Whether or not this association is causal is not known, but plausible biological mechanisms exist that could explain such an effect….

The magnitude of the reported association was modest, but the true association could be substantially larger because of measurement error in the assessment of long-term premenopausal hormone levels.” n Disclosure: The study was funded by Cancer Research UK. The study authors reported no potential conflicts of interest.

Reference 1. Endogenous Hormones and Breast Cancer Collaborative Group: Sex hormones and risk of breast cancer in premenopausal women: A collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 14:1009-1019, 2013.

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Journal Spotlight

Victor G. Vogel, MD, MHS, on Breast Cancer Risk continued from page 96

tosterone and estradiol levels and the risks of estrogen receptor (ER)-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in both invasive breast cancer cases and in control women. Compared with women in the lowest quartile of testosterone level, those in the other three quartiles had half the risk of ER-negative cancer, independent of other risk factors. Perhaps not surprisingly, estradiol level was not associated with ER-negative breast cancer. Thus, higher serum levels of bioavailable testosterone appear to be associated with lower risks of ER-negative breast cancer in postmenopausal women.4

women at the highest risk. Additional data were reported from the UK Collaborative Trial of Ovarian Cancer Screening, in which 200 postmenopausal women who developed ER-positive breast cancer 0.6 to 5 years after sample donation were identified and matched to 400 controls. Estrogen receptor alpha and estrogen receptor beta serum bioactivity were both significantly higher before diagnosis in cases compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ER alpha serum bioactivity was in the top quintile more than 2 years before diagnosis or

Mammographic Density Circulating hormones have potential physiologic and morphologic effects on breast parenchymal tissue that can be assessed mammographically. In nested case-control studies

A strategy that combines quantitative risk assessment, mammographic density, and measurement of circulating hormone levels is likely to identify those women most likely to benefit from breast cancer risk reduction strategies such as chemoprevention.

Women With Other Risk Factors Hormone levels may not be predictive in women who have other risk factors for breast cancer. Among women at increased risk for breast cancer in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial,5 the relative risk of breast cancer for women in the placebo group was not associated with sex hormone levels.6 In addition, the reduced risk of invasive breast cancer in tamoxifentreated women compared with placebo-treated women was not associated with sex hormone levels. Consistent with these observations, in the Multiple Outcomes of Raloxifene Evaluation (MORE) study of raloxifene (Evista) in older postmenopausal women at risk for osteoporotic fractures, the majority of women had very low levels of estradiol.7 This observation raises the question of a possible “threshold effect” (ie, low risk at very low estradiol levels and high risk at estradiol levels above a “threshold” value). Contrary to the data from the Breast Cancer Prevention Trial, in a prospective, nested case-control study within the Nurses’ Health Study, estrone sulfate was associated with breast cancer risk among women with either low (< 1.66%) or high (≥ 2.52%; 75th percentile) Gail model-predicted risk of breast cancer.8 It is likely that there is a plateau in circulating hormone concentrations in

the risk associated with a doubling of testosterone levels was increased by more than 30%. The associations in Japanese American women, who constituted 54% of the sample, were similar to or nonsignificantly stronger than in the overall group. These data provide evidence, therefore, that the association between sex hormones and breast cancer risk is generalizable to an ethnically diverse population.10

—Victor G. Vogel, MD, MHS

if estrone was in the top quintile less than 2 years before diagnosis. Androstenedione levels were significantly higher compared with controls and showed a strong association, with an almost threefold increased breast cancer risk independent of time to diagnosis.9

Multiethnic Cohort These effects do not appear to be unique to white women. The ongoing Multiethnic Cohort study includes Japanese American, White, Native Hawaiian, African American, and Latina women. Investigators conducted a nested case-control study to examine the association between sex hormones and breast cancer risk. Levels of estradiol (E2), estrone (E1), androstenedione, dehydroepiandrosterone (DHEA), and testosterone were quantified by appropriate methods. E1 sulfate, DHEA sulfate (DHEAS), and SHBG were quantified by direct immunoassays. The sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. The odds ratio associated with a doubling of E2 levels was greater than 2, and

within the Nurses’ Health Study, investigators examined plasma levels of estradiol, free estradiol, testosterone, and free testosterone along with mammographic density assessed by computer-assisted analysis of the mammograms. Levels of circulating sex steroids and mammographic density were both statistically significantly and independently associated with breast cancer risk. Circulating levels of estradiol and testosterone were both associated with at least a doubling of breast cancer risk, before and after adjustment for mammographic density. These data suggest that both circulating sex steroid levels and mammographic density are independently associated with the risk of breast cancer in postmenopausal women.11

Further Considerations The data reported by Key and colleagues in the Endogenous Hormones and Breast Cancer Collaborative Group, reviewed in this issue of The ASCO Post, are unique in that they report a relationship of circulating sex hormones to the risk of breast cancer among premenopausal wom-

en similar to that reported in postmenopausal women, although the magnitude of the effect in premenopausal women is modest when compared to the effect in older women.12 Key et al appear to have accounted for the menstrual cycle variability that occurs in the plasma levels of the hormones, and they have made appropriate statistical adjustments to control for known breast cancer risk factors, lending credence to their results. Polymorphisms in the genes coding for enzymes that metabolize sex steroids may also alter the risk of breast cancer. Several other genetic polymorphisms may influence sex hormone concentrations, including CYP17, CYP19, and CYP1B1. Associations between these polymorphisms and serum concentrations of estrogens, androgens, and SHBG and urinary concentrations of 2- and 16 alpha-hydroxyestrone have been studied,13 but whether the circulating levels of hormones or their metabolism is more important is not known. Additional indirect evidence of the role of endogenous hormones in the etiology of breast cancer comes from the adjuvant therapy trials with aromatase inhibitors.14 These agents interrupt hormonal synthesis, cause a greater than 90% decrease in the levels of circulating estrogens in postmenopausal women, and have shown a greater than 50% reduction in primary contralateral breast cancers as a first event among women treated with anastrozole when compared with women receiving tamoxifen. Similarly, the rate of contralateral breast cancer is half as great among postmenopausal women receiving letrozole compared with women taking tamoxifen in two adjuvant treatment trials.15,16

Practical Applications How might we use these data in clinical settings to reduce the risk of breast cancer? In the MORE trial mentioned above, women with the highest estradiol levels (≥ 12 pmol/L) had a twofold increased risk for invasive breast cancer compared with women with lower levels of estradiol.7 In the placebo group, women with estradiol levels greater than 10 pmol/L had a nearly sevenfold higher rate of breast cancer than women with uncontinued on page 100

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The ASCO Post | NOVEMBER 15, 2013

PAGE 100

Journal Spotlight

Victor G. Vogel, MD, MHS, on Breast Cancer Risk continued from page 98

detectable estradiol levels.17 Women with estradiol levels greater than 10 pmol/L in the raloxifene group had a rate of breast cancer that was 76% lower than that of women with estra-

diol levels greater than 10 pmol/L in the placebo group. Importantly, raloxifene reduced breast cancer risk in both the low- and high-estrogen subgroups for all risk factors examined, but the reduction was greatest in those with the highest estradiol levels. In contrast, women with

undetectable estradiol levels had similar breast cancer risk whether or not they were treated with raloxifene. Older postmenopausal women whose testosterone levels were in the highest two quintiles had a fourfold increased risk of ER-positive breast cancer.18

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References 1. Vogel VG, Taioli E: J Clin Oncol 24:1791-1793, 2006. 2. Cauley JA, Lucas FL, Kuller LH, et al: Ann Intern Med 130:270-277, 1999. 3. Farhat GN, Parimi N, Chlebowski RT, et al: J Natl Cancer Inst 105:14961503, 2013. 4. Farhat GN, Cummings SR, Chlebowski RT, et al: J Natl Cancer Inst 103:562-570, 2011. 5. Fisher B, Costantino JP, Wickerham DL, et al: J Natl Cancer Inst 90:1371-1388, 1998. 6. Beattie MS, Costantino JP, Cummings SR, et al: J Natl Cancer Inst 98:110-115, 2006. 7. Lippman ME, Krueger KA, Eckert S, et al: J Clin Oncol 19:3111-3116, 2001. 8. Eliassen AH, Missmer SA, Tworoger SS, et al: J Clin Oncol 24:1823-1830, 2006. 9. Fourkala E-O, Zaikin A, Burnell M, et al: Endocr Relat Cancer 19:137147, 2012. 10. Woolcott CG, Shvetsov YB, Stanczyk FZ, et al: Endocr Relat Cancer 17:125134, 2010. 11. Tamimi RM, Byrne C, Colditz GA, et al: J Natl Cancer Inst 99:11781187, 2007. 12. Endogenous Hormones and Breast Cancer Collaborative Group: Lancet Oncol 14:1009-1019, 2013. 13. Tworoger SS, Chubak J, Aiello EJ, et al: Cancer Epidemiol Biomarkers Prev 3:94-101, 2004. 14. Baum M, Budzar AU, Cuzick J, et al: Lancet 359:2131-2139, 2002. 15. Goss PE, Ingle JN, Martino S, et al: N Engl J Med 349:1793-1802, 2003. 16. Thurlimann B, Keshaviah A, Coates AS, et al: N Engl J Med 353:2747-2757, 2005. 17. Cummings SR, Duong T, Kenyon E, et al: Serum estradiol level and risk of breast cancer during treatment with raloxifene. JAMA 287:216-220, 2002. 18. Cummings SR, Lee JS, Lui L-Y, et al: Cancer Epidemiol Biomarkers Prev 14:1047-1051, 2005.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 101

Journal Spotlight Breast Cancer

In International Study, Patients Prefer Subcutaneous Over Intravenous Trastuzumab for Breast Cancer By Matthew Stenger

ubcutaneous trastuzumab (not available in the United States) has been shown to have noninferior efficacy and similar pharmacokinetic and safety profiles compared with in-

given at 600 mg/5 mL (including 10,000 U of recombinant human hyaluronidase, or rHuPH20) injected into the thigh over approximately 5 minutes.

A fixed dose of 600 mg trastuzumab administered [subcutaneously] every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients. —Xavier Pivot, MD, and colleagues

travenous trastuzumab (Herceptin) in patients with early-stage HER2positive breast cancer. In the PrefHer trial reported in Lancet Oncology, Xavier Pivot, MD, of CHU Jean Minjoz in Besançon, and colleagues found that such patients preferred subcutaneous trastuzumab over intravenous administration.1

Study Details In this international, open-label, crossover study, 248 patients aged 18 years or older with HER2-positive, histologically confirmed primary invasive breast adenocarcinoma were randomized to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a singleuse injection device every 3 weeks followed by four cycles of standard intravenous trastuzumab every 3 weeks (SC/IV group, n = 124) or the reverse sequence (IV/SC group, n = 124). Intravenous trastuzumab was administered as a loading dose of 8 mg/ kg in patients receiving trastuzumab de novo (approximately 90 minutes) and a 6-mg/kg maintenance dose (approximately 60 minutes) thereafter. Subcutaneous trastuzumab was

Patients had to have no evidence of residual, locally recurrent, or metastatic disease after completion of surgery and neoadjuvant or adjuvant chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and baseline left-ventricular ejection fraction ≥ 55% before the first dose of trastuzumab. Radiotherapy and hormone therapy were permitted. Randomization was stratified by de novo vs non–de novo use of intravenous trastuzumab. The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous administration, as assessed by patient interviews conducted at baseline and after

completion of the crossover period. A total of 117 SC/IV patients and 119 IV/SC patients completed both interviews. At baseline, these SC/IV and IV/SC groups had a median age of 55 and 51 years, 81% of both had ECOG performance status of 0, 51% and 33% had T1 disease and 32% and 48% had T2 disease, 54% and 43% had node-negative disease, and 25% and 24% were de novo trastuzumab users. Furthermore, 100% of both had received chemotherapy, 62% and 60% had received radiotherapy, and 43% and 40% had received hormone therapy.

Clear Preference In total, 216 (91.5%) of 236 patients preferred subcutaneous trastuzumab (P < .0001), 16 (7%), preferred intravenous administration, and 4 (2%) had no preference. In the SC/IV group, 112 (96%) of 117 preferred subcutaneous administration and 5 (4%) preferred intravenous administration. In the IV/SC group, 104 (87%) of 119 preferred subcutaneous administration, 11 (9%) preferred intravenous administration, and 4 (3%) had no preference. Preference for subcutaneous administration was found in 54 (95%)

Subcutaneous vs Intravenous Trastuzumab ■■ In an international study, more than 90% of patients with early-stage HER2-positive breast cancer preferred adjuvant trastuzumab given subcutaneously vs intravenously. (Subcutaneous trastuzumab is not available in the United States.)

■■ Subcutaneous administration was preferred by 96% of those receiving

subcutaneous trastuzumab first and by 86% of those receiving intravenous trastuzumab first in the crossover study.

■■ Subcutaneous administration was associated with a higher frequency of mild or moderate injection site reactions.

New from The ASCO Post

of 57 patients in the de novo trastuzumab group and in 162 (90.5%) of 179 who had previously received intravenous trastuzumab. Overall preference for subcutaneous trastuzumab was “very strong” in 67% of patents, “fairly strong” in 19%, and “not very strong” in 5%. Overall preference for intravenous administration was “very strong” in 3%, “fairly strong” in 1%, and “not very strong” in 2%. Factors that significantly influenced preference were study group (odds ratio [OR] = 3.28, 95% confidence interval [CI] = 1.14–9.48) and venous access type (OR = 4.61, 95% CI = 1.48–14.37). Preference for subcutaneous administration was 95% among patients receiving intravenous trastuzumab by cannula (122/129 patients) and 87% among those with a venous access device (90/113 patients). Hypothetical preference for subcutaneous administration was 46% at the baseline interview and did not affect final preference. Among the 216 patients preferring subcutaneous administration, the main reasons cited were “time saving” (90%) and “less pain/discomfort” (41%). Subcutaneous administration was considered to be less painful than intravenous administration by 67% vs 14% of patients (with 19% reporting no difference), to cause less bother from bruising by 46% vs 14% (with 40% reporting no difference), and to cause less bother from irritation to the injection site by 36% vs 15% (with 50% reporting no difference). Among 103 health-care personcontinued on page 105

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

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

INLYTA

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

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

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

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

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

AXU470817

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

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

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

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

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

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

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

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

a b

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

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

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

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

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

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

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

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

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

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

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

May 2012

ASCOPost.com | NOVEMBER 15, 2013

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Journal Spotlight

Subcutaneous Trastuzumab continued from page 101

nel queried on preference, 74% vs 2% were more satisfied with subcutaneous administration, with 24% expressing no preference.

