TAP Vol 4 Issue 19 by Harborside Press LLC

Metastatic Melanoma 14 | Colorectal Cancer

17, 18, 24, 26

VOLUME 4, ISSUE 19

| Fertility Options for Patients With Cancer 47

DECEMBER 1, 2013

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

JCO Spotlight

What Does ‘Myeloma’ Mean?

GeparTrio Long-Term Data Show Response-Guided Neoadjuvant Therapy for Breast Cancer Improves Survival

By Sagar Lonial, MD

By Matthew Stenger

n an exploratory analysis of long-term survival data from the GeparTrio trial reported in Journal of Clinical Oncology, Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg and the University of Frankfurt, Germany, and colleagues found that responseguided neoadjuvant chemotherapy appears to improve disease-free survival and overall survival and appears to be most effective in hormone receptor–positive tumors.1

Study Details In the trial, 2,072 patients with early breast cancer received neoadjuvant therapy with two cycles of TAC (docetaxel, doxorubicin, and cyclophosphamide), with early responders being randomly assigned to an additional four TAC cycles (TAC ×

6, n = 704) or an additional six TAC cycles (TAC × 8, n = 686) and early nonresponders being randomly assigned to four more cycles of TAC (TAC × 6, n = 321) or four cycles of NX (vinorelbine/ capecitabine, n = 301) Gunter von Minckwitz, MD, PhD before surgery. TAC was given as docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2 on day 1 every 3 weeks. NX was given as vinorelbine at 25 mg/m2 on days 1 and 8 plus capecitabine at 1,000 mg/m2 orally twice a day on days 1 to 14 every 3 weeks. continued on page 84

Quality Care Symposium

Innovative Payment Models Needed to Sustain Quality Cancer Care By Ronald Piana

ASCOPost.com

ver the centuries it has become clear that, as physicians, what we say and how we say it can have a major impact on those who seek our help. Our pronouncement that a patient is in remission or harbors a serious illness carries with it a large number of spoken and unspoken implications. So when we say a patient has “myeloma,” what does it mean? When we use certain language, it becomes a common bond by which we as physicians communicate a given set of information, but is that information interpreted similarly among all of us? This question concerning the meaning of myeloma is even more important—and continued on page 115

Dr. Lonial is Professor of Hematology and Medical Oncology at the Winship Cancer Center at Emory University, Atlanta. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

ationally regarded health-care expert Lee N. Newcomer, MD, MHA, began his presentation at this year’s ASCO Quality Care Symposium with a rhetorical question. “Why are we talking about money when we’re gathered in San Diego for 2 days to discuss some wonderful ways to impact the quality of cancer care?” His answer: Unless we create innovative payment models that measure value, our escalating health-care costs will debilitate our ability to deliver quality oncology care.1

Why We Have to Do Something

Dr. Newcomer punctuated his opening statement with fairly ominous projections. “In 2013, the average household income in the United States was about $52,000. If you draw a separate line calculating health-care costs [ie, the money a consumer would pay out-of-pocket plus the health-care premium for a family insurance plan] and trend the two, by the year 2016 it will take 50% of the average U.S. household’s income to cover its health care. Track up for I don’t envision a future in which another 12 to 15 years; it will take every single penthere will be more money in the ny a household makes to health-care system. So we have provide health care in the United States. Of course, to use the same rigor for financial that is not possible,” said measurement as we do in clinical Dr. Newcomer, adding, “If we don’t do something, no trials. one in this meeting will be —Lee N. Newcomer, MD, MHA

Oncology Meetings Coverage Quality Care Symposium �� 1, 28–30 International Symposium on Hodgkin Lymphoma �� 3, 4, 10 European Cancer Congress �� 12–14, 17 Pancreatic Cancer Focus ��31, 35–37 David H. Ilson, MD, PhD, on Gastric Cancer �� 42 FDA Update �� 44–46 Teresa K. Woodruff, PhD, on Fertility in Patients With Cancer �� 47 Direct From ASCO �� 53–56 Head and Neck Cancer �� 97

continued on page 10

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The ASCO Post | DECEMBER 1, 2013

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Harborside Press® Publishing Staff

Editorial Board

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James O. Armitage, MD Editor-in-Chief

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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

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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.

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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.

Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@ asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805.

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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.

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PAGE 3

International Symposium on Hodgkin Lymphoma Hematology

Brentuximab Vedotin Improves Response Rates to ABVD in Hodgkin Lymphoma By Caroline Helwick

or the front-line treatment of advanced Hodgkin lymphoma, ABVD is a standard treatment, but not all patients have good outcomes with this regimen. The addition of brentuximab vedotin (Adcetris), or its substitution for bleomycin, produces high complete response rates but with a moderate increase in toxicity, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic, Rochester, Minnesota. At the 19th International Symposium on Hodgkin Lymphoma, held recently in Cologne, Germany, Dr. Ansell discussed ways to improve upon ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). In an interview with The ASCO Post, Dr. Ansell provided some context for the study of brentuximab. “Over the years, there has been significant debate about what’s the best front-line treatment for advanced Hodgkin lym-

phoma. In Europe, they use escalated BEACOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone), a more intense regimen than ABVD, which is what is commonly used in North America,” Dr. Ansell noted.

BEACOPP vs ABVD A number of head-to-head comparisons have shown that escalated BEACOPP produces higher complete response rates and improved progression-free survival over ABVD, but this comes at the price of more infertility and hematologic toxicity as well as long-term toxicities, he pointed out. “For complete response and progression-free survival, BEACOPP has an edge, but toxicity is the problem,” Dr. Ansell said. The most recent studies, however, have suggested that these two regimens may have similar long-term outcomes when subsequent salvage therapy is also

included in the analysis. “At the end of the day, the roads seem to converge,” he said. With ABVD as the initial therapy, approximately 75% of advanced-stage Hodgkin lymphoma patients obtain a complete response, and the 5-year failure-free survival rate is 75%. “If you are in this 75% group, you can get away with less therapy and far less long-term toxicity,” Dr. Ansell noted.

Improving Upon ABVD A problem with routine acceptance of ABVD, he acknowledged, is that it is less successful in certain patient subgroups, including: • Elderly patients (> 60 years old), who have a 5-year failure-free survival rate of approximately 55% • Patients with stage III/IV disease, who have a 5-year failure-free survival rate of approximately 65% • Patients with an International Prognostic Score (IPS) of 3 to 7, who have a 5-year failure-free survival

rate of approximately 65% Much of the problem is the result of bleomycin-related toxicity. In a subset analysis of the recent E2496 trial of ABVD, 24% of older patients developed bleomycin-related lung toxicity and 18% died.1 Escalated BEACOPP is also not acceptable for patients over 60, creating a large population with an unmet need, Dr. Ansell emphasized. A number of modifications of ABVD have been attempted in an effort to make ABVD less toxic and more suitable for the subgroup of patients who are older, have poor performance status, are at high risk for progression, or have more advanced disease, but these approaches have been unsuccessful. They have included intensification of therapy (which proved too toxic to older patients), omission of dacarbazine (which reduced progression-free survival) and substitution of bleomycin and dacarbazine with gemcitabine continued on page 4

Addition of Novel Agents May Improve Outcomes With ABVD By Caroline Helwick

n North America, the standard front-line treatment for advanced Hodgkin lymphoma is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), but this regimen is not effective in all patient subsets. To improve upon the regimen’s efficacy, researchers are evaluating new combinations, said Stephen M. Ansell, MD, PhD, of The Mayo Clinic, Rochester, Minnesota, who described novel approaches in an interview with The ASCO Post. “Improved combinations should benefit not only young, fit patients but also the elderly or sicker patients with Hodgkin lymphoma,” he said.

Novel Agents The most promising strategy to improve upon ABVD comes in the form of novel agents, especially brentuximab vedotin (Adcetris), rituximab (Rituxan), and lenalidomide (Revlimid), recent studies suggest. According to Dr. Ansell, the strategy attracting the most interest is the use of brentuximab, either in combination with ABVD or substi-

tuting brentuximab for bleomycin in the regimen. At the recent 9th International Symposium on Hodgkin Lymphoma, Dr. Ansell discussed previously reported data showing

it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). The results suggest that the addi-

Improved combinations should benefit not only young, fit patients but also the elderly or sicker patients with Hodgkin lymphoma. —Stephen M. Ansell, MD, PhD

that this strategy achieved a 95% complete response rate (see accompanying report).1 Rituximab added to ABVD also looked promising in a trial of 78 patients, where the complete response rate was 93%, and the 5-year eventfree survival rate was 83%.2 Furthermore, the 5-year event-free survival rate for patients with an International Prognostic Score (IPS) of 0 to 2 was 88%, and for those with an IPS > 2,

tion of rituximab to ABVD is safe and has promising clinical activity in patients with advanced-stage Hodgkin lymphoma.