Adverse Events Clinician-reported adverse events occurred in 141 (58%) of 242 patients during the pooled subcutaneous periods, including grade 1 events in 51%, grade 2 in 22%, and grade 3 in 3%, and in 105 (44%) of 241 during the pooled intravenous periods, including grade 1 events in 32%, grade 2 in 19%, and grade 3 in 2%. The most common grade 3 adverse event was influenza, which occurred in two patients (0.8%). The most common adverse events during subcutaneous administration periods were injection site reactions (19% vs 0% during intravenous periods) and administration-related reactions (9% vs 5%). The most common adverse event during intravenous periods was arthralgia (6% vs 4%). Study drug discontinuation due to adverse events occurred in two patients (0.8%) during subcu-

taneous periods and one patient (0.4%) during intravenous periods. Data collection for Pref Her is ongoing, including data from a cohort using a handheld syringe for subcutaneous administration. A prospective, international, openlabel, nonrandomized study (SafeHer study, NCT01566721) is assessing the safety and tolerability of adjuvant subcutaneous trastuzumab via handheld syringe injection and assisted or self-administered singleuse injection device, with or without chemotherapy, in 2,500 patients with HER2-positive early breast cancer. The study will have a followup period of 5 years to permit longterm safety assessment. The investigators concluded, “Patient preference and safety results from Pref Her, combined with the known non-inferior efficacy and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab administered [subcutaneously] every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients.” n

EXPERT POINT OF VIEW By Edith A. Perez, MD

he Pref Her trial provides notable data showing that > 90% of patients favored the quicker subcutaneous administration of trastuzumab (Herceptin) compared to the standard intravenous infusion. The primary reasons for this preference, as per patients in the trial, included that it was timesaving and was associated with less pain/discomfort. Interestingly, there was an overwhelming preference for the subcutaneous administration among the health-care workers, too. Edith A. Perez, MD These data reflect the value of safe and timeeffective strategies to administer anticancer therapies to our patients. We want our patients to derive significant benefits from therapy, while being allowed to have the least possible disruptions to their lives. This new formulation appears to meet the criteria to be considered an improvement in the therapeutic armamentarium for patients. n Disclosure: Dr. Perez has received research funding from Genentech and GlaxoSmithKline.

Dr. Perez is Deputy Director, Mayo Clinic Cancer Center, Jacksonville, Florida, and Group Vice Chair, Alliance for Clinical Trials in Oncology. Disclosure: The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Pivot X, Gligorov J, Müller V, et al:

Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (Pref Her): An open-label randomised study. Lancet Oncol 14:962-970, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Matthew Lunning, DO, and James O. Armitage, MD, on Deauville Criteria for PET Scans see page 1

Fadlo R. Khuri, MD, on Molecular Targeted Therapy in Lung Cancer see page 34

Laura Williams Goff, MD, MS, on Brivanib in Hepatocellular Carcinoma see page 44

Michael L. LeFevre, MD, MSPH, on Finasteride for Prostate Cancer Prevention see page 58

Visit The ASCO Post online at ASCOPost.com

Leonard B. Saltz, MD, on Mismatch Repair-Deficient Colon Cancer see page 26

Brian J. Druker, MD, on Suspension of Ponatinib Sales see page 48

Tracy T. Batchelor, MD, MPH, on Recurrent Glioblastoma see page 106

The ASCO Post | NOVEMBER 15, 2013

PAGE 106

Journal Spotlight Neuro-oncology

No Progression-Free Survival Difference for Cediranib or Cediranib/Lomustine vs Lomustine in Recurrent Glioblastoma By Matthew Stenger

n a phase III study (REGAL trial) reported in the Journal of Clinical Oncology, Tracy T. Batchelor, MD, MPH, of the Massachusetts General Hospital Cancer Center, and colleagues compared oral monotherapy with the investigational pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor cediranib and the combination of cediranib plus lomustine (CeeNu) vs a control arm of lomustine alone in patients with recurrent glioblastoma.1 There was no significant difference in progression-free or overall survival for either cediranib alone or cediranib/lomustine compared with lomustine alone.

Study Details In the trial, 325 patients aged 18 years or older with recurrent glioblastoma in whom prior radiation therapy and temozolomide had failed were randomly assigned in a 2:2:1 scheme to cediranib at 30 mg/d (n = 131), cediranib at 20 mg/d plus lomustine at 110 mg/m2 once every 6 weeks (n = 129), or lomustine plus placebo (n = 65). Enrollment was contingent on patients not having received prior anti-VEGF therapy. Other eligibility criteria included Karnofsky performance status ≥ 70, Mini-Mental Status Examination score ≥ 15, and life expectancy ≥12 weeks. The cediranib, cediranib/lomustine, and lomustine groups were well matched for age (median, 54 years in all groups) and resection for recurrent disease (38%, 38%, and 37%), but fewer patients in the lomustine group had Karnofsky performance status of 80 or less (ie, Karnofsky performance status = 90–100 in 50%, 51%, and 62.5%) or used corticosteroids at baseline (49%, 55%, and 40%). The primary endpoint was progression-free survival, based on centralized, blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2weighted MRI brain scans.

Progression-Free Survival Outcomes There was no significant difference in progression-free survival for the cediranib group (hazard ratio [HR] = 1.05, P = .90) or the combination

therapy group (HR = 0.76, P = .16) vs the lomustine group. Median progression-free survival was 92 days (1st quartile, 80 days; 3rd quartile, 128 days) in the cediranib group, 125 days (1st quartile, 83 days; 3rd quartile, 201 days) in the combination group, and 82 days (1st quartile, 42 days; 3rd quartile, 168 days) in the lomustine group. There were no significant progression-free survival differences between the cediranib group and the combination group vs the lomustine group on either central review of postcontrast T1-weighted or noncontrast T2/fluid-attenuated inversion recovery MRI scans or local review of postcontrast T1weighted MRI scans. Proportions of patients alive and progression-free at 6 months after randomization were 16% in the cediranib group, 35% in the combination group, and 25% in the lomustine group. A total of 136 patients received postprogression therapy. The majority received bevacizumab (Avastin) alone or in combination, including 51% of combination patients, 51% of lomustine patients, and 27% of cediranib patients.

Secondary Efficacy Measures There were no differences in median overall survival between the cediranib group (8.0 months, HR = 1.43, P = .10) or the combination group (9.4 months, HR = 1.15, P = .50) vs the lomustine group (9.8 months). Predictive power calculations indicated that there was < 0.01% chance of concluding a positive outcome at the final overall survival analysis, and it was thus considered of no value to continue to final analysis. There were no differences in the radiographic response rates between the two cediranib-containing groups. Best overall response rates were 15.3%

in the cediranib group (including one complete response), 17.2% in the combination group (including two compete responses), and 8.9% in the lomustine group. Median changes in contrast-enhanced tumor area were –36% in the cediranib group, –28% in the combination group, and +14% in the lomustine group. Clinical activity of cediranib was suggested by greater reduction in mean corticosteroid use in the cediranib group (–26%) and combination group (–23%) compared with the lomustine group (+5%; P = .01 for each vs lomustine) and by increased

38%, and 22%) and neutropenia (1%, 20%, and 3%). Other grade 3 or 4 adverse events occurring in at least 10% of any treatment group included fatigue (16%, 15%, and 9%), hypertension (14%, 6.5%, and 0%), and leukopenia (0.8%, 11%, and 5%). Serious adverse events occurred in 43%, 37%, and 41% of patients, respectively, and adverse events led to discontinuation of cediranib or placebo in 15%, 18%, and 16% of patients, respectively.

This study did not meet its primary end point of [progression-free survival] prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. —Tracy T. Batchelor, MD, MPH, and colleagues

time to deterioration in neurologic status in the cediranib group (HR = 0.82, P = .57) and the combination group (HR = 0.63, P = .01). There were no differences in time to deterioration of Karnofsky performance status for the cediranib group (HR = 1.03, 95% confidence interval [CI] = 0.65–1.62) or the combination group (HR = 0.73, 95% CI = 0.45–1.17) vs the lomustine group.

Toxicity The most common adverse event was diarrhea (71% in cediranib group, 71% in combination group, and 19% in lomustine group). Adverse events of grade 3 or higher were more common in the combination group (61%, 80%, and 61%), including thrombocytopenia (2%,

Role of Cediranib in Glioblastoma ■■ No difference in progression-free survival was observed for cediranib

(30 mg) or cediranib (20 mg) plus lomustine vs lomustine alone in patients with recurrent glioblastoma.

■■ Clinical activity of cediranib was suggested by reduced use of

corticosteroids and increased time to neurologic deterioration in the cediranib and combination groups.

The investigators concluded, “This study did not meet its primary end point of [progression-free survival] prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.” They noted that since preclinical models suggest synergistic activity of anti-VEGF therapy and radiation therapy, cediranib in combination with chemoradiotherapy is being studied in phase II trials in patients with newly diagnosed glioblastoma (NCT00662506 and NCT01062425). n

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

Reference 1. Batchelor TT, Mulholland P, Neyns B, et al: Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212-3218, 2013.

ASCOPost.com | NOVEMBER 15, 2013

PAGE 107

Lab Notes

Ongoing Molecular Research in the Science of Oncology DISEASE MECHANISMS Tumor-Infiltrating Lymphocytes in Glioblastoma Are Related to Specific Genomic Alterations

sociated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, [tumor-infiltrating lymphocytes] were depleted in the classical class, EGFR-

amplified, and homozygous PTENdeleted tumors and rare in histologies characterized by these alterations.” Rutledge WC, et al: Clin Cancer Res 19:4951-4960, 2013.

Fatty Acid Network Exerts Growth Inhibitory Effects in Pancreatic Cancer In a study reported in Clinical Cancontinued on page 108

The role of tumor-infiltrating lymphocytes in glioblastoma has not been fully defined. In a study reported in Clinical Cancer Research, Rutledge and colleagues assessed the association between tumorinfiltrating lymphocytes and molecular alterations, histologies, and survival in glioblastoma. In the study, histopathologic images from 171 glioblastomas from The Cancer Genome Atlas were used to categorize tumorinfiltrating lymphocytes as absent, present, or abundant, and associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. Histologic findings were validated using CD3G gene expression.

Strong Associations A positive correlation was found between tumor-infiltrating lymphocytes and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1, mutations that are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Tumor-infiltrating lymphocytes were rare in glioblastomas with small cells and oligodendroglioma components and were depleted in the classical transcriptional class and in EGFR-amplified and homozygous PTEN-deleted glioblastomas. These alterations are, in turn, characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association of tumor-infiltrating lymphocytes with survival was observed. The investigators concluded, “[Tumor-infiltrating lymphocytes] were enriched in glioblastomas of the mesenchymal class, strongly as-

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Lab Notes

Ongoing Molecular Research continued from page 107

cer Research, Zhang and colleagues used integrated metabolomics and transcriptomics to investigate genemetabolic networks and identify metabolic pathways that are perturbed in

pancreatic ductal adenocarcinoma. A global metabolite profiling analysis was performed on two independent cohorts of resected pancreatic ductal adenocarcinoma cases to identify critical metabolite alterations that may contribute to the progression of cancer. Gene surrogates significantly cor-

related with the key metabolites were identified by integrating metabolite and gene-expression profiles. A total of 55 metabolites were consistently altered in tumors compared with adjacent nontumor tissues in a test cohort (n = 33) and an independent validation cohort (n = 31). Weighted

network analysis identified a unique set of free fatty acids that were highly coregulated and decreased in pancreatic cancer Pathway analysis of 157 differentially expressed gene surrogates showed a significantly altered lipid metabolism network, including the key lipolytic en-

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PAGE 109

Lab Notes

zymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced levels of free fatty acids. Lower gene expression of PNLIP in tumors was associated with poorer sur-

vival in two independent cohorts. It was further shown that two saturated free fatty acids, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells. The investigators concluded, “Our results suggest that impairment in a li-

polytic pathway involving lipases, and a unique set of [free fatty acids], may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention.” Zhang G, et al: Clin Cancer Res 19:4983-4993, 2013.

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DRUG RESISTANCE Focal Adhesion Kinase Regulates YB-1–Mediated Paclitaxel Resistance in Ovarian Cancer continued on page 110

The ASCO Post | NOVEMBER 15, 2013

PAGE 110

Lab Notes

Ongoing Molecular Research continued from page 109

It has been found that focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to the effects of taxanes. In a study reported in the Journal of the National Can-

cer Institute, Kang and colleagues evaluated the response of taxaneresistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). Reverse-phase protein arrays were used to identify novel downstream targets in taxaneresistant cell lines, and clinical and

pathologic data were correlated with nuclear and cytoplasmic expression of FAK and YB-1, a mediator of taxane resistance present at high levels in taxane-resistant cells, in 105 ovarian cancer samples. It was found that the FAK inhibitor blocked FAK phosphorylation at

the Tyr397 site in a time- and dosedependent manner. The combination of FAK inhibitor and paclitaxel reduced proliferation and increased apoptosis, resulting in 92.7% to 97.9% reductions in tumor weight. Reverse-phase protein array data showed that the FAK inhibitor reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression, and coexpression of nuclear FAK and YB-1 was associated with significantly worse median overall survival (24.9 vs 67.3 months, hazard ratio = 2.64, P = .006). The investigators concluded, “We have identified a novel pathway whereby FAK inhibition with VS6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.” n Kang Y, et al: J Natl Cancer Inst 105:1485-1495, 2013. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger

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2013-2014 Oncology Meetings November

December

Academy of Oncology Nurse

Sixth AACR International

Navigators 4th Annual Navigation

Conference on The Science of

and Survivorship Conference

Cancer Health Disparities in

November 14-17 • Memphis,

Racial/Ethnic Minorities and the

Tennessee

Medically Underserved

For more information:

December 6-9 • Atlanta, Georgia

aonnonline.org/conference

For more information: www.aacr.org

Iowa Oncology Society Fall Membership Conference

55th ASH Annual Meeting

November 15 • West Des Moines,

December 7-10 • New Orleans,

Iowa

Louisiana

For more information:

www.ios-iowa.com

www.hematology.org

Oregon Society of Medical Oncology Fall 2013 Oncology Conference November 15 • West Des Moines, Iowa For more information: www.osmo.org Hawaii Society of Clinical Oncology Fall Membership Conference November 16 • Honolulu, Hawaii

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

For more information:

Current Controversies in the

www.hsco-hawaii.com

Multi-Disciplinary Management of Locally Advanced Non Small Cell Lung Cancer December 12-13 • St. Louis, Missouri For more information: https://cme. wustl.edu/lungcancer/ Third International

1st Indian Cancer Congress 2013 November 21-24 • Delhi, India For more information: www.indiancancercongress2013.org

Gastrointestinal Cancers Conference December 13-15 • Antalya, Turkey For more information: www.igicc2013.org

African Organization for Research & Training in Cancer 9th International Conference: Cancer

January 2014

in Africa: Bridging Science and

AACR-IASLC Joint Conference

Humanity

on the Molecular Origins of

November 21-24 • Durban,

Lung Cancer

South Africa

January 6-9 • San Diego, California

For more information:

www.aortic2013.org

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2013-2014

2014 Gastrointestinal Cancers Symposium January 16-18 • San Francisco, California For more information: www.gicasym.org 10th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 18 • Orlando, Florida For more information: www.flasco.org/events?eventId=7103 10&EventViewMode=EventDetails American Association for Cancer Research-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research January 18-21 • San Diego, California For more information: www.aacr.org 1st World Congress in Controversies in Multiple Myeloma January 23-25 • Bangkok, Thailand For more information: www.comtecmed.com/comy JADPRO Live January 24-26 • St. Petersburg, Florida For more information: www.advancedpractitioner.com/ jadprolive Clinical and Multidisciplinary Hematology and Oncology 2014: The 11th Annual Review January 24-26 • Scottsdale, Arizona For more information: www.mayo. edu/cme/internal-medicine-andsubspecialties-2014s431 Melanoma 2014: 24th Annual Cutaneous Malignancy Update January 25-26 - San Diego, California For more information: med.edu@scrippshealth.org

Clinical Genomics Boston 2014 January 28-30 • Boston, Massachusetts For more information: www.clinicalgenomics-usa.com

2014 Genitourinary Cancers Symposium: Celebrating 10 Years January 30-February 1 • San Francisco, California For more information: www.gucasym.org

February APOS 11th Annual Conference February 13-15 • Tampa, Florida For more information: www.apos-society.org/apos2014/ European Society for Medical Oncology Sarcoma and GIST 2014 February 18-19 • Milan, Italy For more information: www.esmo.org

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/ continued on page 112

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2013-2014 Oncology Meetings continued from page 111

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 SloanKettering Cancer Center March 7-10 • New York, New York For more information: www.mskcc.org/ hemoncreviewcourse 38th Annual Meeting of the American Society of Preventive Oncology March 8-11 - Arlington, Virginia For more information: www.aspo.org

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

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 Illinois Medical Oncology Society 2014 Membership Conference March 21 • Chicago, Illinois For more information: www.imos-illinois.com/

2013-2014

April ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro.org/congressesmeetings/items/estro-33 ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June 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

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

Accelerating Anticancer Agent Development and Validation Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/

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

Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences

JANUARY 24–26, 2014

Renaissance Vinoy St. Petersburg • St. Petersburg, FL

Chair: Pamela Hallquist Viale • Co-Chairs: Sandra E. Kurtin and Wendy H. Vogel

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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 12th Annual Meeting of the Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/

August Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/

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The ASCO Post | NOVEMBER 15, 2013

PAGE 114

JCO Spotlight Supportive Care

Yoga Improves Sleep Quality in Patients With Cancer Suffering From Sleep Disruption By Matthew Stenger

t is estimated that 30% to 90% of patients with cancer experience impairment of sleep quality posttreatment, and such impairment can be severe enough to increase morbidity and mortality. Preliminary evidence indicates that yoga may improve sleep in cancer patients. In a study reported in the Journal of Clinical Oncology, Karen M. Mustian, PhD, MPH, of the University of Rochester Medical Center, and colleagues compared the effects of a standardized yoga intervention vs standard care on global sleep quality in patients with cancer experiencing sleep disruption.1 They found that yoga participants had sig-

nificantly greater improvements in global sleep quality, subjective sleep quality, daytime dysfunction, wake after sleep onset, sleep efficiency, and medication use.