Further Investigations Another strategy being evaluated by the German Hodgkin Study Group (GHSG) is the addition of lenalidomide to ABVD. In a recent phase I/II study, the GHSG evaluated the benefit and safety of four to eight cycles of

AVD plus lenalidomide (5–35 mg/d), followed by radiotherapy, in 25 patients aged 60 to 76 years.3 “The data looked very encouraging, and the regimen was well tolerated, so more elderly patients should be able to receive it,” Dr. Ansell said. n References 1. Ansell SM, Connors JM, Park SI, et al: Front-line therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. 9th International Symposium on Hodgkin Lymphoma, Cologne, Germany. Abstract P005. Presented October 15, 2013. 2. Younes A, Oki Y, McLaughlin P, et al: Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood 119:41234128, 2012. 3. Böll B, Plutschow A, Fuchs M, et al: GHSH phase I/II trial of AVD-Rev (Adriamycin, vinblastine, dacarbazine and lenalidomide) for older Hodgkin lymphoma patients. 9th International Symposium on Hodgkin Lymphoma. Abstract T076. Presented October 14, 2013.

The ASCO Post | DECEMBER 1, 2013

PAGE 4

International Symposium on Hodgkin Lymphoma Hematology

Brentuximab and PET-Adapted Salvage May Eliminate Toxic Chemotherapy for Refractory Hodgkin Lymphoma By Caroline Helwick

elapsed and refractory transplant-eligible Hodgkin lymphoma patients who achieve complete responses after treatment with brentuximab vedotin (Adcetris) can often avoid more toxic salvage chemotherapy, according to investigators from Memorial Sloan-Kettering Cancer Center, New York. Positron-emission tomography (PET)-adapted sequential salvage therapy after treatment with brentuximab allowed 30% of patients to avoid chemotherapy with ICE (ifosfamide, carboplatin, etoposide) and proceed straight to transplant, said Alison J. Moskowitz, MD, a hematologist/ oncologist at Memorial Sloan-Kettering, who presented the study at the 9th International Symposium on Hodgkin Lymphoma in Cologne, Germany.1

Study Rationale The phase II study was based on the following rationale: Current salvage regimens such as ICE are quite toxic, but brentuximab is well tolerated and highly active in Hodgkin lymphoma in patients for whom autologous stem cell transplantation fails,

Brentuximab Plus ABVD continued from page 3

(which led to inferior outcomes). “You can shave 10% to 15% off your enthusiasm for ABVD based on these groups,” he commented.

Adding Brentuximab Perhaps the best way to modify ABVD is to add or substitute a novel agent, Dr. Ansell suggested. At the Cologne symposium, Dr. Ansell discussed the results from a phase I study of brentuximab by the Mayo Clinic, the British Columbia Cancer Research

and pretransplant PET normalization is a strong predictor of outcome following stem cell transplant. “We have previously shown that the outcome for patients with normal pretransplant PET is excellent,

incorporate brentuximab in salvage therapy with the goal of normalizing the PET. We hoped that by doing so we might be able to eliminate the more toxic chemotherapy, when patients normalize on brentuximab

We have seen that 30% of patients become PET-negative with brentuximab alone, but many patients do achieve a very good response after two cycles, and we believe that if they received a third cycle, they may become PET-negative. —Alison J. Moskowitz, MD

regardless of whether PET normalization is achieved following ICE therapy alone or ICE followed by additional non–cross-resistant chemotherapy. Due to its high efficacy and excellent tolerability in [autologous stem cell transplant] failures, we aimed to determine whether brentuximab could replace ICE salvage therapy or increase the rate of PET normalization through PET-adapted sequential administration with augmented ICE,” Dr. Moskowitz said. “In other words, our idea was to Centre, The University of Texas MD Anderson Cancer Center, and The University of North Carolina.2 The study evaluated brentuximab in addition to ABVD or as a substitute for bleomycin (AVD plus brentuximab). The substitution was made after the observation that adding brentuximab created more bleomycin toxicity. “In the second half of the study we eliminated the bleomycin, and the results were very encouraging,” Dr. Ansell told The ASCO Post. Complete responses after the conclusion of front-line therapy were achieved by 21 (95%) of the 22 patients

Brentuximab Vedotin for Advanced Hodgkin Lymphoma ■■ ABVD is a standard regimen in Hodgkin lymphoma but has a poor outcome for several subsets of patients.

■■ Adding brentuximab to ABVD, or substituting the drug for bleomycin in the ABVD regimen, yields complete response rates of 95% and the latter is well tolerated.

alone,” Dr. Moskowitz explained in an interview with The ASCO Post.

Weekly Dosing With Brentuximab The phase II study enrolled 46 patients with relapsed/refractory Hodgkin lymphoma. Patients received two cycles of weekly brentuximab given at 1.2 mg/kg followed by PET imaging. Patients who achieved normalization of PET (≤ Deauville 2) proceeded to stem cell transplant while those with PET scores receiving ABVD plus brentuximab and by 24 (96%) of the 25 receiving AVD plus brentuximab. Only one patient, who was receiving AVD with brentuximab, had disease progression. One patient in the ABVD/brentuximab cohort developed grade 5 pulmonary toxicity during treatment and was not evaluable.

ECHELON-1 “This was a very high response rate, and the addition of the drug was well tolerated, so we initiated the large randomized ECHELON-1 trial,” he said. ECHELON-1 is an international study enrolling more than 1,000 treatment-naive patients with stage IIA bulky or stage IIB–IV disease. Patients will be randomly assigned to two cycles of ABVD or AVD plus brentuximab, and upon response assessment based on Deauville score, they will either continue the protocol-assigned therapy for four additional cycles or

≥ Deauville 3 received two cycles of augmented ICE (ie, double doses of ifosphamide and etoposide). The primary endpoint was complete response rate after brentuximab with or without augmented ICE. Dr. Moskowitz noted that the weekly schedule is not commonly given, but phase I data have suggested responses might occur earlier with more intensive treatment.

High Response Rates Achieved The complete response rate was 80% after brentuximab (with or without ICE), and 30% of patients were able to avoid ICE salvage therapy, Dr. Moskowitz reported. “Of 40 evaluable patients, 36 have completed [autologous stem cell transplant], 3 will undergo [stem cell transplant] shortly, and one remains on treatment for persistent disease,” she said. Only eight patients did not achieve a complete response, and of these, two proceeded directly to autologous stem cell transplant (based on very good, though not complete, responses), five had PET-negative disease and received radiotherapy followed by stem cell transplant, and one received continued on page 10

switch to an alternative treatment. “If positive, this study will define the practice of front-line therapy in advanced Hodgkin lymphoma patients,” Dr. Ansell predicted. n

Disclosure: Dr. Ansell receives research funding from Seattle Genetics and is a member of the steering committee for the ECHELON-1 trial.

References 1. Evens AM, Hong F, Gordon LI, et al: The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: A comprehensive analysis from the North American intergroup trial E2496. Br J Haematol 161:76-86, 2013. 2. Ansell SM, Conors JM, Park SI, et al: Front-line therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. 9th International Symposium on Hodgkin Lymphoma. Abstract P005. Presented October 15, 2013.

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The ASCO Post | DECEMBER 1, 2013

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Quality Care Symposium Health-Care Policy

Innovative Payment Models continued from page 1

exempt from having considerably less money available to care for their patients than we have today.” Dr. Newcomer continued, “We’ll need to learn how to eliminate all the things we do that don’t add value to the care we deliver. In short, that means delivering the best possible outcome with the least amount of resources. In effect, health care is facing an impending crisis akin to the dot.com bubble or the mortgage collapse that threw us into recession. It’s coming, if we don’t change our culture.”

Where’s the Money Going? Dr. Newcomer, Senior Vice President of Oncology, Genetics and Women’s Health at UnitedHealthcare, used his payer experience to describe how oncology dollars are spent. “For cancer care at UnitedHealthcare, we spend about 24% of our budget on drugs, which are inflated at about 15% per year. Hospitals get more than half of the dollar, at about 54%. And physician fees make up the other 22%, the only sector of spending that is actually at negative inflation,” he said. He pointed to three current payment models designed to bring cost-reducing value into cancer care: pay for performance, bundling or episode payments, and capitation. “The concept of pay for performance is the most popular new payment model. Simply put, an out-

Brentuximab Plus ABVD continued from page 4

additional chemotherapy. Adverse events related to brentuximab included neuropathy and rash, which were primarily mild and manageable. Grade 2 neuropathy occurred in only 15% of patients, and grade 2/3 rash, which responded well to steroids, was observed in 18%.

Expansion Study The investigators have initiated an expansion study in which an additional 20 patients will receive weekly brentuximab for three cycles (not two, as in the initial protocol).

come goal is set and a bonus is paid to the hospitals or groups that participate. In oncology, that measure has been tied to adherence to guidelines,” he said. Dr. Newcomer briefly described episode payments, in which a fixed amount of money is given for a discrete medical episode. If the provider completes the course of treatment for less than the projected amount, he gets to keep the difference as a bonus. Capitation, rarely used in the United States, is where an organization takes full responsibility for the costs of its patient population and physicians are paid a fixed sum at regular intervals. This is essentially how health care has been covered in Canada’s universal health-care system, although some provinces are moving away from capitated budgets to episode payments.