Yoga, specifically the YOCAS program, is a useful treatment for improving sleep quality and reducing sleep medication use among cancer survivors.

Study Details In this study, 410 patients aged 21 years or older with moderate or greater sleep disruption between 2 and 24 months after surgery, chemotherapy, or radiation therapy were randomized to standard care (n = 204) or standard care plus a 4-week yoga intervention (n = 206). To be eligible for the study, patients must have completed treatment for cancer and must not have maintained a regular prac-

—Karen M. Mustian, PhD, MPH, and colleagues

tice of yoga within 3 months before the study or be planning to start yoga on their own during the next 4 weeks. Among other entry criteria, patients could not have a confirmed diagnosis of sleep apnea, could not be receiv-

ing any form of treatment for cancer, with the exception of hormonal or monoclonal antibody therapy, and could not have metastatic cancer. The yoga intervention used the continued on page 117

Yoga to Manage Sleep Disruption in Cancer Survivors: A Low-Risk Intervention With High Potential for Benefit Kathleen M. Wesa, MD, Lara Benusis, E-RYT 500, and Barrie R. Cassileth, MS, PhD

mpaired sleep quality is a concerning problem for many patients with cancer, and pharmacologic treatments come with many negative effects. Several small studies indicate that yoga improves persistent fatigue, sleep disturbance, anxiety, and quality of life, in addition to reducing the need for sleep medication.1-5 A systematic review and meta-analyses found reductions in distress, anxiety, depression, and fatigue, but the effects on sleep were small and not significant.6 The recent study by Mustian and colleagues provides evidence for the use of a standardized multimodal yoga intervention to improve sleep quality.7

Mustian et al Study Design and Results Of 410 patients randomized in this study, 321 completed baseline and postintervention assessments. As a randomized, multicenter nationwide trial, this is considerably larger than most Dr. Wesa is an integrative medicine specialist with the Integrative Medicine Service; Ms. Benusis is a yoga therapist with the Integrative Medicine Service; and Dr. Cassileth is Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York.

phase II yoga studies, which typically enroll 20 to 40 patients. The Mustian et al intervention—the Yoga for Cancer Survivors (YOCAS) program—included a sequence of gentle hatha yoga postures (asanas), passively held restorative yoga poses, specific breathing practices (pranayama), and meditation, compared with standard care. Intervention participants attended 75-minute sessions twice weekly for 4 weeks. Control participants received mainstream care to address sleep issues, and were offered the 4-week YOCAS program free of charge after study completion. Sleep quality for both groups was assessed using the Pittsburgh Sleep Quality Index and actigraphy (a validated, objective measure of sleep quality) preand postintervention. Compared with control participants, those randomized to the YOCAS arm reported significantly greater improvement in the primary outcome of global sleep quality (P < .01), as well as secondary outcomes including daytime dysfunction (P < .01), subjective sleep quality, and use of sleep medication (P < .05 for both). Objective measures from actigraphy showed significantly greater improvements in wake after sleep onset and sleep efficiency (P < .01 for both).

For the 319 patients who completed the study, yoga participants reduced sleep medication use by 21% per week, while control participants increased usage by 5% per week. Investigators also found that patients across the symptom severity spectrum benefited, and that participants with very poor sleep efficiency benefited the most. These results were achieved even though the average “total dose” of yoga for the entire 4-week intervention was 80% of that prescribed.

Yoga Theory and Clinical Considerations Asana, pranayama, and meditation are core components of classical hatha yoga, which is part of the Indian Systems of Philosophy and closely related to Ayurveda, the traditional medical system of India. Restorative poses that use props such as blocks, bolsters, and blankets to facilitate total relaxation into a pose have evolved since the 1970s, most notably by the Iyengar style of yoga (a form of hatha yoga with an emphasis on detail, precision, and alignment in posture and breath control). The study authors note that the restorative component was selected on the basis of yoga theory that postulates its positive influence on sleep. Indeed, restorative postures allow for the experience of complete support

and deep relaxation. It also has been noted that such restorative postures, breathing techniques, and meditation encourage what is traditionally known as “pratyahara,” a turning inward of the senses that can modulate nervous system activity and subsequently improve sleep.8 That the intervention was conducted in the late afternoon or evening after 4:00 PM also fosters the practice of good sleep hygiene, which encourages control over behavioral and environmental factors prior to sleep. The objective use of actigraphy as a clinical endpoint as well as a standardized yoga intervention allow for more widespread generalization of trial results. While the authors identified posture, breath, and awareness as the unifying components in both hatha and restorative yoga, both the tempo of transitions and holding time also should be considered in future research. That said, one might weigh author comments that additional phase III trials are needed against the limited financial resources available for research and the high cost of performing large-scale trials. The significant proportion of patients lost to followup or not fully evaluable (22%) is in line with the attrition rate of other clinical trials of yoga. continued on page 116

The ASCO Post | NOVEMBER 15, 2013

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JCO Spotlight

Managing Sleep Disruption continued from page 114

Lifestyle Interventions Gaining Traction It may be unnecessary to wait for additional data to recommend yoga and other lifestyle interventions such as breathing practices, meditation, stress reduction, and physical exercise. These practices are well databased as effective treatments for disease-related symptoms including pain, dyspnea, digestion problems, skeletal issues, mobility and postural problems, depression, fatigue, anxiety, and sleep disturbance.9-15 Physical activity is well-documented as associated with survival benefits.16-19 Cancer patient engagement in symptom management and the recovery process is stronger than ever. Yoga, meditation, and exercise classes for cancer survivors are more routinely available throughout the country. Many of these modalities are self-selected by patients. But many patients require guidance on practices of self-care, especially with respect to nonpharmacologic interventions that help manage symptoms. Comprehensive lifestyle interventions that extend beyond a single application can provide significant clinical benefits,20-23 especially in impaired sleep quality and other problems that have many contributing factors. The hallmarks of these techniques are that they are easily taught, inexpensive, safe, and beneficial.

Compound Benefits As with other nonpharmacologic interventions, the YOCAS program engages participants in a lifestyle intervention. The risk of physical injury from participation in gentle supervised yoga sessions with experienced instructors is low, while the potential for clinical benefit is high. Adding an intervention such as YOCAS also may prove to be cost-effective in the long run, as some studies suggest that is the case for comparable modalities.24,25 It likely confers other benefits, as preliminary studies in other groups show that yoga reduces pain, improves cognition and cardiovascular function, and improves quality of life.26-28 Longterm practice may reduce inflammatory response to stress.29 Most yoga research in the oncology setting, including this study, tends to enroll women with breast cancer. Although data on other cancer patient subgroups may not yet be available, it

is likely that they too can benefit. As is true of most fitness programs, yoga is readily adaptable to a broad range of clinical levels and goals.

6. Buffart LM, van Uffelen JG, Riphagen II, et al: Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized

The use of nonpharmacologic interventions for symptom control can considerably empower cancer survivors in their pursuit to self-manage symptoms, improve self-care, and speed recovery. —Kathleen M. Wesa, MD, Lara Benusis, E-RYT 500, and Barrie R. Cassileth, MS, PhD

Conclusion In a busy practice, it can be tempting to prescribe medications for sleep disturbance, but these are not without side effects. The use of nonpharmacologic interventions for symptom control can considerably empower cancer survivors in their pursuit to self-manage symptoms, improve selfcare, and speed recovery. n

Disclosure: Drs. Wesa and Cassileth, and Ms. Benusis reported no potential conflicts of interest.

References 1. Bower JE, Garet D, Sternlieb B, et al: Yoga for persistent fatigue in breast cancer survivors: A randomized controlled trial. Cancer 118:3766-3775, 2011. 2. Dhruva A, Miaskowski C, Abrams D, et al: Yoga breathing for cancer chemotherapyassociated symptoms and quality of life: Results of a pilot randomized controlled trial. J Altern Complement Med 18:473-479, 2012. 3. Peppone LJ, Janelsins MC, Peoples AR, et al: Effect of YOCAS yoga on insomnia and sleep medication usage among breast cancer patients receiving hormone therapy: A URCC CCOP randomized, controlled clinical trial. J Clin Oncol 31(suppl):Abstract 9531, 2013. 4. Cohen L, Warneke C, Fouladi RT, et al: Psychological adjustment and sleep quality in a randomized trial of the effects of a Tibetan yoga intervention in patients with lymphoma. Cancer 100:2253-2260, 2004. 5. Danhauer S, Suzanne CD, Shannon LM, et al: Restorative yoga for women with breast cancer: Findings from a randomized pilot study. Psycho-oncology 18:360-368, 2009.

controlled trials. BMC Cancer 12:559, 2012. 7. Mustian KM, Sprod LK, Janelsins M, et al: Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol 31:3233-3241, 2013. 8. Woodyard C: Exploring the therapeutic effects of yoga and its ability to increase quality of life. Int J Yoga 4:49-54, 2011. 9. Oh B, Butow P, Mullan B, et al: Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial. Ann Oncol 21:608-614, 2010. 10. Sheinfeld Gorin S, Krebs P, Badr H, et al: Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. J Clin Oncol 30:539-547, 2012. 11. Birnie K, Garland SN, Carlson LE: Psychological benefits for cancer patients and their partners participating in mindfulness-based stress reduction (MBSR). Psychooncology 19:1004-1009, 2010. 12. Peppone LJ, Mustian KM, Janelsins MC, et al: Effects of a structured weight-bearing exercise program on bone metabolism among breast cancer survivors: A feasibility trial. Clin Breast Cancer 10:224-229, 2010. 13. Mishra SI, Scherer RW, Snyder C, et al: Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev 8:CD008465, 2012. 14. Selman LE, Williams J, Simms V: A mixed-methods evaluation of complementary therapy services in palliative care: Yoga and dance therapy. Eur J Cancer Care 21:8797, 2012. 15. Deng G, Cassileth BR: Integrative oncology: Complementary therapies for

pain, anxiety, and mood disturbance. CA Cancer J Clin 55:109-116, 2005. 16. Irwin ML, Smith AW, McTiernan A, et al: Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 26:3958-3964, 2008. 17. Holick CN, Newcomb PA, Trentham-Dietz A, et al: Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 17:379386, 2008. 18. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:24792486, 2005. 19. Chen Z, Meng Z, Milbury K, et al: Qigong improves quality of life in women undergoing radiotherapy for breast cancer: Results of a randomized controlled trial. Cancer 119:1690-1698, 2013. 20. Fearon KC: Cancer cachexia: Developing multimodal therapy for a multidimensional problem. Eur J Cancer 44:1124-1132, 2008. 21. Oldervoll LM, Loge JH, Lydersen S, et al: Physical exercise for cancer patients with advanced disease: A randomized controlled trial. Oncologist 16:1649-1657, 2011. 22. Gulde I, Oldervoll LM, Martin C: Palliative cancer patients’ experience of physical activity. J Palliat Care 27:296-302, 2011. 23. Jarden M, Baadsgaard MT, Hovgaard DJ, et al: A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT. Bone Marrow Transplant 43:725-737, 2009. 24. Hameed KA: Optimizing pain care delivery in outpatient facilities: Experience in NCI, Cairo, Egypt. J Pediatr Hematol Oncol 33(suppl 1):S19-S22, 2011. 25. Montgomery GH, Bovbjerg DH, Schnur JB, et al: A randomized clinical trial of a brief hypnosis intervention to control side effects in breast surgery patients. J Natl Cancer Inst 99:1304-1312, 2007. 26. Oken BS, Zajdel D, Kishiyama S, et al: Randomized, controlled, six-month trial of yoga in healthy seniors: Effects on cognition and quality of life. Altern Ther Health Med 12:40-47, 2006. 27. Kolasinski SL, Garfinkel M, Tsai AG, et al: Iyengar yoga for treating symptoms of osteoarthritis of the knees: A pilot study. J Altern Complement Med 11:689-693, 2005. 28. Bharshankar JR, Bharshankar RN, Deshpande VN, et al: Effect of yoga on cardiovascular system in subjects above 40 years. Indian J Physiol Pharmacol 47:202-206, 2003. 29. Kiecolt-Glaser JK, Christian L, Preston H, et al: Stress, inflammation, and yoga practice. Psychosom Med 72:113-121, 2010.

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Yoga Improves Sleep Quality continued from page 114

Yoga for Cancer Survivors (YOCAS) program consisting of pranayama (breathing exercises), 16 gentle hatha and restorative yoga asanas (postures), and meditation. Participants attended two 75-minute sessions per week. Standard care consisted of standard follow-up care provided by treating oncologists as appropriate for patients’ individual diagnoses. The primary outcome measure was global sleep quality score on the Pittsburgh Sleep Quality Index (PSQI), and the subscale scores of global sleep quality characteristics were secondary endpoints. Objective sleep characteristics were assessed by actigraphy, a noninvasive method of monitoring human rest/activity cycles. There were no significant differences between yoga and standard care groups in age (mean, 54 years in both), sex (96% women in both), race/ethnicity (96% and 91% white), marital status (married or long-term committed relationship in 71% and 72%), education level (47% of both completed college), employment status (83% and 78% employed), cancer type (breast in 74% and 77%), cancer stage (I or II in 68% and 72%, III in 16% of both, IV in 4% and 2%), previous cancer treatments (surgery in 90% and 91%, chemotherapy in 72% and 70%, radiation therapy in 67% and 65%), current hormone therapy (49% and 54%), time since first cancer treatment (mean, 14.9 and 17.7 months), Karnofsky performance status (mean, 86.9 and 87.8), or exercise status (53% and 51% exercising for less than or more than 6 months). Yoga patients attended an aver-

age of 6.5 of the 8 prescribed sessions. Patients in the yoga group were told that they could practice the yoga they learned in class on their own; daily diaries showed that they had three sessions combining class-based and home-based yoga each week for an average of 182 minutes with a perceived exertion rating of 3.4 (moderate). In the control group, seven patients reported an average of 20 minutes of yoga one time each week with a perceived exertion rating of 1.0 (very weak) during the study period.

Improved Sleep Quality Both groups met the clinical cutoff criterion for impaired sleep quality at baseline with PSQI scores > 8. Compared with the control group, the yoga group had a significantly greater improvement in global sleep quality (P < .01). The PSQI global sleep quality score improved from a mean of 9.20 at baseline to 7.23 (–1.96 difference) in the yoga group compared with improvement from 8.96 to 7.89 (–1.07) in the control group. Yoga patients exhibited large improvements in sleep quality compared with baseline (effect size [d] = 0.62), suggesting that the improvement was clinically significant, whereas improvement from baseline in the control group was less robust (d = 0.37). Compared with the control group, the yoga group also had significantly greater improvements in the secondary outcome measures of daytime dysfunction (P < .01), subjective sleep quality (P < .05), and sleep medication use (P < .05). Yoga patients reduced sleep medication use by 21% per week, and control patients increased sleep medication use by 5% per week. Overall, 90% of the yoga group found yoga use-

Yoga for Sleep Impairment in Cancer Survivors ■■ Yoga patients had significantly greater improvements in global sleep

quality, subjective sleep quality, daytime dysfunction, wake after sleep onset, sleep efficiency, and sleep medication use compared with control patients.

■■ Actigraphy showed that the yoga group had significantly greater

improvements in wake after sleep onset and sleep efficiency compared with the control group.

ful for improving their sleep quality, with 100% stating that they would recommend yoga to other cancer survivors with sleep problems and 63% stating they would highly recommend it. Compared with baseline, the yoga group had significant improvements in sleep quality, including global sleep quality (P < .01), sleep latency (P < .01), sleep duration (P < .05), sleep efficiency (P < .01), sleep disturbances (P < .05), subjective sleep quality (P < .01), and daytime dysfunction (P < .01), but not sleep medication use. Compared with baseline, the control group had significant improvements in global sleep quality (P < .01), sleep efficiency (P < .05), sleep disturbance (P ≤ .01), and subjective sleep quality (P < .01), but not in sleep latency, sleep duration, daytime dysfunction, or sleep medication use.

Actigraphy Actigraphy studies showed that the yoga group had significantly greater improvements in wake after sleep onset (P < .01) and sleep efficiency (P < .01) compared with the control group. Patients in the yoga group who had 60 minutes or more of wakefulness after sleep onset or a sleep efficiency of ≤ 60% at baseline showed the greatest reductions in

wake after sleep onset and the greatest improvements in sleep efficiency. One patient had supraventricular tachycardia during the study period, which was considered grade 2 and unrelated to the study intervention. No other serious adverse events were reported. The investigators concluded, “Yoga, specifically the YOCAS program, is a useful treatment for improving sleep quality and reducing sleep medication use among cancer survivors.” They noted that further phase III studies are needed to replicate their findings, assess the effects of increased length and intensity of yoga, provide longterm follow-up of the sustainability of benefits, and to compare yoga with such established treatments as cognitive behavioral therapy and drug treatments. They also stated that additional research should examine the potential impact of yoga on cancer recurrence and survival rates. n Disclosure: The study was supported by the National Cancer Institute and the Office of Cancer Complementary and Alternative Medicine. The study authors reported no potential conflicts of interest.

Reference 1. Mustian KM, Sprod LK, Janelsins M, et al: Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol. August 12, 2013 (early release online).

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To prevent SREs in patients with BREAST CANCER and bone metastases

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Better prevent SREs1 MEDIAN TIME TO FIRST SRE IN BREAST CANCER1*

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XGEVA® 120 mg Q4W (n = 1,026)

XGEVA® acts precisely to bind RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival1

zoledronic acid 4 mg Q4W (n = 1,020)

HR = 0.82; P = 0.010, superiority

• XGEVA® reduced the risk of first SRE by 16% vs zoledronic acid in patients with other solid tumors or multiple myeloma (P < 0.001, noninferiority; P = 0.060, NS for superiority)1* XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma Convenient 120 mg subcutaneous injection administered once every 4 weeks1 Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia1 Approximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2† *Data from the international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046) and in patients with bone metastases from other solid tumors (excluding breast and prostate cancer) or multiple myeloma (N = 1,776). The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1 † Estimated amount of Medicare beneficiaries with supplemental coverage and commercially insured patients with no OOP cost; based on XGEVA® payor mix and coverage of XGEVA® and other similar products. Does not include costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®.

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypersensitivity • XGEVA is contraindicated in patients with clinically significant hypersensitivity to any component of the product. ®

Hypocalcemia

• XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ)

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • In clinical trials in patients with osseous metastasis, 2.2% of patients receiving XGEVA® developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance. In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. A number of reports note that patients were also receiving treatment with glucocorticoids at the time of fracture. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Interruption of XGEVA® therapy should be considered, pending a risk/ benefit assessment, on an individual basis.

Embryo-Fetal Toxicity

• XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects. • Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions

• The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen. 2. Data on file, Amgen.

T:9.5” S:9”

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Preparation and Administration. Visually inspect Xgeva for particulate matter and Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that Severity (Trials 1, 2, and 3) may contain trace amounts of translucent to white proteinaceous particles. Do not use xgeva Zoledronic Acid if the solution is discolored or cloudy or if the solution contains many particles or foreign n = 2841 n = 2836 particulate matter. Prior to administration, Xgeva may be removed from the refrigerator Body System % % and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How GASTROINTESTINAL Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the Nausea 31 32 entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. Diarrhea 20 19 CONTRAINDICATIONS: GE NERAL Hypersensitivity. Xgeva is contraindicated in patients with clinically significant Fatigue/ Asthenia 45 46 hypersensitivity to any component of the product (see Adverse Reactions). WARNINGS AND PRECAUTIONS: Hypocalcemia. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

INVESTIGATIONS Hypocalcemiab Hypophosphatemiab

18 32

9 20

NEUROLOGICAL Headache

RESPIRATORy Dyspnea Cough

21 15

18 15

Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an extended Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral treatment phase of approximately 4 months in each trial are included, the fracture has been reported with Xgeva (see Adverse Reactions). These fractures can incidence of confirmed ONJ was 2.2% in patients who received Xgeva. The Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were occur anywhere in the femoral shaft from just below the lesser trochanter to above median time to ONJ was 14 months (range: 4 – 25). the supracondylar flare and are transverse or short oblique in orientation without Postmarketing Experience. Because postmarketing reactions are reported observed between these patients and younger patients. oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRyO-FETAL TOxICITy: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time (see Use in Specific Populations).

voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.

Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There ADVERSE REACTIONS: The following adverse reactions are discussed below and was no evidence that various anticancer treatments affected denosumab systemic elsewhere in the labeling: exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 • Hypocalcemia (see Warnings and Precautions) months were not altered by concomitant chemotherapy and/or hormone therapy. The • Osteonecrosis of the Jaw (see Warnings and Precautions) median reduction in uNTx/Cr from baseline to month 3 was similar between patients The most common adverse reactions in patients receiving Xgeva (per-patient receiving concomitant chemotherapy and/or hormone therapy (see Clinical incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, Pharmacology [12.2] in full Prescribing Information). and nausea (see Table 1). The most common serious adverse reaction in patients USE IN SPECIFIC POPULATIONS: receiving Xgeva was dyspnea. The most common adverse reactions resulting in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva discontinuation of Xgeva were osteonecrosis and hypocalcemia. can cause fetal harm when administered to a pregnant woman based on findings in Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations)

Advise patients of the need for: • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased Advise patients that denosumab is also marketed as Prolia®. Patients should fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, inform their healthcare provider if they are taking Prolia. abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not Amgen Manufacturing Limited, a subsidiary of Amgen Inc. to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the One Amgen Center Drive patient becomes pregnant while taking this drug, the patient should be apprised of the Thousand Oaks, California 91320-1799 potential hazard to the fetus. Women who become pregnant during Xgeva treatment ©2010-2013 Amgen Inc. All rights reserved. are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their Printed in USA.

T:13”

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Pregnancy).

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Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in (0.71 – 0.9 mmol/L) for phosphorus] patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, Severe Mineral/Electrolyte Abnormalities tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less Persistent pain or slow healing of the mouth or jaw after dental surgery may also be than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% 1.3% of patients treated with zoledronic acid. Of patients who experienced of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of severe hypocalcemia, 33% experienced 2 or more episodes of severe these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a hypocalcemia and 16% experienced 3 or more episodes (see Warnings and dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with Precautions and Use in Specific Populations). prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less doses. Perform an oral examination and appropriate preventive dentistry prior to the than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding 7.4% of patients treated with zoledronic acid. a

physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

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ASCO State Affiliates Focus on the Texas Society of Clinical Oncology By Jo Cavallo

The ASCO Post spoke with TxSCO President Gladys Rodriguez, MD, about the Society’s past accomplishments and its future goals.

Part of a Larger Community

Gladys Rodriguez, MD

he second largest state in the nation (after Alaska), Texas covers a total area of 268,581 square miles and has a diverse population of over 26 million people. In 1987, the Texas Society of Medical Oncology, now the Texas Society of Clinical Oncology (TxSCO), was formed to address the oncology needs of Texas residents. With over 500 members, which include more than 450 hematology and medical oncologists from every discipline as well as nurses, social workers, and pharmacists, TxSCO is among the largest and oldest of ASCO’s State Affiliates, officially becoming a State Affiliate in 1994. The Society is also the largest organization in the state representing oncologists.

Why was it important for TxSCO to become an ASCO State Affiliate? Initially, the Society was formed to represent medical and radiation oncologists, but about 4 years ago the bylaws were changed to include other oncology professionals who help in the care of patients with cancer, such as nurses, pharmacists, and social workers. Texas is a very large state with a diverse population living in both rural and urban cities. We have a large Hispanic population and a huge underserved and underinsured population, so ensuring quality care for every patient can be challenging. Being an ASCO State Affiliate allows us to collaborate with physicians both in community practices and academic cancer centers to improve oncology care for patients. It also gives us the opportunity to have a national platform and to work with other State Affiliates that might have similar problems so we can learn from other groups, share resources, and be part of a larger community.

ASCO Daily News Seeks New Editor The American Society of Clinical Oncology is seeking candidates for Editor of the ASCO Daily News. The 5-year term will begin as of June 2014. The ASCO Daily News is the official daily news source of the ASCO Annual Meeting. Content in electronic and print formats includes live coverage of scientific highlights, editorials by leaders in the field, information about ASCO products and resources, and video interviews with key thought leaders regarding timely and essential topics. The Editor will be responsible for providing leadership and strategic vision for the ASCO Daily News, as well as editorial oversight for the content of both the print and electronic formats. Candidates must be ASCO members. Interested candidates or those wishing to nominate a candidate should submit a letter of interest, along with a curriculum vitae, to the ASCO Daily News Managing Editor Joy Curzio (Joy.Curzio@asco.org) by November 30, 2013. Selected candidates will receive further information regarding the application process from the ASCO Daily News Editor Search Committee.

Addressing Challenges What are some of the challenges you face that are unique to Texas? Because our state is so large, patients living in rural areas may have to travel 300 or 400 miles to find oncology care, and the care may be uneven because some areas lack the resources oncology practices in larger cities have. Our mission is to provide advocacy for cancer patients and to promote standards of excellence for high-quality cancer care. The theme of our annual meeting in September was Changes in Oncology: How to Improve Care. We had sessions on ASCO’s Quality Oncology Practice Initiative (QOPI®), implementation of the Centers for Medicare & Medicaid Services ICD10 codes, genomics and cancer care,

and how to ensure patient access to treatment. We provide information on our website to help patients and private oncology practices find the latest information on changes to health-care laws and to Medicare and Medicaid. We also post clinical trial details and patient assistance and reimbursement resources.

Public Policy Activities How active is TxSCO in crafting or advocating public policy? We are very active. We have a legislative committee, which studies issues relevant to our patients and physicians, and we partner with other societies and groups like the Texas Medical Association to ensure that all medical decisions remain between the physician and patient. We also use a lobbying group called HillCo Partners to help us with changes to laws proposed by the Texas legislature, including Medicaid issues, and in providing information to patients about the Patient Protection and Affordable Care Act and how to access the health insurance exchanges. Texas has opted out of creating a state-based health insurance marketplace, so we are evaluating how we can help patients access the federally created marketplace. What legislative successes have you had? One of the first pieces of legislation we championed was the Oral Chemotherapy Drug Parity bill Texas passed into law in 2011. We also were instrumental in helping low-income, uninsured women diagnosed with breast or cervical cancer get medical assistance through the Medicaid for Breast and Cervical Cancer program. In 2007, any woman diagnosed with continued on page 122

The ASCO Post | NOVEMBER 15, 2013

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ASCO State Affiliates Texas Society of Clinical Oncology

they’ve been diagnosed with breast or cervical cancer.

continued from page 121

breast or cervical cancer who met eligibility requirements began receiving services. This was an important breakthrough because it allows patients to get care, including chemotherapy, radiation, or surgery, for 5 years after

Is TxSCO currently involved in other public policy issues? Yes. In 2009, the Cancer Prevention and Research Institute of Texas (CPRIT) was created to issue $3 billion in bonds to fund groundbreaking

cancer research programs throughout the state. Several of TxSCO’s board members worked with CPRIT to establish a statewide clinical trials network so promising cancer treatments could be matched with the genetic makeup of a patient’s tumor and the patient could be immediately enrolled in the trial.

Fast Facts ■■ The Texas Society of Clinical

Oncology (TxSCO) was founded in 1987 and incorporated in 1988.

■■ TxSCO became an ASCO State Affiliate in 1994.

■■ The current TxSCO President is Gladys Rodrigues, MD.

■■ TxSCO’s mission is to provide

Missed an ASCO meeting? Want to revisit some of your favorite presentations? Then the Virtual Meeting is for you.

ASCO Virtual Meeting (includes mobile access)

advocacy for patients with cancer and to promote standards of excellence for high-quality cancer care.

■■ The Society has 500 members, including 450 hematologists and medical oncologists, as well as nurses, social workers, and pharmacists. TxSCO is also the largest organization in the state representing oncologists.

■■ The Society holds one annual

meeting in the fall and smaller regional meetings every 2 to 3 months, featuring topics such as the Best of ASH and ASCO Highlights.

About Virtual Meeting

Available Virtual Meetings

• Gain access to meeting sessions that are fully searchable by speaker, session name, presentation title, and abstract number

• ASCO Annual Meeting

• Includes videos, presentation slides, abstracts, podcasts and access to ASCO’s comprehensive iMeeting App • Stay connected via computers, tablets, and mobile devices

• Gastrointestinal Cancers Symposium

Importance of State Societies

• Genitourinary Cancers Symposium

Why is it necessary for ASCO members to belong to a State Affiliate? I know that probably not every ASCO member belongs to a State Affiliate, and I’d like members to know that there are state societies available to them. It’s important to join a state society because it makes you aware of the problems colleagues and patients in your local community are dealing with. It also provides a forum to find common solutions that could help not only the individual practitioner, but also colleagues across the state. You can then use ASCO’s resources to help solve some of those problems. n

• Best of ASCO • Breast Cancer Symposium • ASCO’s Quality Care Symposium • Markers in Cancer

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We were very proactive with major cancer centers, including MD Anderson Cancer Center and Baylor Charles A. Sammons Cancer Center, to liaison with the medical and patient communities to ensure that patients had access to those clinical trials. Unfortunately, the program is on hold due to some accountability issues involving how CPRIT picked projects. But reforms have since been put in place so, hopefully, CPRIT will soon begin taking new grant applications and the clinical trials program will resume.