Potential Barriers As with any innovation, developing and implementing a new payment model is fraught with challenges. “The first barrier is what I call the N problem. In other words, how do you get enough patients to measure the difference in outcomes between the established method and the new model? And that problem is based on the size of a medical group and the size of the payer,” said Dr. Newcomer. “Moreover, the average study takes 2 to 3 years to complete, and 3 years is a very long time before you get an indication of how you’re doing. Then there’s the question of comparing the results, which can get very confusing,” he said. He used a study from UnitedHealthcare “So far, we have seen that 30% of patients become PET-negative with brentuximab alone, but many patients do achieve a very good response after two cycles, and we believe that if they received a third

to illustrate his point. “A large group practice in a metro area instituted a pathways program, and we wanted to compare their outcomes to a cohort of breast, lung, and colorectal cancer patients we have in United’s database. When they put in their pathway, their costs declined and the control groups’ actually rose. It looked like a win for pathways,” said Dr. Newcomer. However, he explained, what looked like a win was based solely on a numeric average. “When we did the multivariate analysis—actually matching for stage and type of cancer—all the benefits went away. There was no cost-saving difference prepathways and no difference postguidelines. The point is that you need to use the same kind of rigor in a financial analysis that you use in a clinical trial,” said Dr. Newcomer. He used several more case studies looking at pathways, all of which faced the same barriers, such as long accrual time and funding.

Are We Measuring the Wrong Thing? “When you add up all the barriers to developing a new payment model, you come to realize that this is really hard stuff, it’s not easy to accomplish,” said Dr. Newcomer, adding, “Which is leading me to thinking a little differently than I would have a few years ago. I’m starting to wonder if we’re measuring the wrong thing as a payer.” He continued, “Instead of measuring physicians, perhaps we should be measuring chemotherapy regimens. In a large organization like UnitedHealthcycle, they may become PET-negative,” Dr. Moskowitz explained. PET-negative patients will proceed to stem cell transplant, while PET-positive patients will receive augmented ICE for two cycles. In a second PET

Brentuximab and PET-Adapted Salvage in Hodgkin Lymphoma ■■ Brentuximab vedotin, followed by PET-adapted sequential salvage therapy, allows 30% of transplant-eligible refractory Hodgkin lymphoma patients to avoid ICE-based chemotherapy.

■■ At the end of treatment, brentuximab vedotin followed by PET-adapted salvage therapy yielded complete responses in 80% of patients.

■■ Brentuximab is well tolerated.

care, in a couple of years we could literally have thousands of patients on each regimen for breast, colon, and lung cancer. That gives us the data to do good comparative effectiveness studies,” said Dr. Newcomer. He stressed that this method of measurement gives us the best, most cost-effective way to lower costs and eliminate underperforming regimens.

What Do We Do Now? “We can’t stop testing just because it’s hard. Clearly, based on the cost trend lines I opened this discussion with, we have a lot of work to do. We simply cannot afford to stay on the current course, and the better we get at doing the right clinical things for less money, the better the entire system will be,” said Dr. Newcomer. His parting message: “I don’t envision a future in which there will be more money in the health-care system. So we have to use the same rigor for financial measurement as we do in clinical trials. It’s not as simple as comparing last year’s cost with this year’s cost, and we’ll subtract the difference. In short, we’ll have to do the case mix adjustments and the statistical analysis to make sure that we know the results we’re looking at are real.” n

Disclosure: Dr. Newcomer is Senior Vice President of Oncology, Genetics and Women’s Health at UnitedHealthcare.

Reference 1. Newcomer L: Innovative payment models and measurement. 2013 Quality Care Symposium. Presented November 1, 2013.

assessment, those who are still PETpositive will receive further treatment while the PET-negative patients will undergo stem cell transplant. n

Disclosure: Research support provided by Seattle Genetics

was

Reference 1. Moskowitz AJ, Schoder H, Gerecitano J, et al: PET adapted sequential salvage therapy with brentuximab vedotin and augmented ICE for transplant eligible patients with relapsed and refractory Hodgkin lymphoma. 9th International Symposium on Hodgkin Lymphoma. Abstract T128. Presented October 15, 2013.

ASCOPost.com | DECEMBER 1, 2013

PAGE 11

European Cancer Congress Thoracic Oncology

Early Evidence Supports Novel ALK Inhibitor in Patients with Non–Small Cell Lung Cancer With Brain Metastases By Alice Goodman

dentifying ALK rearrangements as a cancer target in patients with lung cancer led to the development and FDA approval of crizotinib (Xalkori) to treat ALK-positive non–small cell lung cancer (NSCLC). Several secondgeneration ALK inhibitors are in development, and these agents appear to work in ALK-positive NSCLC, including brain metastasis. At the recent European Cancer Congress, a study was presented showing that a novel ALK/EGFR inhibitor called AP26113 had robust antitumor activity in crizotinib-resistant and crizotinib-naive NSCLC patients, including those with brain metastasis after crizotinib treatment. “Most if not all patients with NSCLC will become resistant to crizotinib, and half of those who are resistant have brain metastasis,” explained lead author D. Ross Camidge, MD, PhD, Associate Professor and Director of the Thoracic Oncology Clinical Program at University of Colorado, Denver.

Study Details The first-in-human phase I/II trial of AP26113 was a 3×3 dose escalation study in 30 to 60 patients with various advanced malignancies refractory to other therapies or with no available standard or curative therapy. There were five cohorts in phase II—four with NSCLC totaling 85 patients and another cohort of 20 patients with other ALK-positive tumors. In phase I, a range of 30 to 300 mg/d was explored, and the dose of 180 mg/d orally was selected for further study. AP26113 was generally well tolerated. Common adverse events of all grades were nausea (38%), fatigue (34%), and diarrhea (32%); 12% had elevated liver enzymes. Treatmentemergent grade 3 or higher adverse

The updated results of this ongoing phase I/II study show that AP26113 continues to exhibit antitumor activity in crizotinib-naive and crizotinibresistant NSCLC and is active in ALKpositive brain metastasis. —D. Ross Camidge, MD, PhD

events were reported in 2% to 4% across all dose levels, and included dyspnea, fatigue, diarrhea, hypoxia, and pneumonitis. Pulmonary events, which occurred early in 3/25 patients at the 180-mg/d level and seemed to be rarer at lower doses, were responsive to drug interruption, although resolution, despite continued dosing, was also reported. Future studies will employ a step-up approach, initiating the drug at 90 mg/d for 7 days before moving up to 180 mg/d. Tapered dose steroids were used to resolve symptoms over 1 week, and patients restarted the drug at 90 mg/d without further pulmonary symptoms, he said. Future studies will employ a step-up approach, initiating the drug at 90 mg/d for 7 days before moving up to 180 mg/d.

Marked Response Response was determined by serial computed tomography scans using RECIST criteria. An objective response was observed in 22 (65%) of 34 ALKpositive NSCLC patients. The response rate in patients previously treated with crizotinib was 61%; all three crizotinibnaive patients responded (100%), one with a complete response. Eight of 10 patients (80%) with preexisting CNS metastasis had radiographic evidence of regression, and ongoing improvements lasting more than 40 weeks were reported. In vitro, at 30- to 50-fold higher concentrations than those required to

Treating ALK-Positive Lung Cancer ■■ Preliminary study of a second-generation ALK inhibitor, AP26113, shows

robust activity in ALK-positive non–small cell lung cancer, including brain metastasis and tumors with the T790M mutation.

■■ This drug is one of several second-generation ALK inhibitors, all of which show activity in previously treated patients and in brain metastasis.

hit ALK, the drug also hits common activating and resistance mutations in EGFR. Of 12 patients with the T790M EGFR mutation who were evaluable for response, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before going on treatment.

“The data are immature,” Dr. Camidge acknowledged, “but 80% remain on therapy after 6 months, and we see a marked response in CNS metastases. The updated results of this ongoing phase I/II study show that AP26113 continues to exhibit antitumor activity in crizotinibnaive and crizotinib-resistant NSCLC and is active in ALK-positive brain metastasis, demonstrating responses of clinically meaningful duration.” n

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

Reference 1. Camidge DR, Bazhenova L, Salgia R, et al: 2013 European Cancer Congress. Abstract 3401. Presented September 28, 2013.