ASCOPost.com | NOVEMBER 15, 2013

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Awards Tobacco Cessation

IOM Presents 2013 Lienhard Award to Leader of Smoking Cessation and Tobacco Prevention Efforts

he Institute of Medicine has (IOM) presented the 2013 Gustav O. Lienhard Award to Steven A. Schroeder, MD, whose pioneering efforts to control tobacco use have helped save millions from premature, smoking-related deaths. The award

Steven A. Schroeder, MD

also recognizes Dr. Schroeder’s leadership in general medicine as well as his work to improve end-of-life care. “It is my great privilege to present this award to a dedicated champion of health for Americans and citizens around the world,” said IOM President Harvey V. Fineberg. “Dr. Schroeder’s perseverance in funding tobacco research and creating breakthrough strategies to help smokers quit facilitated a shift in public attitudes toward smoking and shaped policies to prevent smoking.”

Initiated Smoking Cessation Efforts As president of the Robert Wood Johnson Foundation from 1990 to 2002, Dr. Schroeder established and led programs to reduce smoking, enhance end-of-life care, expand health

insurance for children, and encourage physical activity. His most influential initiative focused on leveraging research, policy, advocacy, and education to reduce tobacco use and drive systemwide changes that created higher tobacco taxes, smoke-free indoor air laws, and better access to addiction treatment. Robert Wood Johnson Foundation tobacco research was cited in the formulation of and advocacy for such policy adoption. The impact of anti-smoking campaigns by the Robert Wood Johnson Foundation and its partners was profound. Smoking rates among adults declined from 25.5% in 1993 to 18% in 2011, meaning that 5.3 million fewer people were smoking and more than 60,000 smoking-related deaths had been avoided by 2010. At Robert Wood Johnson Foun-

a series of national programs to improve such care at hospitals. Bringing together physicians, nurses, palliative care experts, clergy, and patients, the initiative attempted to minimize legal barriers to prescribing pain medications at the end of life, expand hospice and hospital-based palliative care, energize patient groups, and work with hospital chaplains. As a result, more than 500 hospitals have received training in palliative care and many have instituted their own programs.

Founded Smoking Cessation Leadership Center Upon leaving Robert Wood Johnson Foundation and returning in 2003 to the University of California, San Francisco -- he was originally on the faculty from 1976 to 1990 – Dr. Schro-

[Dr. Schroeder’s] most influential initiative focused on leveraging research, policy, advocacy, and education to reduce tobacco use and drive systemwide changes that created higher tobacco taxes, smoke-free indoor air laws, and better access to addiction treatment. dation, Dr. Schroeder also funded the Dartmouth Atlas of Health Care, which was influential in documenting large regional variations in medical services that do not correlate to desired health-care outcomes. Furthermore, after negative results from a controlled trial to improve care for seriously ill hospital patients, known as the SUPPORT study, Dr. Schroeder instituted

eder continued his dedication to curbing tobacco use by founding the Smoking Cessation Leadership Center. Under his direction, the center aims to increase the cessation rate of smokers and the number of clinicians who help smokers quit by creating partnerships to develop and implement action plans. By working with leaders at more than 80 health organizations na-

tionwide, the center has expanded the types of groups that support smokers’ attempts to quit, such as dental hygienists, pharmacists, emergency physicians, and nurses; created new ways to market toll-free telephone quit lines; and engaged the mental health community in treating tobacco addiction. Dr. Schroeder earned his his medical degree from Harvard Medical School. He trained in internal medicine at the Harvard Medical Service of Boston City Hospital and in epidemiology as an epidemic intelligence service officer at the Centers for Disease Control and Prevention. Dr. Schroeder is the past chair of the American Legacy Foundation (now known as Legacy for Health), which in 2006 established the Schroeder Institute for Tobacco Research and Policy Studies in his honor. He was elected to the IOM in 1982 and is the former chair of IOM’s Board on Health Care Services. Dr. Schroeder is the 28th recipient of the Lienhard Award, which includes a medal and $40,000 prize. Given annually, the award recognizes outstanding achievement in improving personal health care services in the United States. Nominees are eligible for consideration without regard to education or profession, and award recipients are selected by a committee of experts convened by the IOM. This year’s selection committee was chaired by Raynard S. Kington, president of Grinnell College. Additional information about the Lienhard Award can be found at http://www.iom.edu/lienhard. n

FDA Update

FDA Approves Transducer Array Layout System for Use in Patients With Recurrent Glioblastoma Multiforme

ovocure recently announced that it has received FDA approval for its NovoTAL (Transducer Array Layout) System through a Premarket Approval supplement. The NovoTAL

System allows certified physicians to use the individual magnetic resonance imaging data of recurrent glioblastoma multiforme patients to optimize the field distribution and intensity of tumor treating fields (TTF) therapy.

NovoTAL System The NovoTAL System is a workstation-based software tool that uses

MRI head morphology, tumor size and location measurements, and tissue dielectric properties to optimize tumor treating field distribution and intensity within the brain tumor.

NovoTTF-100A System In 2011, the FDA approved Novocure’s NovoTTF-100A System, a noninvasive medical device that

produces a low-intensity, alternating electric field within a tumor, resulting in malignant cell death. The device is approved in the treatment of adult patients aged 22 and older with histologically confirmed glioblastoma multiforme, following confirmed recurrence in an upper region of the brain after receiving chemotherapy. n

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1282b 09/13

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus kinase.

• Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

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Awards

NIH Awards $17 Million in Grants to Augment Genomics Research in Africa

he National Institutes of Health has awarded 10 new grants totaling up to $17 million over the next 4 years to support genomics research in Africa, as part of the Human Heredity and Health in Africa (H3Africa) program. This set of grants is the second

disbursement of H3Africa awards and brings the total amount of funding since the 2010 launch of the program to about $74 million. In addition to genomics research, the new awards will support training of African genomic scientists and

building scientific infrastructure on the continent. H3Africa is funded by a partnership between NIH and the United Kingdom’s Wellcome Trust. “These H3Africa awards demonstrate our continued commitment to

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions]. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All a Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Grades (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: June 2013 RUX-1216

furthering the capacity for genomics research on the African continent,” said Eric D. Green, MD, PhD, Director of the National Human Genome Research Institute. “Studying human diseases within populations with the greatest genetic variability and encouraging the contributions of our African colleagues should yield new insights about the role of genetics in health and disease.”

Funding to Support Additional Centers The new awards include funding for two additional H3Africa collaborative centers, one that will study the risk factors for stroke and another that will study the role of the human vaginal microbiome in cervical cancer. New individual research projects will study several other health conditions important in Africa, including neurological disorders, respiratory diseases, fevers of unknown origin, tuberculosis, and African sleeping sickness.

NIH Common Fund H3Africa is a global health program of the NIH Common Fund, and is coordinated by the National Human Genome Research Institute, in partnership with a number of other NIH institutes and offices. These include the National Institute of Allergy and Infectious Diseases, the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH Office of AIDS Research, and the NIH Office of Research on Women’s Health. H3Africa’s goals are to enhance the capacity of African researchers to undertake cutting-edge research to advance understanding of the genomic and environmental determinants of common diseases, and in the long run, to use this knowledge to improve the health of African populations. The NIH Common Fund encourages collaboration and supports a series of exceptionally high-impact, trans-NIH programs. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could manage alone. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov. n

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FDA Update Targeted Therapy

FDA Hears Proposals on Codevelopment of Companion Diagnostics for Breakthrough Therapies By Caroline McNeil

companion diagnostic developed for use with a drug that has received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) should automatically be eligible for priority review, according to an expert panel that presented this proposal and four others to the FDA in early September (see sidebar). With members representing cancer centers, industry, and the National Cancer Institute, the panel presented a report suggesting ways to modify FDA’s standard review procedures specifically for in vitro diagnostics associated with Breakthrough Therapies, the FDA’s newest pathway for expedited approval.

A major issue in the field is now codevelopment of a drug and its companion diagnostic to ensure that they can be evaluated and cleared for use in the clinic at the same time. Codevelopment is “probably the biggest development in the in vitro diagnostics world in the past few years,” said FDA’s Elizabeth Mansfield, PhD, Director of the Personalized Medicine Staff at the Center for Devices and Ra-

Dr. Mansfield said that she believed this administrative section of the proposal would be “relatively easy to do.” The Breakthrough Therapy designation was not accompanied by recommendations on the diagnostic side, she said, “but we do have processes” related to codevelopment. She added that a draft guidance on codevelopment— for companion diagnostics associated with any targeted drug, not only those

Codevelopment is probably the biggest development in the in vitro diagnostics world in the past few years. —Elizabeth Mansfield, PhD

Burgeoning Field The five proposals and FDA’s consideration of them are among the latest developments in the burgeoning field of companion diagnostics, the tests designed to show whether a patient can benefit from a specific targeted therapy. Companion diagnostics have come to the fore, especially in oncology, with the increasing number of molecular targeted therapies. In the 12 months following Congressional approval of the Breakthrough Therapy designation in July 2012, the FDA received 82 applications for the designation, most of them for targeted drugs.

diological Health. Responding to the five proposals at a public forum in September, convened by Friends of Cancer Research, she said “we know the questions. We don’t have all the answers.”

Key Recommendation First and foremost, the panel recommended that a companion diagnostic be closely linked to its associated Breakthrough Therapy, making it automatically eligible for priority review and, importantly, receiving the same intensive guidance from FDA’s senior management.

Five Proposals for the FDA

t a forum convened by Friends of Cancer Research in September 2013, a panel of experts presented five proposals outlining how sponsors and FDA may be able to improve and expedite the process for the codevelopment and review of a companion diagnostic designed for use with a drug that has received the FDA’s Breakthrough Therapy designation. The proposals included: 1. Automatic designation of in vitro companion diagnostic devices for use as part of a Breakthrough Therapy drug approval as eligible for priority review 2. Use of highly coordinated administrative processes and management commitments for the review of in vitro companion diagnostics associated with Breakthrough Therapies that are commensurate with those processes offered for Breakthrough Therapies 3. Use of risk-based processes to determine required analytic studies for each assay at time of premarket approval filing 4. Use of risk-based approaches to determine requirements for data and testing related to quality systems, manufacturing processes, and software testing and documentation 5. Use of a Continued Access investigational device exception supplement to enable a broader set of laboratories to be ready for testing immediately upon contemporaneous approval of the companion diagnostic and therapeutic product. n

with the breakthrough designation— will be published soon. Mike Pacanowski, PharmD, FDA’s Associate Director for Genomics and Targeted Therapy, Office of Clinical Pharmacology, noted that timing is key to successful codevelopment. The biggest issue, he said, is early development of biomarkers by sponsors so that they can be reviewed along with the Breakthrough Therapy. “When developed later, it takes more planning to accommodate them,” he said.

Analysis and Production Issues The panel’s third and fourth proposals outlined modifications to the usual FDA requirements for analytic studies and for quality systems and manufacturing processes and software. On the analytic side, for instance, one current requirement is that full specificity studies be included in the premarket approval. The recommendation is that FDA consider limiting the number of substances to be tested for cross-reactivity, endogenous interferences, effect of pharmaceuticals, or a human anti-mouse antibody (HAMA) effect (for immunoassays only). Consideration would be based on risk, on a case-by-case basis. The sponsor would present data to justify modifications during presubmission discussions, supplying the agency with a study plan for the specificity studies, any reduced requirements, and any mitigations. On the production side, one pro-

posed modification would allow an abbreviated description of a manufacturing system in place of a full description, based on whether the sponsor had an approved or pending premarket approval that contained the same or highly similar information. Similarly, instead of a full description of quality systems, the FDA could consider an abbreviated description if the sponsor had an approved or pending premarket approval that contained essentially the same information, according to another proposed modification. In general, Dr. Mansfield said, these risk-based modifications are reasonable. “Choosing what data can wait makes sense,” she said. However, she added that it may be difficult to implement the proposals related to quality systems—procedures to ensure that the process of manufacturing a diagnostic test, when repeated, results in the same response. “The biggest challenge is not from the analysis and review sides but from quality systems,” she said. “That’s the biggest hurdle.”

Investigational Device Exception The fifth proposal would allow additional laboratories, not part of the clinical trial, to conduct testing immediately upon approval of the companion diagnostic, rather than waiting several weeks for verification and approval as under current regulations. This would be done through a Continued Access investigational device exception supplement. Currently a diagnostic can be shipped at any time to other laboratories, but cannot be used except for validation purposes until FDA approval is received. Dr. Mansfield said the agency has been considering an investigational device exception supplement. “We have struggled with this,” she said, “but it is not solidified yet; we’re hoping to be able to do it.” Asked whether any of the five proposals might need legislation to implement, both FDA officials said probably not. “I think there’s a lot we can do with our current authority,” said Dr. Mansfield. “We’re looking at whether we could take it further with legislation.” n Disclosure: Dr. Mansfield reported no potential conflicts of interest.

The ASCO Post | NOVEMBER 15, 2013

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Patient’s Corner

Having Bladder Cancer Has Taught Me Important Life Lessons Before my diagnosis, I was used to being in control and independent. Now, I value having the support of family, friends, and a caring medical team. By Fred Wright, as told to Jo Cavallo

think one of the most frightening— and embarrassing—things that can happen to an adult is losing control of your bladder and wetting the bed. When that happened to me in the spring of 2012 while I was on a camping trip with my wife Kimberly and our two teenage daughters, I knew something was very wrong and immediately sought medical attention. In my mid50s at the time, I had been diagnosed with an enlarged prostate and I was having some difficulty urinating, but losing control like that was alarming.

After a second opinion confirmed my surgeon’s recommendation, I had to think long and hard about what to do. Because I was still so young, I wanted to do everything in my power to save my bladder and not have my anatomy altered. But I also wanted to live and

Despite the physical and mental trauma of having cancer, I feel that my experience has been positive. I’ve learned so much about myself, and I’m now a more open person, as well as a better husband, father, and friend.

Surprising Biopsy Result A CT scan showed that I had a 7-cm tumor on my bladder situated in front of my left kidney. A cystoscopy later confirmed that the tumor was malignant. Because the tumor was so large, it was surprising when the initial biopsy report showed that the cancer was stage I. When subsequent biopsies confirmed the staging, I was faced with a difficult choice. My surgeon was convinced that the position and size of the tumor were good indicators that the cancer had, in fact, spread, and he wanted to treat me for invasive bladder cancer rather than early-stage cancer.

der cancer had metastasized to my prostate and I was restaged to stage IV disease and prescribed a 3-month adjuvant regimen of cisplatin and gemcitabine. Although there certainly are physical and emotional ramifications of having such radical surgery, I knew

—Fred Wright

see my daughters grow into adulthood, so I reluctantly agreed to a radical cystectomy in which my kidney, bladder, and prostate were removed and a valve created in a pouch made from a piece of my intestine—a continent diversion—to store my urine.

Putting Life First The pathology report showed that I had made the right decision. The blad-

all along that I really wanted to live, and I’m thrilled to say that today I am in remission. The cancer experience has been transformative for me. As a former Marine, I was used to being in control and independent and keeping my feelings to myself. When I was diagnosed with cancer, I worried about being a burden on my family and friends, but I found that their love and support gave me the

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courage to go through treatment and face my fear of having cancer.

Giving Back To show my appreciation for all the support I received from family, friends, and a wonderful medical team—including my oncologist, who was forthright and consoling throughout my diagnosis and treatment—I’ve dedicated myself to giving back to the cancer community. I speak before groups of cancer survivors and share with them five lessons I’ve learned after having cancer. They include the importance of confronting your fears, accepting emotional support, building a strong medical team, setting priorities, and being comfortable with your decisions. Despite the physical and mental trauma of having cancer, I feel that my experience has been positive. I’ve learned so much about myself, and I’m now a more open person, as well as a better husband, father, and friend. I appreciate every day and don’t fear the future—and that’s perhaps the greatest lesson of all. n Fred Wright lives in Leesburg, Virginia.

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NOW ENROLLING – A RANDOMIZED PHASE lll STUDY

A Phase III study of the pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in patients with HR+/HER2−, aromatase inhibitor-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor Postmenopausal women with HR+/HER2–, inoperable, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor (N≈615) Evidence of progression on or after mTOR inhibitor-based therapy No more than one prior line of chemotherapy for metastatic disease Tumor tissue for analysis of PI3K pathway activation

Molecular prescreening*

ECOG Performance Status ≤2

Randomization (2:1)

Additional inclusion/exclusion criteria apply.

Buparlisib + fulvestrant

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival *Molecular prescreening for PI3K activation status can occur at any time prior to randomization after obtaining prescreening informed consent.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. For more information Contact your local Novartis representative. Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only). Visit www.clinicaltrials.gov (NCT01633060). Visit the PRI3M program website at www.pri3m.com or scan the QR code.

Pioneering Research of PI3K inhibitors in Malignancies

www.pri3m.com Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

August 2013

G-BKE-1069108

Novartis Pharma AG CH-4002 Basel Switzerland

The ASCO Post | NOVEMBER 15, 2013

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

Omega-3 Common Name: Polyunsaturated fatty acids (PUFAs) Brand Names: Omegaven, Max-EPA

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 evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose omega-3 fatty acids for this issue because of their growing use by cancer patients.

Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial SloanKettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, LAc, Memorial SloanKettering Cancer Center.

Overview

Omega-3 fatty acids are polyunsaturated fatty acids that play a crucial

GUEST EDITOR

role in many physiologic processes. Because our bodies cannot synthesize them, omega-3s must be obtained through diet or dietary supplements. Good sources of omega-3 include fatty fish, some plants, and nut oils. The three most studied omega-3s are alpha-linolenic acid, eicosapentanoic acid, and docosahexanoic acid. These are also the form most commonly used in dietary supplements. Following consumption, alpha-linolenic acid is converted to eicosapentanoic acid and docosahexanoic acid, forms that are readily used by the body. The current U.S. Food and Drug Administration recommendation is to limit intake of eicosapentanoic acid and docosahexanoic acid to 3 g/d (due to a potential risk of excessive bleeding in some individuals at higher intakes). Available data strongly support the protective effects of omega-3s against cardiovascular disease. Benefits have been reported also for a wide range of conditions, including depression, inflammatory bowel disease, and autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. Omega-3s may play a role in cancer prevention, but definitive data are lacking.

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 maintains a free website—About Herbs (www. Barrie R. Cassileth, MS, PhD mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 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, was launched last fall. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. related cognitive decline,2 although data on omega-3 supplementation and cognition in young children3 and

The Science

A large survey of Finnish adults found that depressive symptoms were significantly higher among infrequent fish consumers.1 Supplementation with docosahexanoic acid improved learning and memory function in age-

elderly subjects4 remain inconclusive. Omega-3 supplements lowered cholesterol levels in individuals with

hypercholesterolemia,5 and reduced recurrence in patients with history of stroke.6 In another study of patients with rheumatoid arthritis, omega-3 supplementation reduced nonsteroidal anti-inflammatory drug use.7 Fish oil also was shown to relieve symptoms associated with systemic lupus erythematosus.8 Findings of a systematic review support beneficial effects of omega-3 consumption on insulin sensitivity and adipocyte function.9 Omega-3s may reduce colon cancer risk10 and improve immune response in patients undergoing colorectal cancer resection,11 but they did not affect cancer outcomes.12 Similarly, studies of fish oil supplements suggest that they reduce the risk of breast cancer,13 but data from the Se-

Learn More About

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

www.mskcc.org/aboutherbs

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Integrative Oncology lenium and Vitamin E Cancer Prevention Trial (SELECT) found increased risk of prostate cancer in patients with high blood levels of omega‑3.14 Further research is needed to determine the likely specific cancer preventive potential of omega-3s. Preliminary findings from recent studies suggest that fish oil supplementation increases the efficacy of chemotherapy, improves survival,15 and helps maintain weight and muscle mass16 in patients with non–small cell lung cancer (NSCLC). Further, an eicosapentanoic acid–enriched oral supplement improved the tolerability of chemotherapy in patients with advanced colorectal cancer.17

Adverse Effects

Fishy aftertaste,10 loose stools, and nausea18 were reported after consuming large doses of omega-3 fatty acids.

Herb-Drug Interactions

Nonsteroidal anti-inflammatory drugs: Fish oil can have additive anticoagulant/antiplatelet effects,19 but a recent study reported that omega-3s do not affect coagulation or platelet function postsurgery.20

Lab Interactions

Omega-3s may reduce levels of alpha-tocopherol and beta-carotene.10,21 High levels of omega-3s may decrease triglycerides, and increase lowdensity lipoprotein cholesterol levels.22 Doses higher than 3 g/d may increase bleeding time.23 n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

OF NOTE The role of omega-3s in cancer prevention awaits further investigation. Oncologists should be aware of their potential to interact with anticoagulant medications. References 1. Tanskanen A, Hibbeln JR, Tuomilehto J, et al: Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 52:529-531, 2001. 2. Sinn N, Milte CM, Street SJ, et al: Br J Nutr. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: A 6-month randomised controlled trial. Br J Nutr 20:1-12, 2011. 3. Ryan AS, Nelson EB: Assessing the effect of docosahexaenoic acid on cognitive functions in healthy, preschool children: A randomized, placebo-controlled, double-blind study. Clin Pediatr (Phila) 47:355-362, 2008. 4. van de Rest O, Geleijnse JM, Kok FJ, et al: Effect of fish oil on cognitive performance in older subjects: A randomized, controlled trial. Neurology 71:430-438, 2008. 5. Gunnarsdottir I, Tomasson H, Kiely M, et al: Inclusion of fish or fish oil in weightloss diets for young adults: Effects on blood lipids. Int J Obes 32:1105-1112, 2008. 6. Tanaka K, Ishikawa Y, Yokoyama M, et al: Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: Subanalysis of the JELIS trial. Stroke 39:2052-2058, 2008. 7. Galarraga B, Ho M, Youssef HM, et al: Cod liver oil (n-3 fatty acids) as an nonsteroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatol-

ogy (Oxford) 47:665-669, 2008. 8. Duffy EM, Meenagh GK, McMillan SA, et al: The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J. Rheumatology 31:1551-1556, 2004. 9. Wu JH, Cahill LE, Mozaffarian D: Effect of fish oil on circulating adiponectin: A systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 98:2451-2459, 2013. 10. Anti M, Armelao F, Marra G, et al: Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 107:1709-1718, 1994. 11. Liang B, Wang S, Ye YJ, et al: Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol 14:2434-2439, 2008. 12. Andreeva VA, Touvier M, KesseGuyot E, et al: B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Arch Intern Med 172:540-547, 2012. 13. Brasky TM, Lampe JW, Potter JD, et al: Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) cohort. Cancer Epidemiol Biomarkers Prev 19:1696-1708, 2010. 14. Brasky TM, Darke AK, Song X, et al: Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst 105:1132-1141, 2013. 15. Murphy RA, Mourtzakis M, Chu QS, et al: Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung

cancer. Cancer 117:3774-3780, 2011. 16. Murphy RA, Mourtzakis M, Chu QS, et al: Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer 117:1775-1782, 2011. 17. Trabal J, Leyes P, Forga M, et al: Potential usefulness of an EPA-enriched nutritional supplement on chemotherapy tolerability in cancer patients without overt malnutrition. Nutr Hosp 25:736-740, 2010. 18. Fugh-Berman A, Cott JM: Dietary supplements and natural products as psychotherapeutic agents. Psychosom Med 61:712728, 1999. 19. Haller C, Kearney T, Bent S, et al: Dietary supplement adverse events: Report of a one-year poison center surveillance project. J Med Toxicol 4:84-92, 2008. 20. Heller AR, Fischer S, Rossel T, et al: Impact of n-3 fatty acid supplemented parenteral nutrition on haemostasis patterns after major abdominal surgery. Br J Nutr 87(suppl 1):S95-S101, 2002. 21. Holm T, Berge RK, Andreassen AK, et al: Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients. Transplantation 72:706-711, 2001. 22. Rizos E, Ntzani E, Bika E, et al: Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA 308:1024-1033, 2012. 23. Lewis CJ: Letter Regarding Dietary Supplement Health Claim for Omega-3 Fatty Acids and Coronary Heart Disease. FDA Docket No. 91N-0103. Available at www.fda.gov/ohrms/dockets/ DOCKETS/95s0316/95s-0316-Rpt027238-Appendix-D-Reference-F-FDA-vol205. pdf. Accessed August 28, 2013.

CancerCare Launches New Edition of Financial Resource Guide for People With Cancer

ancerCare recently announced the launch of a new edition of A Helping Hand: The Resource Guide for People With Cancer, Financial Edition, a reference guide to assist patients with cancer and their families in navigating the financial resources available to them. A Helping Hand is a comprehensive handbook featuring up-to-date contact information and descriptions for hundreds of national and regional organizations offering financial help

to people with cancer. The new edition also provides valuable tips patients and caregivers can use to manage finances and easily access support in their local community.

Roadmap to Guide Patients and Families “Even with insurance, most people are unprepared for the out-of-pocket expenses that accompany cancer. These can include copayments and medications for side effects, as well

as costs for transportation to and from treatment and childcare,” said CancerCare Director of Patient Assistance Programs Jane Levy, MSW, LCSW-R. “Finding help with the expenses of daily living can be overwhelming. A Helping Hand is a roadmap that guides patients and their families to organizations that can best address their unique needs,” Ms. Levy said. The new edition provides valuable tips patients and caregivers can use

to manage finances and easily access support in their local community. Health-care professionals can also rely on A Helping Hand for accurate information about which services can directly benefit their patients. Copies of A Helping Hand may be ordered fee of charge for anyone interested by visiting www.cancercare. org/publications. n

The ASCO Post | NOVEMBER 15, 2013

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Book Review Movie Review

Decoding Annie Parker: Hunting the Breast Cancer Gene By Jo Cavallo

ased on true events, Decoding Annie Parker follows the parallel stories of two women obsessed with finding a genetic link to breast cancer. And from the film’s opening frame until the closing credits roll, the absorbing tale never allows your mind to wander.

over medical journals looking for any common thread that might give a clue to a genetic link to the disease. But in 1980 little was known about the causes of breast cancer. And while Annie was seeking answers to the reason for her disease, another woman,

Attempting to Elude Fate One woman is Annie Parker, played by Samantha Morton, whose mother was diagnosed with breast cancer when she was pregnant with Annie and died of the disease when Annie was 13. In 1978, when Annie’s older sister Joan and first cousin also die of breast cancer, she is convinced that the disease is coming for her too. Two years later, at age 29, it does. Told by doctors that it was just “bad luck” that so many immediate family members died of breast cancer, Annie instinctively knows that there has to be an inherited cause and not random chance that doomed the women in her family to cancer and an early death. And she is desperate to avoid their fate. After undergoing a mastectomy of her left breast, followed by grueling regimens of chemotherapy that leave her bald, sick, and exhausted from vomiting, Annie grills her doctors about the possibility of breast cancer being an inherited disease and pours

responsible for breast and ovarian cancers in many families.

Never Maudlin While the film tracks Annie’s devastation over the loss of so many family members to cancer and the

Decoding Annie Parker is an inspiring film that gives testament to the courage and perseverance of patients with cancer and showcases the determination of scientists to identify the causes of the disease. geneticist Mary-Claire King, PhD, played by Helen Hunt, was also on a quest to prove a genetic susceptibility to breast cancer. With a clock in her office marked off every 12 minutes by pink tape to signify how often a woman dies of breast cancer, Dr. King had been researching a potential genetic link to the disease since the mid-1970s. When the film begins, Dr. King has compiled data on about 80 women with a family history of breast cancer. Because it could take a decade or more to sequence gene mutations using the only available computer technology at the time—a primitive 2.5ton mainframe computer—it took Dr. King until 1990 to finally discover that a single gene on chromosome 17q21, which she named BRCA1, was

challenges she faced after her own breast cancer diagnosis—including a diagnosis of ovarian cancer 8 years later and the humiliation of her husband’s infidelity—the movie never

Helen Hunt in role of Mary-Clair King, PhD, in Decoding Annie Parker, a film expected to be released early in 2014.

becomes maudlin. Directed by Steven Bernstein, who also cowrote and coproduced the film, the movie successfully uses Annie’s quick wit and humor as a buffer against the serious subject matter. Decoding Annie Parker is an inspiring film that gives testament to the courage and perseverance of patients with cancer and showcases the determination of scientists to identify the causes of the disease.

Raising Money for Breast Cancer Research Although the film is scheduled for commercial release early in 2014, Decoding Annie Parker has been shown at film festivals and charity events around the country since the spring, to raise awareness of breast cancer and funds for research. In October, the Hamptons International Film Festival and The Sloan Foundation awarded director Steven Bernstein the $25,000 Alfred P. Sloan Feature Film Prize, which encourages the creation of more realistic and accurate films about science and technology. Decoding Annie Parker stars Samantha Morton (Annie Parker), Helen Hunt (Dr. Mary-Claire King), Aaron Paul (Paul, Annie’s husband), Marley Shelton ( Joan, Annie’s sister), Rashida Jones (Kim), and Bradley Whitford (Marshall, Annie’s second husband). n

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In the News

‘Clear and Consistent Protective Effect of Marriage’ Found in Patients With 10 Most Clinically Significant Cancers By Charlotte Bath

“A

clear and consistent protective effect of marriage among patients harboring one of the 10 most clinically significant malignancies affecting Americans” was found in a study analyzing Surveillance, Epidemiology, and End Results

“We were very surprised by this. We certainly suspected that marriage had some kind of beneficial effect, but we didn’t realize it would be this big. That really speaks to the importance of social support in the care of patients with can-

That [beneficial effect of marriage] really speaks to the importance of social support in the care of patients with cancer. —Paul L. Nguyen, MD

(SEE) data for 734,889 patients diagnosed with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, head/neck, ovarian, or esophageal cancer, or non-Hodgkin lymphoma. “For five cancers studied (prostate, breast, colorectal, esophageal, and head/neck cancers), the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy,” noted the study authors.1

cer,” the study’s corresponding author, Paul L. Nguyen, MD, told The ASCO Post in a joint interview with lead author Ayal A. Aizer, MD, MHS. “We definitely recognize that chemotherapy is important, but so is making sure that patients actually follow through and get access to therapies and the social support that they need to make it through these kinds of therapies,” Dr. Nguyen said. He is Director of Prostate Brachytherapy

at Dana-Farber/Brigham and Women’s Cancer Center and Assistant Professor of Radiation Oncology at Harvard Medical School in Boston. Dr. Aizer is Chief Resident of the Harvard Radiation Oncology Program. The study was published in the Journal of Clinical Oncology1 and widely reported by the major media, including The New York Times, USA Today, the Cleveland Plain Dealer, CNN, and NBC Nightly News. “We don’t ultimately know with 100% certainty what marriage is doing for patients, but our suspicion—and we have some data to support this—is that it is to provide support for patients with cancer,” Dr. Aizer said. “I think most of the media outlets have picked up on that, and I think that they have represented the study well.”