EXPERT POINT OF VIEW

ormal discussant of the AP26113 trial at the European Cancer Congress, Frances A. Shepherd, MD, FRCPC, Professor at the University of Toronto Faculty of Medicine and Scott Taylor Chair in Lung Cancer Research at the Princess Margaret Cancer Centre, Toronto, Canada, explained that ALK rearrangements do not represent a single mutation but many mutations. Even though about 60% of patients with ALK-positive non–small cell lung cancer

Future studies may require rebiopsy to determine exact mechanisms of resistance, and we may treat differently depending on what new mutations or other resistance mechanisms are identified. —Frances A. Shepherd, MD, FRCPC

(NSCLC) respond to crizotinib (Xalkori), by 2 years, 90% have had disease progression or died, suggesting that newer approaches are needed. It is not clear whether an ALK/EGFR inhibitor such as AP26113 will improve outcomes compared with crizotinib. Second-generation ALK inhibitors, including AP26113, LDK378, and ASP3026, all show responses in patients previously treated with crizotinib, and even in brain metastasis. “This is an attractive feature,” she noted. An important issue in this setting is how best to incorporate these newer drugs and how best to use them: sequentially or in combination. “Future studies may require rebiopsy to determine exact mechanisms of resistance, and we may treat differently depending on what new mutations or other resistance mechanisms are identified,” she commented. n Disclosure: Dr. Shepherd has served as a consultant or in an advisory role for Roche, Lilly, Biodesix, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Boehringer Ingelheim, and Recombio. She has stock ownership in Pfizer and Lilly. Dr. Shepherd has received honoraria from Roche, Lilly, and GlaxoSmithKline.

The ASCO Post | DECEMBER 1, 2013

PAGE 12

FDA Update

FDA Approves Ibrutinib for Mantle Cell Lymphoma

he U.S. Food and Drug Administration has approved ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma, a rare and aggressive form of non-Hodgkin lymphoma representing about 6% of all non-Hodgkin lymphoma cases in the United States. By the time mantle cell lymphoma is diagnosed, it usually has already spread to the lymph nodes, bone marrow, and other organs. Ibrutinib is intended for patients with mantle cell lymphoma who

the companies to expedite the drug’s development, review, and approval, reflecting the promise of the Breakthrough Therapy Designation program,” Dr. Pazdur said. Imbruvica is the second drug with breakthrough therapy designation to

receive FDA approval. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave the FDA the ability to designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer

a substantial improvement over available therapies for patients with serious or life-threatening diseases.

Accelerated Approval The FDA has approved ibrutinib under the agency’s accelerat-

What if you could help the immune system respond to cancer cells? PD-L1 expression helps tumor cells evade the immune system

The agency worked cooperatively with the companies to expedite [ibrutinib’s] development, review, and approval, reflecting the promise of the Breakthrough Therapy Designation program.

programmed death-ligand 1 (PD-L1), which binds to the PD-1 and B7.1 receptors on Tumor expression of

T cells, deactivates T-cell–mediated cytotoxicity. This inhibits the immune system and allows the tumor to continue to grow.1 Nearly all cancer types show increased expression of PD-L1.2

PD-1

Inactivated T cell

PD-L1

—Richard Pazdur, MD

have received at least one prior therapy. It works by inhibiting the enzyme needed by the cancer to multiply and spread. Ibrutinib is the third drug approved to treat mantle cell lymphoma, following the 2006 approval of bortezomib (Velcade) and lenalidomide (Revlimid) to treat the disease.

TCR

B7.1

MHC

Tumor cell

PD-L1

Breakthrough Therapy Designation “Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The agency worked cooperatively with

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307-314. 3. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129-1132.

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PAGE 13

FDA Update

ed approval program, which allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while the com-

pany conducts confirmatory clinical trials. The FDA also granted ibrutinib 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 orphan-product designation because the drug is intended to treat a rare disease.

Clinical Efficacy and Side Effect Profile Ibrutinib’s accelerated approval for mantle cell lymphoma is based on a study where 111 participants were given ibrutinib daily until their disease progressed or side effects became intolerable. Results showed an overall response rate of

nearly 66%. An improvement in survival or disease-related symptoms has not been established. The most common side effects reported in participants receiving ibrutinib are thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and decreased appetite. Other clinically significant side effects include bleeding, infections, kidney problems and the development of other types of cancers. n

FDA Drug Approvals, 2013 Blocking PD-L1 may restore the body’s adaptive immune response Genentech is investigating the strategy of inhibiting the interaction between tumor-expressed PD-L1 and its receptors on T cells; blocking this interaction may restore the body’s adaptive immune system to respond to cancer cells.1 Research is also under way to validate PD-L1 as a potential biomarker for cancer immunotherapy.3

Activated T cell

B7.1

TCR

MHC

Tumor cell death

PD-1

Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

• Ibrutinib (Imbruvica) for mantle cell lymphoma • Obinutuzumab (Gazyva) for chronic lymphocytic leukemia • Pertuzumab (Perjeta) for breast cancer • Paclitaxel protein-bound particles (Abraxane) for pancreatic adenocarcinoma • Afatinib (Gilotrif) for nonsmall cell lung cancer, with Therascreen EGFR RGQ PCR Kit (Qiagen) test • Denosumab (Xgeva) for giant cell tumor of bone • Lenalidomide (Revlimid) for mantle cell lymphoma • Trametinib (Mekinist) for melanoma • Dabrafenib (Tafinlar) for melanoma • Radium RA 223 dichloride (Xofigo injection) for prostate cancer bone metastases • Erlotinib (Tarceva) for nonsmall cell lung cancer, with Cobas EGFR Mutation Test • Ado-trastuzumab emtansine (Kadcyla) for breast cancer • Pomalidomicde (Pomalyst) for multiple myeloma • Doxorubicin hydrochloride liposome injection (generic Doxil Injection) for ovarian cancer • Bevacizumab (Avastin) for colorectal cancer

The ASCO Post | DECEMBER 1, 2013

PAGE 14

European Cancer Congress Melanoma

Metastatic Melanoma: Encouraging Data Keep Coming By Caroline Helwick

xcitement continues to build in the metastatic melanoma arena, as novel agents keep upping the ante for efficacy. The following news from the 2013 European Cancer Congress has added to the buzz.

New MEK Inhibitor In the phase IB BRIM7 study, cobimetinib, a novel MEK inhibitor, when combined with vemurafenib (Zelbo-

Grant McArthur, MD

raf), showed strong antitumor activity in melanoma patients not previously treated with a BRAF inhibitor, reported Grant McArthur, MD, of the Peter MacCallum Cancer Centre in Victoria, Australia.1 Acquired resistance to vemurafenib frequently results in MAPK reactivation through MEK. Combined MEK and BRAF inhibition can overcome or delay acquired resistance, and for this reason, combinations of BRAF and MEK inhibitors are of interest. BRIM7 evaluated the safety, tolerability, dose-limiting toxicities, and maximum tolerated dose of cobimetinib, and its efficacy in 65 patients who had disease progression on vemurafenib and 63 patients not previously treated with a BRAF inhibitor. Patients in the dose-escalation portion received vemurafenib at 720 mg or 960 mg twice daily, continuously, and cobimetinib at 60, 80, or 100 mg daily for 14 days on, 14 days off (14/14); 21 days on and 7 days off (21/7), or continuously. Two dose levels were expanded: vemurafenib at 720 mg and 960 mg twice daily plus cobimetinib at 60 mg/d (21/7). Overall, 53 of 63 BRAF inhibitor– naive patients responded to this combination, with an objective response rate of 85%, including 6 (10%) complete responses. Another 8 (13%) had stable disease. Only 2 patients (3%) had disease progression while on the combination. “Most responses occurred by the

first tumor assessment,” he said, “and median progression-free survival was not reached, despite a median followup time of 10 months.” Of 61 patients whose disease had progressed on vemurafenib, 9 (15%) responded and 26 (43%) had stable disease on the combination. After 3 months’ follow-up, median progression-free survival was 2.8 months. “Antitumor activity of the combination in ‘vemurafenib progressors’ is modest, and investigations are ongoing to identify a subpopulation that may benefit from cobimetinib plus vemurafenib after progression on vemurafenib monotherapy,” he said. Four patients experienced doselimiting toxicities, including grade 3 fatigue, QT prolongation, mucositis, and arthralgia. The most common treatment-related adverse events of grade ≥ 3, regardless of treatment assignment, were non-acneiform rash, diarrhea, photosensitivity, and liver abnormalities (7%–19%). Grade ≥ 3 squamous cell carcinoma/keratoacanthoma was observed in four patients (6%). Diarrhea was common, affecting 81% of the BRAF inhibitor–naive patients, with grade ≥ 3 noted in 8%.

caution is necessary.” Dr. Larkin added, “I would distinguish toxicity that is generally easier to manage, such as diarrhea, from that which is more difficult to manage, such as fever/chills and skin toxicity,” he said. “The main differences appear to be the incidence of fever/chills with dabrafenib/trametinib and skin toxicity with vemurafenib/cobimetinib.” With vemurafenib/cobimetinib, acneiform rash (all grades) was observed in 33%, non-acneiform rash in 89%, and photosensitivity and sunburn in 70%; grade ≥ 3 side effects were seen in 3%, 13%, and 0%, respectively. The vemurafenib/cobimetinib combination is currently being evaluated in a phase III trial.