Less Likely to Die as Result of Cancer “Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.82–0.84, P < .001), more likely to receive definitive therapy (adjusted OR = 1.53, 95% CI = 1.51–1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demo-

graphics, stage, and treatment (adjusted hazard ratio = 0.80, 95% CI = 0.79–0.81, P < .001) than unmarried patients,” according to the study report. “These associations remained significant when each individual cancer was analyzed (P < .05 for all endpoints for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases).” Longer follow-up is needed to determine median overall survival. Being married may contribute to improved outcomes because spouses may encourage their counterparts to seek medical attention for worrisome symptoms and to undergo definitive treatments. “There are many explanations for the vital question of why marriage is associated with improved cancerspecific survival after adjustment for demographics, stage, and treatment, but the most likely reason is that married patients have better adherence with prescribed treatments than unmarried patients,” the researchers reported.

Particularly Important for Head and Neck Cancers Just making sure patients get to treatment is important. “We’ve looked

Expect Questions About Support Systems for Unmarried Patients

he study finding that unmarried patients with cancer “are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer,” generated a lot of comments from colleagues, family members, and patients, the study’s lead author Ayal A. Aizer, MD, MHS, told The ASCO Post. “We’ve had patients we’ve never even met before calling us from different parts of the country because they heard about the study and they have insights that they want to offer. Several patients contacted me and wanted to highlight the message about depression,” Dr. Aizer added. “They thought that their mental status was improved by a spouse, which really got them through the treatment. They felt that just having someone to talk with and share the burden gave them the motivation to get through the treatment, to have something to fight for, something to live for.”

Rallying Support Physicians can capitalize on the interest in the report to stress the importance of good support systems for patients with cancer and their

just relying on others, rallying support from the community,” Dr. Aizer stated. “The most important kind of social support is the kind that comes

We should be asking our patients about the support they have if they are not married, and frankly, if they are married, too, and think about ways to get them better supported if it looks like these support systems are lacking for them. —Ayal A. Aizer, MD, MHS

families. “Anything patients can really be doing to get the support that they need is good. That could mean reaching out to families or friends,

from your friend, your neighbor, somebody who knows and cares about you,” Paul L. Nguyen, MD, added. “We want to empower every-

body who has a friend or a loved one with cancer to go to the doctor with their friend and be there for him.” Dr. Nguyen is Director of Prostate Brachytherapy at Dana-Farber/ Brigham and Women’s Cancer Center in Boston and Assistant Professor of Radiation Oncology at Harvard Medical School. Dr. Aizer, MD, is Chief Resident of the Harvard Radiation Oncology Program. “What we really want people to start thinking and talking about is that unmarried patients with cancer seem to do more poorly after their diagnosis,” Dr. Aizer said. “This is something that we need to be thinking about as doctors. We should be asking our patients about the support they have if they are not married, and frankly, if they are married, too, and think about ways to get them better supported if it looks like these support systems are lacking for them.” n

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In the News

at several cancers where that is particularly important, and the one that jumps out at us is head and neck cancer. For this disease, patients have to come in for radiation treatment every day, usually for about 7 weeks, and it is not an easy treatment to tolerate…. So that physical element of having someone not only help manage the side effects, but also get the patient to the doctor on a day-to-day basis, which we know is so important, may be making a difference,” Dr. Aizer said. “In our clinic for head and neck patients at Dana-Farber, when you meet with your physician, it is in a multidisciplinary setting. Not only is there a surgeon, a medical oncologist, and a radiation oncologist, but there is a social worker who is part of the team, who is always thinking about the social situation of the patient and what kind of social support they may might need,” Dr. Nguyen said. “The social worker can set up rides for you to get to your treatment, can help you with the logistics so that you can show up every day. We don’t have that in treatment for all disease sites, but in head and neck, it is such an important thing to show up every day for your treatment,” he added.

Sharing the Emotional Burden “Having someone to share the emotional burden of the diagnosis and cope with everything that is going on” is also important, Dr. Aizer said. “Physicians should consider screening for depression among unmarried persons and refer patients to mental health specialists if needed. In addi-

tion, physicians should consider closer observation of unmarried patients with cancer to maximize adherence,” the study report advises. “We know that people who are married in general show lower rates of depression and that patients who are depressed after diagnosis of cancer tend not to adhere to the therapies that are

continued on page 140

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-2: A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

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

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

‘Not Just a Pat on the Back’ Both Dr. Aizer and Dr. Nguyen stressed that the findings of their study should not be construed as “just a pat on the back” for married patients. “The importance of this study is that it highlights the consistent and substantial impact that features of marriage, particularly social support, can have on cancer detection, treatment, and survival,” the study authors noted. “It raises the possibility that investments in targeted social support interventions aimed at vulnerable populations, such as unmarried patients, could significantly improve the likelihood of achieving cure.” Dr. Nguyen said, “What we see from this research is that social support really helps. If a patient is single, we might need to help that patient a little more. To me, it is not so much about whether you’re married or you’re single, but more about whether you are coming by yourself to appointments or if there is somebody there with you to support you,” he commented. “Hospitals should really be focusing on this as a way to potentially improve outcomes among their cancer populations,” Dr. Aizer stated.

recommended for them. That may be one of the reasons for the differences in survival that we saw in our study,” Dr. Aizer noted. “If you are psychologically distressed, it is harder for you to think rationally about your decision, make the right choice for your cancer care,

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

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

Trebananib15 mg/kg IV QW + PLD 50 mg/m2 IV Q4W

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

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

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

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

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Key Inclusion Criteria: • Subjects must have had one to three prior chemotherapeutic regimens • Radiographically documented disease progression either on or following the last dose of prior chemotherapeutic regimen • ECOG performance status of 0 or 1

Key Inclusion Criteria: • FIGO Stages III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin • No prior use of any anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer • ECOG performance status of 0 or 1

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2009-017946-30 • www.ClinicalTrials.gov (NCT01281254)

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2011-001112-53 • www.ClinicalTrials.gov (NCT01493505)

The ASCO Post | NOVEMBER 15, 2013

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In the News

Protective Effect of Marriage continued from page 139

and also to just keep your life in order so that you can show up every day for your treatment. That’s a lot of work, a lot that you have to juggle,” Dr. Nguyen said. “Sometimes unmarried patients with cancer may not be asking for the support that they need. They may not recognize that they really may need more physical and emotional support,” Dr. Aizer said. “We wonder if this is more of an issue with men than women—not asking for the support they may need.” Single women, he said, “may be more effective in rallying support from other sources.”

Care for the Caregiver “When we assess the patient, we should think about how the caregiver is doing,” Dr. Nguyen said. “That is something that is being taught at a

lot more medical schools and in residencies—to really look at the caregiver, who this person’s supports are, and spend some time thinking about them and how they fit into the entire care team as well. To a certain degree, this borrows from the pediatric literature, where in the pediatric setting you are not just the patient’s doctor, but also the parents’ doctor. We are starting to incorporate that kind of thinking into a lot more disease sites, although not necessarily in a formal way,” he added. “Cancer centers would do well to screen for the at-risk family,” noted an accompanying editorial by David W. Kissane, MD, of Monash University, Victoria, Australia, and Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York.2 “The provision of family-focused therapy ought to be a routine outpatient service for couples and families in modern cancer.”

Unmarried Subgroups In the study, marital status was classified as either married on unmarried and then reanalyzed as married vs single, separated, divorced, or widowed. “When we looked at different types of unmarried patients, we didn’t find any differences among them in terms of how well they did after the diagnosis of cancer, be it what stage they presented at with their cancer, whether they got the treatment that they should receive, and most importantly, did they survive their cancer. The fact that the widowed population—who were once married—did just as poorly as some of the other unmarried groups seems to indicate that there really is something about what marriage is providing, rather than some innate characteristic of people who get married, that is driving the results in our studies,” Dr. Aizer remarked. It is not known how many people in the unmarried category in the study

were in relationships. “They may be dating someone, they may be engaged, they may be in a same-gender relationship in a state where marriage is not recognized,” Dr. Aizer noted, but “those patients would be characterized as unmarried in our study, given the database we used. The fact that all unmarried patients were put together in the same cohort, whether they were in relationships or not, tells us that the differences we saw may be even greater than what we appreciated.” n

Disclosure: Drs. Nguyen, Aizer, and Kissane reported no potential conflicts of interest.

References 1. Aizer AA, Chen M-H, McCarthy EP, et al: Marital status and survival in patients with cancer. J Clin Oncol. September 23, 2013 (early release online). 2. Kissane DW: Marriage is as protective as chemotherapy in cancer care. J Clin Oncol. September 23, 2013 (early release online).

The Power of Human Attachment By David Kissane, MD

or those patients with cancer who may be single, widowed, separated, or divorced, those for whom a natural social support system may be weak, the role of the cancer support group should not be overlooked. In leading a previous trial of supportive-expressive group therapy as a key pathway to foster social support, I found that patients who successfully connected with a cancer support group felt better supported and were more adherent with conventional anticancer therapy than those who did not.1

Major Debate One conundrum not addressed in this article for The ASCO Post is why three earlier randomized controlled trials of supportive-expressive group therapy failed to extend survival.1-3 The question arises that if being married extends survival, which it clearly does, shouldn’t other forms of support also help in extending survival? This Dr. Kissane is a Recent Chairman of the Department of Psychiatry & Behavioral Sciences at Memorial Sloan-Kettering Cancer Center (2003-2012); Adjunct Professor of Psychiatry at Weill Cornell Medical College. He is currently Head of Discipline of Psychiatry and Chairman of the Department of Psychiatry, Monash University, Australia.

has been a major debate in oncology. In my editorial that accompanied the paper by Aizen et al,4,5 I suggested that the sample sizes in these group therapy studies were too small, that the cohorts should have targeted unmarried women, and that group sup-

its treated members compared to those receiving usual oncology care.1 Improving treatment adherence and preventing depression are such important goals of psycho-oncology. To achieve these goals, however, institutions need to open up staffing to

The question arises that if being married extends survival, which it clearly does, shouldn’t other forms of support also help in extending survival? —David Kissane, MD

port remains vital in cancer care, with the Aizen et al article stressing the importance of social support. The three group therapy trials had many married participants, which might have caused them to fail to show a survival benefit through a “ceiling effect.” That is, so many were well supported by already being married that the margin of gain for those who were single was masked. Further, our supportive-expressive group therapy trial prevented the development of depression among

include psychiatrists, psychologists, and social workers who can deliver these supportive services to patients.

Conclusions The study by Aizer et al verifies the power of human attachment. It shows a relationship between marriage status and cancer survival, and perhaps serves as an important reminder to clinicians that a patient’s single status may be a red flag for poor social support. In such cases, referral to psychooncology services may be warranted.

Clinicians ought to be reminded of the importance of that 16th century axiom, “To cure sometimes, to relieve often, to comfort always (Anonymous).” Targeted supportive programs are necessary to attend to those individuals most in need of social support and an opportunity for better quality of life and improved survival. n

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

References 1. Kissane DW, Grabsch B, Clarke DM, et al: Suportive-expressive group therapy for women with metastatic breast cancer: Survival and psychosocial outcome from a randomized controlled trial. Psycho-Oncology 16:277-286, 2007. 2. Goodwin PJ, Leszcz M, Ennis M, et al: The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med 345:1719-1726, 2001. 3. Spiegel D, Butler LD, Giese-Davis J, et al: Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: A randomized prospective trial. Cancer 110:1130-1138, 2007. 4. Aizer AA, Chen M-H, McCarthy EP, et al: Marital status and survival in patients with cancer. J Clin Oncol 31:38693876, 2013. 5. Kissane DW: Marriage is as protective as chemotherapy in cancer care. J Clin Oncol 31:3852-3853, 2013.

The big PicTure

Journal of CliniCal onCology

Yes, Journal of Clinical Oncology (JCO) has one of the highest Impact Factors of any cancer journal—18.038, but that’s only part of the story.

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Respected globally with 3.2 million unique visits annually to JCO.org

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High-caliber content including exceptional article types such as Oncology Grand Rounds, Rapid Communications, and Understanding the Pathway

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Trusted answers with 9 out of 10 medical oncologists and hematologists describing JCO as “Essential Reading” 1

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Over 128,000 citations in the scientific literature published in 2012 ranking JCO 1st for clinical oncology journals 2

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The highest Eigenfactor® Score - 0.40051 - of all journals in the 2012 JCR® oncology category 2

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Ranked as the most widely read oncology publication by Kantar Media 3

JCO Essential Reading. Influential Information.

1. The Matalia Group Essential Journal Study, Medical Oncology & Hematology Oncology, 2011 2. Thomson Reuters 2012 Journal Citation Reports® 3. Kantar Media, June 2013 Medical/Surgical Readership Study, Oncology

To submit your manuscript, please visit http://submit.jco.org. Or e-mail the JCO Editorial Office at jco@asco.org Subscribe online at jcomps.asco.org or by calling 888-273-3508 or 703-519-1430

Stephen A. Cannistra, MD Editor-In-Chief

The ASCO Post | NOVEMBER 15, 2013

PAGE 142

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Variations in Risk Factors Suggest Distinct Etiology for Inflammatory Breast Cancer “Varying risk factor associations between inflammatory and noninflammatory breast cancer suggest a distinct etiology for [inflammatory] breast cancer,” according to a study in the Journal of the National Cancer Institute. High body mass index was shown to increase risk of inflammatory breast cancer “irrespective of menopausal status and estrogen receptor (ER) expression,” the researchers reported. The study included 617 inflammatory breast cancer case subjects in a nested case–control study from the Breast Cancer Surveillance Consortium database (1994–2009), reported Catherine Schairer, PhD, of the National Cancer Institute, and colleagues. “We also included 1,151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement, 7,600 noninflammatory invasive case subjects without chest wall/breast skin involvement, and 93,654 control subjects matched to case subjects on age and year at diagnosis, and mammography registry.” “The average age of diagnosis for [inflammatory breast cancer] case subjects was 4 years younger than for [noninflammatory disease] case subjects,” the authors noted. Risk factor associations with family

history of breast cancer and mammographic breast density were similar for all groups. Besides high body mass index, other risk factor variations were later age at first birth (which was associated with a reduced risk of ER-negative inflammatory breast cancer greater than for ER-negative noninflammatory disease) and education level. A higher level of education was “associated with reduced risk of ER-positive [inflammatory breast cancer], more so than for noninflammatory breast cancer,” the investigators reported. “Notably, overweight and obesity statuses were associated with increased [inflammatory breast cancer] risk regardless of the internal hormonal milieu or the ER status of the tumors,” the researchers commented. They found that among patients with inflammatory breast cancer, the “rate ratios for [body mass index of] 30 and greater vs [body mass index] less than 25 were 3.90 (95% CI = 1.50–10.14) in premenopausal women and 3.70 (95% CI = 1.98–6.94) in peri/postmenopausal women not currently using hormones.”

Accompanying Commentary According to an editorial accompanying the article, “These findings show conclusively that obesity is a strong risk factor for [inflammatory breast cancer], and they are in stark contrast with the far lower rate ratios for the association of obesity with other breast cancer types, which ranged

from 1.02 to 1.36. This finding supports the idea that [inflammatory breast cancer] is a distinct epidemiologic entity, in addition to being a distinct clinicopathologic entity,” wrote the editorialists. “Understanding the mechanism by which obesity contributes to the risk of breast cancer is important and may lead to identification of some biologic targets. However, the greatest need is to modify behavior and stop the obesity epidemic in the first place,” they concluded. Schairer C, et al: J Natl Cancer Inst 105:1373-1384, 2013. Amiri-Kordestani L, et al: J Natl Cancer Inst 105:1340-1342, 2013.