Nivolumab Plus Ipilimumab Mario Sznol, MD, of Yale University School of Medicine, New Haven, presented early results for combined

sponses,” Dr. Sznol noted. “Objective responses were observed in patients irrespective of absolute lymphocyte count or baseline tumor PD-L1 expression.” Clinical activity of nivolumab/ipilimumab was much less pronounced in the sequential cohort, of whom 20% responded, and 13% had ≥ 80% tumor reduction at 12 weeks. “Based on these results, a phase III trial is open to investigate the efficacy of concurrent nivolumab plus ipilimumab vs nivolumab and vs ipilimumab in patients with advanced melanoma.

Long-Term Survival With Ipilimumab In the largest survival analysis of the CTLA-4 monoclonal antibody to date, melanoma patients receiving ipilimumab in phase II and III clinical trials had a median overall survival of 11.4 months, and 22% of patients were alive at 3 years, reported F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston.3 The pooled analysis included 1,861 patients from 12 prospective and retrospective trials, and an additional 2,985 patients who were treated with ipilim-

Toxicity Differences vs Other Regimens Commenting on the cobimetinib/ vemurafenib combination, James Larkin, MD, PhD, of the Royal Marsden Hospital in London, said, “There is encouraging efficacy in the BRAF inhibitor–naive population and limited

James Larkin, MD, PhD

efficacy in BRAF inhibitor–pretreated population,” but beyond this observation, “further comments on efficacy are not possible,” he said. He did note that there appear to be some differences between the cobimetinib/vemurafenib regimen and the regimen of dabrafenib (Tafinlar)/ trametinib (Mekinist) in terms of toxicity, “though the data are very early, so

Mario Sznol, MD

immunotherapy with the anti–PD-1 agent nivolumab and ipilimumab (Yervoy), reporting the combination to have “a manageable safety profile and clinical activity that appears distinct from published monotherapy data.”2 In the phase I study of 86 stage III and IV melanoma patients, 53 received concurrent treatment and 33 received sequential treatment, first with nivolumab and then with ipilimumab. In the concurrent cohorts, 38% had received prior treatment, whereas 100 % of the sequential cohort was previously treated. The overall response rate for the concurrent cohort was 40%, and 31% of patients had ≥ 80% tumor reduction at 12 weeks. Overall survival at 1 year was 82%. “In the concurrent cohort, for the 21 patients with confirmed objective responses, responses ranged from 6-plus to 72-plus weeks at the time of data analyses. A total of 19 of the 21 responding patients had ongoing re-

F. Stephen Hodi, MD

umab 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.

T-VEC Oncolytic Virus A phase III trial of talimogene laherparepvec (T-VEC) met its primary and secondary endpoints, producing durable responses in 16% of melanoma patients who received the injections, reported Howard Kaufman, MD, of Rush University Medical Center, Chicago.4 “T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III trial,” he said. T-VEC is a novel oncolytic immucontinued on page 16

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The ASCO Post | DECEMBER 1, 2013

PAGE 16

European Cancer Congress Metastatic Melanoma

Novel Treatments for Metastatic Melanoma

continued from page 14

notherapy derived from the herpes simplex virus type-1, designed to selectively replicate within tumors and produce endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance locoregional and systemic antitumor immune responses. The phase III OPTiM study included 436 patients with stage III/IV melanoma randomly assigned 2:1 to T-

Howard Kaufman, MD

VEC or recombinant GM-CSF (Leukine), which was injected into cutaneous, subcutaneous, or nodal lesions every 2 weeks for 24 weeks. There were no limits on number of lesions injected per visit; precedence was given to new lesions, then larger lesions. The primary endpoint, durable response rate per endpoint assessment committee, was met, as were

■■ In the phase IB BRIM7 trial, the investigational MEK inhibitor cobimetinib,

when given with vemurafenib, produced responses in 85% of patients not previously treated with a BRAF inhibitor.

■■ In a phase I trial, dual immunotherapy with the anti–PD-1 antibody

nivolumab plus ipilimumab (given concurrently) led to a 40% response rate in patients previously untreated with a BRAF inhibitor.

■■ Long-term survival was validated with ipilimumab, based on phase II and III trial data that showed 22% of patients alive at 3 years.

■■ In a phase III trial, talimogene laherparepvec (T-VEC), an oncolytic

immunotherapy, produced durable responses in 16.3% of the T-VEC group vs 2.1% of patients receiving GM-CSF, for an unadjusted odds ratio of 8.9 (P < .0001).

secondary endpoints. Durable responses (≥ 6 months) were observed in 16.3% of the T-VEC group vs 2.1% of the GM-CSF group, for an unadjusted odds ratio of 8.9 (P < .0001). Objective response rates were 26.4% and 5.7%, respectively. About half the responders exhibited interval progression before achieving a response. The interim analysis found median overall survival to be 23.3 months with T-VEC and 19.0 months with GM-CSF—a nonsignificant trend favoring the vaccine (hazard ratio [HR] = 0.79; P = .07). At 3 years, overall survival rates were 40.6% and 27.8%, respectively. “T-VEC significantly improved

both durable response rates and objective response rates vs GM-CSF in patients with unresected stage IIIB/ IV melanoma with limited visceral disease, both by investigator and independent central review, Dr. Kaufman reported. “Responses occurred as early as 1.2 months and as late as 16.9 months, with a median of 4.1 months after the first dose. Median duration of response was not reached in the T-VEC arm, with the majority of responders still in response as of the last tumor assessment.” n Disclosure: Drs. McArthur, Larkin, Sznol, Hodi, and Kaufman reported no potential conflicts of interest.

References 1. McArthur G, Gonzalez R, Paulick A, et al: Vemurafenib and MEK inhibitor, cobimetinib (GDC-0973) in advanced BRAF V600-mutated melanoma (BRIM7): Dose-escalation and expansion results of a phase IB study. 2013 European Cancer Congress. Abstract 3703. Presented September 28, 2013. 2. Sznol M, Callahan MK, Kluger H, et al: Combined nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab in the treatment of advanced melanoma patients: Safety and clinical activity. 2013 European Cancer Congress. Abstract 3734. Presented September 30, 2013. 3. 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. 4. Kaufman H, Andtbacka RHIU, Harrington K, et al: Secondary endpoints from OPTiM: A multicenter, randomized phase 3 trial of talimogene laherparepvec vs GM-CSF for the treatment of unresected stage IIIB/C and IV melanoma. 2013 European Cancer Congress. Abstract 3733. Presented September 30, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Lee N. Newcomer, MD, MHA, on Innovative Payment Models see page 1

Frances A. Shepherd, MD, FRCPC, on Novel ALK Inhibitor see page 11

Andrew H. Ko, MD, on Metastatic Pancreatic Cancer see page 37

David H. Ilson, MD, PhD, on Gastric Cancer see page 42

Theresa Woodruff, PhD, on Fertility Options in Patients With Cancer see page 47

Brad Kahl, MD, on Radiotherapy in DLBCL see page 67

Visit The ASCO Post online at ASCOPost.com

Eileen M. O’Reilly, MD, on Adjuvant Therapy for Pancreatic Cancer see page 31

Roisin M. Connolly, MB, BCh, and Vered Stearns, MD, on Neoadjuvant Therapy for Breast Cancer see page 86

ASCOPost.com | DECEMBER 1, 2013

PAGE 17

European Cancer Congress Gastrointestinal Oncology

In Operable Rectal Cancer, No Support Found for Adjuvant Chemotherapy By Caroline Helwick

or patients with operable rectal cancer, there is no clear role for adjuvant chemotherapy, according to an analysis of the PROCTOR and SCRIPT trials from the Dutch Colorectal Cancer Group. The findings were presented by Anne J. Breugom, MD, of Leiden University Medical Center in the Netherlands, at the 2013 European Cancer Congress.1

PROCTOR/SCRIPT was a multicenter randomized trial of 470 patients with stage II or III rectal adenocarcinoma, 238 of whom received adjuvant chemotherapy and 232 underwent observation. Patients

included 177 from PROCTOR, randomly assigned to observation or to postoperative chemotherapy (fluorouracil [5-FU]/leucovorin) with or without preoperative radiotherapy followed by total mesorec-

tal excision, and 292 from SCRIPT, randomly assigned to observation or to postoperative chemotherapy (capecitabine) after preoperative radiotherapy or chemoradiation folcontinued on page 18

Anne J. Breugom, MD

“The role of adjuvant chemotherapy after preoperative radiotherapy or chemoradiation followed by total mesorectal excision surgery is still under discussion,” she said.

PROCTOR/SCRIPT Study A Cochrane review2 showed a significant reduction in the risk of death (17%) among patients undergoing postoperative chemotherapy as compared to the observation arm and a 25% reduction in the risk of disease recurrence. However, many of those trials did not evaluate contemporary strategies, Dr. Breugom pointed out. “The aim of this study, which includes data from both the PROCTOR study and the SCRIPT study, is to investigate the additional value of postoperative chemotherapy with respect to overall survival and the risk of disease recurrence,” she said.

Adjuvant Chemotherapy After Rectal Surgery ■■ Adjuvant chemotherapy does

not have a clear role in patients with rectal cancer who have undergone total mesorectal excision.

■■ In the PROCTOR and SCRIPT

trial cohorts, disease-free and overall survival rates were similar for patients who received adjuvant chemotherapy compared to the observation arm.

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The ASCO Post | DECEMBER 1, 2013

PAGE 18

European Cancer Congress Gastrointestinal Oncology

TP53 Status May Predict Benefit From Cetuximab in Locally Advanced Rectal Cancer By Caroline Helwick

n a retrospective analysis of the randomized phase II EXPERT-C trial, TP53 emerged as a strong, independent predictive biomarker for the benefit of cetuximab (Eribitux) in MRI-defined high-risk, locally advanced rectal cancer, according to Francesco Sclafani, MD, of The Royal Marsden NHS Foundation Trust in the United Kingdom, who presented the data at the European Cancer Congress in Amsterdam.1 Among patients with TP53 wildtype tumors, the addition of cetuximab to neoadjuvant chemotherapy and chemoradiotherapy significantly improved 5-year progression-free survival by 24% and 5-year overall survival by 25%, Dr. Sclafani reported. “TP53 mutational status was not prognostic but emerged as an independent predictive factor for cetuximab

benefit,” Dr. Sclafani said. “The benefit from cetuximab in patients with TP53 wild-type tumors was independent of RAS and did not appear to be related to its radiosensitizing effect,” he said. After neoadjuvant chemoradiotherapy or short-course radiotherapy and surgery, systemic relapses occur in 25% to 30% of locally advanced rectal cancer cases. Alternative multimodality strategies have largely failed to provide a significant advantage over standard chemoradiotherapy, and there are no validated prognostic or predictive biomarkers to guide optimal treatment selection. If the current study results can be validated, TP53 status could prove to be a valuable biomarker, Dr. Sclafani suggested. The European multicenter EXPERTC trial evaluated the benefit of cetuximab when given in association with neoadjuvant capecitabine/oxaliplatin followed by chemoradiotherapy prior to

Adjuvant Chemotherapy in Rectal Cancer

No Rationale for Adjuvant Chemotherapy

continued from page 17

“Currently, there is no indication to administer adjuvant chemotherapy as a standard treatment,” Dr. Breugom concluded. She acknowledged the study was underpowered, which reflected poor accrual. “If there is an effect after long-term follow-up, this effect will be small,” she predicted. A meta-analysis is currently in progress that will include the 470 patients of PROCTOR/SCRIPT, the 113 patients from CHRONICLE (who are receiving capecitabine /oxaliplatin), and 634 from an Italian study evaluating adjuvant 5FU/leucovorin). She added that identification of molecular biomarkers in tumor material from the study’s patients could offer prognostic or predictive information about the benefits of adjuvant chemotherapy in rectal cancer patient subgroups. n

Independent Predictive Factor

lowed by total mesorectal excision. Approximately three-quarters of the patients had stage III disease, and essentially all had R0 resections. More than 82% had received neoadjuvant radiotherapy, and approximately 13% received chemoradiation. Three-quarters of patients completed their chemotherapy.

Outcomes Similar on All Endpoints At a median follow-up of 4 years, overall survival was not significantly different between the arms (hazard ratio [HR] = 0.878, P = .527). Five-year overall survival was 74.4% with chemotherapy and 75.9% with observation. Ten-year survival was 65.1% and 55.8%, respectively, but at 10 years, fewer than 15 patients were at risk in either group, she said. Disease-free survival was also similar (HR = 0.835, P = .247): 67.4% for chemotherapy and 66.1% for observation, at 3 years; 62.0% and 58.4% at 5 years; and 55.6% and 43.5% at 10 years. There was a hint that tumors ≥ 10 cm may benefit from chemotherapy (HR = 0.552; P = .028), but overall a disease-free survival advantage was lacking, she emphasized.

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

References 1. Breugom AJ, van den Broek CBM, van Gijn W, et al: The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemoradiation followed by TME-surgery: The PROCTOR/

EXPERT-C Trial Results ■■ TP53 wild-type status in high-risk, locally advanced rectal cancer was

predictive of benefit from cetuximab in a retrospective analysis of the EXPERT-C trial.

■■ Patients with wild-type TP53 tumors receiving cetuximab had a 5-year overall survival rate of 93%.

■■ Patients with TP53 mutations derived no benefit from cetuximab, vs capecitabine/oxaliplatin alone.

total mesorectal excision in MRI-defined high-risk patients. In the KRAS/BRAF wild-type population, no significant improvement in progression-free survival or overall survival was observed in patients with the addition of cetuximab after a median follow-up of 64 months.

Determining TP53 Status TP53 is a tumor-suppressor gene involved in the control of cell proliferation and response to DNA damage, and mu-

tations in TP53 occur in about 50% of colorectal cancers. Preclinical evidence has suggested an association between p53 function and the activity of agents targeting the epidermal growth factor receptor. The EXPERT-C investigators retrospectively analyzed 144 samples for TP53 mutations (exons 4–9) and their association with outcomes, identifying TP53 mutations (primarily missense) in 75 (52.1%) patients. After a median continued on page 23

EXPERT POINT OF VIEW

avid Sebag-Montefiore, MD, Professor of Clinical Oncology at the University of Leeds and St. James’s Institute of Oncology in the United Kingdom, was the invited discussant of the PROCTOR/SCRIPT study. He noted that in this 470-patient study, the disease-free and overall survival hazard ratios were less favorable than were observed in the Cochrane analysis of approximately 4,000 patients. “The study lacks power, despite considerable ef- David Sebag-Montefiore, MD fort. This was an extremely difficult trial to perform, and I congratulate the investigators for their perseverance,” he said.

Inconsistent Guidelines “SCRIPT/PROCTOR findings do not change current practice, and they will reinforce existing views and guidelines,” he suggested, though he noted that various European guidelines are not completely consistent. The [European Society for Medical Oncology (ESMO)] guidelines say that adjuvant chemotherapy can be provided for stage III and high-risk stage II disease, while the [National Institute for Health and Care Excellence (NICE)] guidelines advise clinicians to consider it for these patients. The Dutch guidelines, on the other hand, state that there is no indication for adjuvant chemotherapy in rectal cancer. The findings will, however, contribute to the ongoing current meta-analysis, he added, and will provide a valuable dataset for prognostic and predictive biomarker studies. n Disclosure: Dr. Sebag-Montefiore reported no potential conflicts of interest.

SCRIPT study. 2013 European Cancer Congress. Abstract 1. Presented September 28, 2013. 2. Petersen SH, Harling H, Kirkeby

LT, et al: Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 3:CD004078, 2012.

Announcing a

NEW INDICATION Neoadjuvant treatment of HER2+ breast cancer Indication PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated for: • Treatment of metastatic breast cancer in combination with Herceptin® (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 • Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival Limitations of Use: —The safety of PERJETA as a part of a doxorubicin-containing regimen has not been established —The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. 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 WARNINGS and the following pages for additional Important Safety Information.

Significant improvement in pathologic complete response (pCR) with PERJETA-based neoadjuvant therapy NeoSphere trial overview1,2* • Randomized, multicenter trial in 417 patients with HER2+ breast cancer (T2-4d) • Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen-receptor (ER) or progesterone-receptor (PR) positivity • Primary endpoint: pathologic complete response (pCR) in the breast (ypT0/is) —FDA-preferred endpoint: pCR in breast and nodes (ypT0/is ypN0), (reported below) *The NeoSphere trial is referred to as “Study 2” in the PERJETA full Prescribing Information.