Impact of Hormone Replacement Therapy on Breast Cancer Risk Varies by Race, Weight, and Breast Density The impact of hormone replacement therapy on breast cancer risk varies according to the patient’s to race/ethnicity, body mass index, and breast density. An analysis of 1,642,824 screening mammograms with 9,300 breast cancer cases in postmenopausal women aged 45 years or older found that hormone replacement therapy was more strongly associated with breast cancer in leaner women with dense breasts. “Black women, obese women, and women with breast tissue composed largely of fat may benefit from [hormone replacement therapy] use with minimal excess breast cancer risk,” Ningqi Hou, MD, PhD, of the University of Chicago, reported in the Journal of the National Cancer Institute.

Key Findings

Data for the study was from the Breast Cancer Surveillance Consortium, a longitudinal registry of mammography screening in the United States, and “multiple imputation methods were used to accommodate missing data for [hormone replacement therapy] use (14%) and other covariables,” the researchers reported. Use of hormone replacement therapy was associated with more than a 20% increased risk in white women (odds ratio [OR] = 1.21; 95% CI = 1.14–1.28), Asian women (OR = 1.58; 95% CI = 1.18–2.11), and Hispanic women (OR = 1.35; 95% CI = 1.09–1.67) but not black women (OR = 0.91; 95% CI = 0.72–1.14; Pinteraction = .04). “In women with low/normal [body mass index] and extremely dense breasts, [hormone replacement therapy] use was associated with the highest breast cancer risk (OR = 1.49; 95% CI = 1.21–1.83), compared with nonusers. In overweight/

obese women with less-dense breasts, no excess risk was associated with [hormone replacement therapy] use (adjusted ORs = 0.96–1.03),” the investigators wrote. About 55% of the study population had an increased risk of breast cancer due to hormone replacement therapy use, the researchers found. For the 20% of the study population that was overweight and obese with less-dense breasts, “the association between [hormone replacement therapy] use and breast cancer risk was essentially absent (adjusted ORs = 0.96–1.03). The remaining 25% of the study population had an elevated risk of breast cancer due to [hormone replacement therapy] use, but statistical significance was not reached.” The study did not include information on the type of hormone replacement therapy used and the duration of use. The authors concluded that if their findings are confirmed in other studies with more detailed information about these and other risk factors, hormone replacement therapy use “may be reasonable for some women.”

Cautious Interpretation In an accompanying editorial, Mary Beth Terry, PhD, and Parisa Tehrnifar, DrPH, of Columbia University, Mailman School of Public Health, in New York, commented, “Results from studies such as that by Hou et al that lack details of [hormone replacement therapy] use, including type and duration, should be interpreted cautiously before drawing conclusions about risk stratification by race/ethnicity…. Beyond single stratifications by [body mass index] and race, however, the Hou et al study advances the literature by examining breast density in combination with these factors. Even this large study, though, is underpowered for examining race/ethnicity interactions with both [body mass index] and breast density,” the editorialists wrote. “Ultimately, efforts that improve risk stratification, whether made through improved risk models or through measuring valid intermediate biomarkers such as breast density, will inform appropriate use of not only [hormone replacement therapy], but also other medications including chemopreventive drugs,” they added. Hou N, et al: J Natl Cancer Inst 105:1365–1372, 2013. Terry MB, Tehranifar P: J Natl Cancer Inst 105:1342–1343, 2013.

Patient Assistance Programs Provide Psychosocial but Not Practical Help “Patients with breast cancer who con-

ASCOPost.com | NOVEMBER 15, 2013

PAGE 143

In the Literature

nect to relevant patient assistance programs receive useful informational and psychosocial but not practical help,” concluded Nina A. Bickell, MD, MPH, of Mount Sinai School of Medicine in New York, and colleagues who conducted a randomized trial among 374 women in need of adjuvant treatment after surgery for early-stage breast cancer. “Although these programs can provide patients with cancer with resources and support beyond those provided by hospitals at little to no cost to the institution, they do not affect rates of treatment,” the authors added. Recruited from eight inner city New York teaching hospitals, 190 women were randomly assigned to intervention and 184 to usual care. The average age was 56.7 years; 79% were high school graduates, and about 50% lived with a significant other. High rates of patients in both groups received treatment: 87% of intervention patients and 91% of usual care patients who underwent lumpectomy received radiotherapy (P = .39); 93% of intervention recipients and 86% of usual care recipients with estrogen receptor (ER)negative tumors ≥ 1 cm received chemotherapy (P = .42); 92% of the intervention group and 93% of the usual care group with ER-positive tumors ≥ 1 cm received hormonal therapy (P = .80).

Study Design “All patients were surveyed at baseline to measure breast cancer experiences, knowledge, attitudes, and beliefs, followed by a needs assessment,” the investigators explained. An individual action plan was created for each patient to enable contact with identified high-quality assistance programs, and at follow-up 2 weeks later, intervention patients were asked whether they had contacted the programs specified in their action plan. If not, they were asked if they still needed help, and those with unmet needs were assigned to an outreach worker. Usual care patients were mailed a New York State Department of Health pamphlet about breast cancer that included resource contact information and were called to confirm they received it. “High rates of [intervention] patients with needs connected with a program within 2 weeks (92%),” the authors reported. At 6 months, both groups used patient-assistance programs at similar rates (75% vs 76%, P = .54). The intervention did not result in more women connecting with programs or receiving treatment. A majority of women (288 [77%]) reported at least one need; 143 were

randomly assigned to intervention, and 145 to usual care. Many had multiple needs, with 63% reporting informational; 55%, psychosocial; and 53%, practical needs, such as paying for and getting to and from treatment. “Women with informational or psychosocial needs were more likely to re-

ceive help” (relative risk [RR] = 1.77, 95% CI = 1.51–1.90; and RR = 1.37; 95% CI = 1.06–1.61, respectively), the researchers reported. While 76% reported receiving specific help from the programs, only 7% of women in the intervention group and 4% in the usual care group with practical needs reported receiving help from a program.

The authors noted that the rates for treatment and use of assistance programs were “were significantly higher than national and previously reported rates, suggesting a possible healthy volunteer bias or Hawthorne effect.” n Bickell NA, et al: J Oncol Pract. September 10, 2013 (early release online).

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The ASCO Post | NOVEMBER 15, 2013

PAGE 144

Issues in Oncology

ASCO’s 2013 Top Five List in Oncology for Choosing Wisely Campaign

SCO recognizes the importance of evidence-based cancer care and making wise choices in the diagnosis and management of patients with cancer. After careful consideration by experienced oncologists, ASCO annually highlights five categories of tests, procedures and/or treatments annually whose common use and clinical value are not supported by available evidence as part of the American Board of Internal Medicine’s (ABIM) Choosing Wisely® Campaign.

Antiemetic Drugs Do not give patients starting on a chemotherapy regimen that has a low or moderate risk of causing nausea and vomiting anti-emetic drugs intended for use with a regimen that has a high risk of causing nausea and vomiting. Over the past several years, a large number of effective drugs with fewer side effects have been developed to prevent nausea and vomiting from chemotherapy. When successful, these medications can help patients avoid spending time in the hospital, improve their quality of life, and lead to fewer changes in the chemotherapy regimen. Oncologists customarily use different antiemetic drugs depending on the likelihood (low, moderate, or high) for a particular chemotherapy program to cause nausea and vomiting. For chemotherapy programs that are likely to produce severe and persistent nausea and vomiting, there are new agents that can prevent this unfortunate side effect. However, these drugs are very expensive and not devoid of side effects. For this reason, these drugs should be used only with the chemotherapy drugs that have a high likelihood of causing severe or persistent nausea and vomiting. When using chemotherapy that is less likely to cause nausea and vomiting, there are other effective drugs available at a lower cost.

Combination Chemotherapy Do not use combination chemotherapy (multiple drugs) instead of chemotherapy with one drug when treating an individual for metastatic breast cancer unless the patient needs a rapid response to relieve tumor-related symptoms. Although chemotherapy with multiple drugs, or combination chemotherapy, for metastatic breast cancer may slow tumor growth for a somewhat longer time than occurs when treating with a single agent, use of combination chemotherapy has not been shown to increase overall survival. In fact, the trade-offs of more frequent and severe side effects may have a net effect of worsening a patient’s quality of life, necessitating a reduction in the dose of chemotherapy. Combination chemotherapy may be useful and worth the risk of more side effects in situations in which the cancer burden must be reduced quickly because it is causing significant symptoms or is life threatening. As a general rule, however, giving effective drugs one at a time lowers the risk of side effects, may improve a patient’s quality of life, and does not typically compromise overall survival.

Imaging Avoid using PET or PET-CT scanning as part of routine followup care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome. PET and PET-CT are used to diagnose, stage, and monitor how well treatment is working. Available evidence from clinical studies suggests that using these tests to monitor for recurrence does not improve outcomes and therefore generally is not recommended for this purpose. False positive tests can lead to unnecessary and invasive procedures,

overtreatment, unnecessary radiation exposure, and incorrect diagnoses. Until high-level evidence demonstrates that routine surveillance with PET or PET-CT scans helps prolong life or promote well-being after treatment for a specific type of cancer, this practice should not be done.

PSA Testing Do not perform PSA testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live less than 10 years. Since PSA levels in the blood have been linked with prostate cancer, many doctors have used repeated PSA tests in the hope of finding “early” prostate cancer in men with no symptoms of the disease. Unfortunately, PSA is not as useful for screening as many have hoped because many men with prostate cancer do not have high PSA levels, and other conditions that are not cancer (such as benign prostate hyperplasia) can also increase PSA levels. Research has shown that men who receive PSA testing are less likely to die specifically from prostate cancer. However when accounting for deaths from all causes, no lives are saved, meaning that men who receive PSA screening have not been shown to live longer than men who do not have PSA screening. Men with medical conditions that limit their life expectancy to less than 10 years are unlikely to benefit from PSA screening as their probability of dying from the underlying medical problem is greater than the chance of dying from asymptomatic prostate cancer.

Targeted Therapy and Biomarkers Do not use a targeted therapy intended for use against a specific genetic aberration unless a patient’s tumor cells have a specific biomarker that predicts an effective response to the targeted therapy.

Targeted therapy can significantly benefit people with cancer because it can target specific gene products, i.e., proteins that cancer cells use to grow and spread, while causing little or no harm to healthy cells. Patients who are most likely to benefit from targeted therapy are those who have a specific biomarker in their tumor cells that indicates the presence or absence of a specific gene alteration that makes the tumor cells susceptible to the targeted agent. Compared to chemotherapy, the cost of targeted therapy is generally higher, as these treatments are newer, more expensive to produce, and under patent protection. In addition, like all anti-cancer therapies, there are risks to using targeted agents when there is no evidence to support their use because of the potential for serious side effects or reduced effiacy compared with other treatment options. Note: These test and treatment options should not be administered unless the physician and patient have carefully considered if their use is appropriate in the individual case. As an example, when a patient is enrolled in a clinical trial, these tests, treatments, and procedures may be part of the trial protocol and therefore deemed necessary for the patient’s participation in the trial. These items are provided solely for informational purposes and are not intended to replace a medical professional’s independent judgment or as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their health care provider. New evidence may emerge following the development of these items. ASCO is not responsible for any injury or damage arising out of or related to any use of these items or to any errors or omissions. n Commentary on page 145

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

ASCOPost.com | NOVEMBER 15, 2013

PAGE 145

Perspective

Choosing Wisely: Good Care With Efficiency By Richard J. Boxer, MD, FACS

s more care better care? It is often said, by Americans, that the United States has the best care in the world. However, there are many population-based statistics that do not support that humble opinion. We certainly spend more money than any other nation by far. In fact, we may spend more money than nearly all other countries in the world combined. This begs a number of questions: (1) Are we getting our money’s worth? (2) Are patients being overtested and overtreated? (3) Can we physicians together decide what is reasonable to discuss with our patients to avoid unnecessary treatments and tests, and yet simultaneously improve care?

has been a leader in this extraordinary pursuit of excellence and has created its own set of recommended topics for discussion and consideration. As a demonstration of the per-

ceived value of this effort, private companies have developed sets of discussion points that help guide patients at the time of tremendous stress.

Once again, and appropriately so, our physician colleagues are taking the leadership role in creating better care for our patients. It is now up to all of us to follow the guidelines. n

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Richard J. Boxer, MD, FACS

Look inside for these important topics!

Yes We Can

• Preparation for the rash, itching, or dry skin that may come with cancer treatment

The answer to these questions is “Yes.” A program originally conceived by the National Physicians Alliance through an America Board of Internal Medicine (ABIM) Foundation Putting the Charter into Practice grant, created a set of three lists of specific steps physicians in internal medicine, family medicine, and pediatrics could take in their practices to promote the more effective use of health-care resources. These lists were first published in Archives of Internal Medicine.

Pursuit of Excellence Over 50 national medical organizations have created discussion points that emphasize quality of care without overtesting and overtreating. ASCO 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.

• Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

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

T:10.25" S:9.5" The ASCO Post | NOVEMBER 15, 2013

PAGE 146

FDA Update

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.

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).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

FDA Approves Obinutuzumab for Chronic Lymphocytic Leukemia

he U.S. Food and Drug Administration (FDA) has approved obinutuzumab (Gazyva) for use in combination with chlorambucil (Leukeran) to treat patients with previously untreated chronic lymphocytic leukemia (CLL). Obinutuzumab is the first drug with Breakthrough Therapy designa-

ment, review, and availability of important new drugs.”

Pivotal Study Obinutuzumab’s approval for CLL is based on a study of 356 participants in a randomized open-label multicenter trial comparing obinutuzumab in combination with chlorambucil

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

This approval reflects the promise of the Breakthrough Therapy designation program, allowing [FDA] to work collaboratively with companies to expedite the development, review, and availability of important new drugs.

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).]

—Richard Pazdur, MD

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).]

tion to receive FDA approval. This designation was requested by the sponsor, Genentech, and granted soon after the Biologic License Application to support marketing approval was submitted to the FDA. The FDA also granted obinutuzumab priority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. And the FDA granted obinutuzumab orphan product designation because it is intended to treat a rare disease. “Today’s approval represents an important new addition to the treatments for patients with CLL,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval reflects the promise of the Breakthrough Therapy designation program, allowing us to work collaboratively with companies to expedite the develop-

to chlorambucil alone in participants with previously untreated CLL. Participants receiving obinutuzumab in combination with chlorambucil demonstrated a significant improvement in progression-free survival: an average of 23 months compared with 11.1 months with chlorambucil alone. The most common side effects observed in participants receiving obinutuzumab in combination with chlorambucil were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and pyrexia. Obinutuzumab is being approved with a boxed warning regarding hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. These are known risks with other monoclonal antibodies in this class, and rare cases were identified in participants on other trials of obinutuzumab. Patients should be advised of these risks and assessed for hepatitis B virus and reactivation risk. n

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

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.

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites

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

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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.

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)

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%).

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).]

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).]

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

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).]

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. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

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

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. 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. 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

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

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for 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

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.

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. 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.

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

S:12.5"

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). [See Warnings and Precautions (5.8).]

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

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 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%.

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

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)

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

Think Avastin

Because survival matters most

Percentage Surviving

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

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

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

20 0

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

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

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

Indication

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

Boxed WARNINGS

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

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

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

Most common adverse events

Across all studies, 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 NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/ pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

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. November 2012. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

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