NeoSphere trial results1 PERJETA + Herceptin + docetaxel (n=107)

Herceptin + docetaxel (n=107)

PERJETA + Herceptin (n=107)

PERJETA + docetaxel (n=96)

pCR (ypT0/is ypN0), n (%)

42 (39.3%)

23 (21.5%)

12 (11.2%)

17 (17.7%)

[95% CI]

[30.0, 49.2]

[14.1, 30.5]

[5.9, 18.8]

[10.7, 26.8]

P=0.0223 (vs Herceptin + docetaxel)

P=0.0018 (vs PERJETA + Herceptin + docetaxel)

P=0.0063 (vs Herceptin + docetaxel)

Important Safety Information Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • 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 —Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Additional Important Safety Information PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. Left Ventricular Dysfunction (LVD) • In Study 1, for patients with MBC, left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • In Study 2, for patients receiving neoadjuvant treatment, the incidence of LVSD was higher in PERJETA-treated groups than in the trastuzumab and docetaxel group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination

with trastuzumab and docetaxel. In the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel • In Study 3, for patients receiving neoadjuvant treatment, in the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, in 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and in 10.5% of patients treated with PERJETA in combination with TCH • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting and every 6 weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% 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 LVEF has not improved or has declined further Infusion-Associated Reactions • PERJETA has been associated with infusion reactions • In Study 1, 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 Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0) Grades 1-2 • 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

TRYPHAENA trial overview1,3† • Phase II, randomized, multicenter trial in 225 patients with HER2+ breast cancer (T2-4d) • Patients were randomized to 1 of 3 neoadjuvant regimens —PERJETA + TCH —FEC followed by PERJETA + Herceptin + docetaxel —PERJETA + Herceptin + FEC followed by PERJETA + Herceptin + docetaxel • Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PR positivity • Primary endpoint: cardiac safety in the neoadjuvant treatment period —Incidence of left ventricular dysfunction (LVD) and symptomatic left ventricular dysfunction (LVSD) (congestive heart failure, CHF) • Secondary endpoints included pCR in breast and nodes (ypT0/is ypN0) †

The TRYPHAENA trial is referred to as “Study 3” in the PERJETA full Prescribing Information.

TRYPHAENA trial results1 • Incidence of LVD • Incidence of symptomatic LVSD (CHF) • pCR (breast and nodes) —PERJETA + TCH: 2.6% —PERJETA + TCH: 0.0% —PERJETA + TCH: 63.6% —FEC/PERJETA + Herceptin + —FEC/PERJETA + Herceptin + —FEC/PERJETA + Herceptin + docetaxel: 4.0% docetaxel: 2.7% docetaxel: 54.7% —PERJETA + Herceptin + FEC/PERJETA —PERJETA + Herceptin + FEC/PERJETA —PERJETA + Herceptin + FEC/PERJETA + Herceptin + docetaxel: 5.6% + Herceptin + docetaxel: 0.0% + Herceptin + docetaxel: 56.2% FEC = 5-fluorouracil, epirubicin, and cyclophosphamide; TCH = docetaxel + carboplatin + Herceptin.

Hypersensitivity Reactions/Anaphylaxis • In Study 1, 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 Grades 3-4 reactions was 2.0% and 2.5%, respectively, according to NCI-CTCAE (version 3) • In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1 • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions Metastatic Breast Cancer • 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) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue Neoadjuvant Treatment of Breast Cancer • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea

• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting • The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. September 2013. 2. Gianni L, Pienkowski T, Im Y-H, 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. 2012;13:25-32. 3. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284.

PER0002063200

Printed in USA.

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PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) 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. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) 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. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 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 Study 1, for patients with MBC, 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 placebo-treated 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. In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated

with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. 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 in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% 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)].

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. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. 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 in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. 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 v3.0 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%).

5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 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 PERJETAtreated 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 PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related 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)].

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

Placebo PERJETA + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 0.0 Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome

5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, 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 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 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)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. 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 using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally 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.

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: 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)

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-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, 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%).

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical

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Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2. Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 10.3 0.0 2.8 0.0 0.9 0.0 Edema peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory 12.1 0.9 8.4 0.9 1.9 0.0 Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

25.5 1.1 16.0 2.1 5.3 0.0 25.5 0.0 8.5

0.0

67.0 0.0 28.7 1.1 54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 0.0 8.5

0.0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3 Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0 Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0 Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 0.0

Body System/ Adverse Reactions

Eye disorders Lacrimation increased 12.5 Psychiatric disorders Insomnia 11.1 Investigations ALT increased 6.9

In contrast, for patients receiving cetuximab, TP53 status was important, as patients with TP53 wild-type tumors on this treatment arm had a statistically significant improvement in progression-free survival and overall survival, Dr. Sclafani reported. While 5-year overall survival was 67% in patients with TP53-mutant tumors, regardless of treatment (cetuximab or not), the survival rate rose to 92.7% for patients with TP53 wildtype tumors assigned to cetuximab, compared to 67.5% for patients with TP53 wild-type tumors treated without cetuximab (HR = 0.16; P = .02). The test for interaction was significant (P = .036), and the multivariate analysis of treatment by TP53 interaction carried a P value of .038, he reported.

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

0.0

5.3

0.0

7.9

0.0

13.3

0.0

21.1

0.0

2.7

0.0

10.5

3.9

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 20fold 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.

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/ Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/ Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm) Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in Study 1 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

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 Study 1, 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. 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 1-800690-6720 [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.

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

EXPERT POINT OF VIEW

continued from page 18

Cetuximab Benefit

PTZ + T + D Ptz + T + FEC following FEC PERJETA + TCH followed by n=75 n=76 Ptz + T + D Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

TP53 Status follow-up of 65 months in the group of patients treated without cetuximab, no differences in progression-free survival (hazard ratio [HR] = 1.23; P = .59) or overall survival (HR = .97; P = .94) were observed between patients with TP53 wild-type tumors and those with TP53 mutant tumors. Five-year progression-free survival was 61% to 65%, and overall survival was approximately 67%, regardless of TP53 status.

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.

Table 3 Summary of Adverse Reactions ≥ 10% in Study 3 (Cont)

ric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, the formal discussant of the late-breaking abstract, noted there is strong rationale for studying TP53 status in relation to rectal cancer outcomes, but he felt the findings of EXPERT-C could not yet be considered practice-changing. “TP53, a tumor-suppressor gene, has a possible role in predicting response to radiotherapy, and, based on preclinical studies, a role in modulating response to therapies targeting the epidermal growth factor receptor,” he said. “But there have been very few, very small studies evaluating the predictive role of TP53 in metastatic colorectal cancer, and they

have not been conclusive.” EXPERT-C is an “innovative and important conceptual study” conducted by expert centers. It is “well designed” and of “high quality,” he noted, “but it is not without its weaknesses.”

Study Limitations The small, retrospective study has a sample size that is inadequate for validating biomarkers, there was a relatively high degree of discordance for TP53 status between the biopsy and resection samples, and the use of capecitabine/oxaliplatin as a backbone for cetuximab (Erbitux) is questionable, based on the MRC COIN trial, which did not confirm a benefit for the addition of cetuximab to oxalipl-

The benefit—an overall 84% reduction in risk—was observed in all patients with TP53 wild-type tumors, including KRAS wild-type or mutant, KRAS/NRAS wild-type or mutant, KRAS/NRAS/BRAF wild-type or mutant, or KRAS/NRAS/BRAF/PIK3CA wild-type or mutant. Similarly, 5-year progression-free survival in patients with TP53 wild-type tumors was significantly increased with the addition

of cetuximab, from 65.0% to 89.3% (HR = 0.23; P = .02). Tumor response after neoadjuvant chemotherapy or chemoradiotherapy, however, did not differ significantly according to TP53 status or treatment assignment, though patients with TP53 wild-type tumors had numerically higher response rates to capecitabine/ oxaliplatin plus cetuximab, vs capecitabine/oxaliplatin alone. n

Cosmos Communications K

atin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer,1 Dr. Van Cutsem pointed out. “Nevertheless, it is very important to evaluate the potential role of TP53 in nonmetastatic patients,” he acknowledged. “This is an interesting, hypothesis-generating study that may be the basis for further translational studies,” he said. n

Disclosure: Dr. Van Cutsem has received research funding paid to his institution by Merck Serono.

Reference 1. Maughan TS, Adams RA, Smith CG, et al: Results of the randomized phase 3 MRC COIN trial. Lancet 377:2103-2114, 2011.

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

Reference 1. Sclafani F, Gonzalez D, Cunningham D, et al: TP53 status may predict benefit from cetuximab in high-risk, locally advanced rectal cancer: Results of the EXPERT-C trial. 2013 European Cancer Congress. Abstract 7. Presented September 29, 2013.

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European Cancer Congress Gastrointestinal Oncology

Time to Think Beyond KRAS in Metastatic Colorectal Cancer By Caroline Helwick

ric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, told attendees at the 2013 European Cancer Congress that in the management of metastatic colorectal cancer, it is time to expand KRAS testing to include more rare mutations. Until recently, KRAS status was the only validated predictive biomarker in this disease, with KRASmutated tumors demonstrating resistance to inhibitors of the epidermal growth factor receptor (EGFR). But while KRAS wild-type patients are likely to respond to anti-EGFR agents, response is not universal, leading to the quest to find reasons for this lack of response. “One of the next challenges has been to fine-tune, in this KRAS wild-type population, which patients will be responders and which will not,” Dr. Van Cutsem said.

rates rose to 36% in the KRAS exon 2 wild-type selected population and to 41% in patients with no mutations at all in KRAS, BRAF, NRAS, and PIK3CA exon 20, Dr. Van Cutsem reported.

Hotspots of Mutations “Traditional KRAS testing identifies mutations in codons 12 and 13 of exon 2. We have now learned that in KRAS wild-type patients, around 15% to 20% have other, more rare mutations that are also very important,” he said. These include NRAS mutations in exons 2, 3, and 4, and BRAF mu-

ons 3 and 4, NRAS exons 2, 3, and 4, and BRAF exon 15, outcomes became much more favorable with panitumumab, including a statistically significant survival benefit for “all-RAS” wild-type patients. Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 vs 7.9 months with FOLFOX4 alone (hazard ratio [HR] = 0.72; P = .004). Overall survival was 26.0 vs 20.2 months, respectively (HR = 0.78; P = .04). In the original analysis, the hazard ratios were 0.80 for progression-free survival and 0.83 for overall survival.

The bottom line message from PRIME and FIRE-3, is that we should expand the testing of KRAS. —Eric Van Cutsem, MD, PhD

European Consortium The European Consortium evaluated the role of various genetic markers in a large cohort of chemorefractory metastatic colorectal cancer patients treated with cetuximab plus irinotecan. In 773 primary tumor samples, they aimed to identify KRAS, BRAF, NRAS and PIK3CA mutations and relate these to clinical endpoints.1 They found that approximately 40% of tumors harbored a KRAS mutation, 14% had a PIK3CA mutation, 5% had a BRAF mutation, and about 3% had an NRAS mutation. In KRAS wild-type patients, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wildtypes. PIK3CA exon 20 mutations also conferred worse outcomes. The authors concluded that if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutational status gives additional predictive information for lack of benefit to cetuximab (Erbitux). When the study population was not enriched at all by mutational status, the response rate to cetuximab/irinotecan was 24%. With KRAS mutational analysis, response

tations in exon 15. These mutations outside of KRAS exon 2 are now being tested in several studies, including PRIME and PEAK, for panitumumab (Vectibix), and FIRE-3 for cetuximab (see related article on page 26). “Today, we should not talk about testing for ‘KRAS’ but about ‘RAS’ testing,” he said. “These mutations are relatively rare, but very relevant.”

RAS Analyses in Panitumumab Studies Recent analyses from the major anti-EGFR trials are supporting the findings made by the European Consortium. An extensive RAS analysis from the PRIME study, which evaluated FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin) with and without panitumumab, was published this year in The New England Journal of Medicine.2 In the initial analysis, only a nonsignificant trend for a survival benefit was observed with the addition of the EGFR inhibitor in KRAS exon 2 wild-type patients. In a prospective-retrospective analysis, with longer follow-up and mutational analysis for KRAS ex-

A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations, and these were associated with inferior progression-free survival and overall survival with panitumumabFOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor, according to Douillard and colleagues. “Aligning this recent concept of extending KRAS exon 2 testing to RAS, and looking at patients with all-RAS wild-type tumors, we can see the hazard ratio for panitumumab becomes more favorable [for overall survival, HR improved from 0.83 to 0.78]. For progressionfree survival, there is a larger benefit when we exclude the more rare mutations,” Dr. Van Cutsem noted. Even more importantly, he added, panitumumab in patients with wild-type KRAS exon 2 and mutations in the other RAS genes was potentially harmful in PRIME. Hazard ratios in this arm were 1.29 (P = .31) for overall survival and 1.28 (P = .32) for progression-free survival. “This is the reason why we rec-

ommend using these drugs only with RAS wild-type patients, and we are not just talking anymore about KRAS wild-type. These are important data showing and endorsing the concept that we should test for the other RAS mutations,” he emphasized. In the PICCOLO study, which evaluated the effect of adding panitumumab to irinotecan, patients with any mutation fared worse than those with all-RAS wildtype tumors.3 Similar findings were made in a recent study by Dr. Van Cutsem and colleagues using nextgeneration sequencing on 299 samples from a KRAS wild-type subset receiving panitumumab.4 They found mutation rates of 45% for KRAS, 5% for NRAS, 7% for BRAF, 9% for PIK3CA, along with a number of other aberrations. Among KRAS wild-type patients, only 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. Among wild-type KRAS patients, a treatment effect for progressionfree survival favoring panitumumab occurred in patients with wild-type NRAS (HR = 0.39) and wild-type BRAF (HR = 0.37) but not mutant NRAS (HR = 1.94). For BRAF, mutation status was not predictive, he said.

RAS Analyses in Cetuximab Trials In a retrospective pooled analysis from the CRYSTAL and OPUS trials, KRAS wild-type patients who had BRAF mutations had a poor prognosis, regardless of receiving chemotherapy or chemotherapy plus cetuximab: 9.9 and 14.1 months, respectively.5 “These BRAF-mutated patients really have worse survival than BRAF wild-type patients in the various trials, regardless of treatment,” he said. “The conclusion is that BRAF is prognostic, but not predictive.” A preplanned subset analysis of the FIRE-3 trial, which evaluated cetuximab vs bevacizumab (Avastin) given with FOLFIRI (5-FU, leucovorin, irinotecan), also accentuates the importance of thinking

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PAGE 25

European Cancer Congress beyond KRAS. While progressionfree survival (a secondary endpoint) was similar between the arms in the KRAS exon 2 wild-type population, in the all-RAS wild-type analysis, a difference emerged favoring bevacizumab. The overall survival analysis (another secondary endpoint), however, favored cetuximab, which makes these findings “open to discussion,” he added. “We are awaiting other head-tohead trials with overall survival as the primary endpoint,” he said, “but meanwhile, the bottom line message for me, from PRIME and FIRE-3, is that we should expand the testing of KRAS.” n

ysis. Lancet Oncol 11:753-762, 2010. 2. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013. 3. Seymour MT, Brown SR, Middleton G, et al: Panitumumab and irinotecan versus irinotecan alone for patients

with KRAS wild-type, fluorouracilresistant advanced colorectal cancer (PICCOLO): A prospectively stratified randomised trial. Lancet Oncol 14:749-759, 2013. 4. Peeters M, Oliner KS, Parker A, et al: Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III

study of metastatic colorectal cancer. Clin Cancer Res 19:1902-1912, 2013. 5. Bokemeyer C, Van Cutsem E, Rougier P, et al: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48:1466-1475, 2012.

Disclosure: Dr. Van Cutsem has received research funding paid to his institution by Merck Serono.

References 1. De Roock W, Claes B, Bernasconi D, et al: Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium anal-

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The ASCO Post | DECEMBER 1, 2013

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European Cancer Congress Gastrointestinal Oncology

Cetuximab Confers Survival Benefit in All-RAS Wild-Type Colorectal Tumors By Caroline Helwick

he FIRE-3 study compared the two epidermal growth factor receptor (EGFR) antibodies, on top of chemotherapy, in the first-line treatment of metastatic colorectal cancer. A preplanned analysis of KRAS wild-type patients without RAS mutations, ie, “all-RAS wild-type,” showed overall survival to be significantly longer with cetuximab (Erbitux) than with bevacizumab (Avastin).

ness of this secondary endpoint has been debated. The mutational analysis presented at the 2013 European Cancer Congress found overall survival with FOLFIRI/cetuximab to be “markedly superior” to that achieved with FOLFIRI/bevacizumab—a gain of 7.5 months (P = .011), reported Volker Heinemann, MD, PhD, Professor of Medical Oncology at the University of Munich in Germany.2 No differential benefit was observed when patients with RAS-mutant tumors were treated with FOLFIRI plus cetuximab as compared to FOLFIRI plus bevacizumab. “The exclusion of patients with RAS mutations identifies a population that is more likely to benefit from cetuximab. Upfront determination of RAS mutation status appears highly recommendable Volker Heinemann, MD, PhD Josep Tabernero, MD in patients with metastatic disease,” Dr. Heinemann said. The RAS category includes both New Mutations Identified KRAS and NRAS genes. The so-called The preplanned analysis presented all-RAS wild-type tumors are those at the European Cancer Congress lacking mutations not only in KRAS examined the effect of various muexon 2 but in other KRAS exons and tations within the KRAS wild-type also NRAS. (exon 2) population, of whom 15% Key Endpoints were found to harbor mutations beFIRE-3 compared FOLFIRI (fluoyond the customary KRAS exon 2 rouracil, leucovorin, irinotecan) plus mutations. These included mutations cetuximab to FOLFIRI plus bevain KRAS (exon 3 [codon 59/61], exon 4 [codon 117/146]), NRAS (exon cizumab as first-line treatment for 2 [codon 12/13], exon 3 [codon metastatic colorectal cancer. In the 59/61], exon 4 [codon 117/146]), primary analysis, the two regimens and BRAF (V600E). were comparable in terms of objective The analysis involved 342 RAS response rate, which was the primary wild-type patients and 178 RAS muendpoint, and progression-free surtant patients, which included the vival, a secondary endpoint. Overall 113 with mutations in KRAS exon 2 survival, however, which also was a mutant plus 65 with newly identified secondary endpoint, was 3.7 months RAS mutations. longer (P = .017) in the FOLFIRI/ RAS wild-type patients had a mecetuximab arm.1 Since approximately 40% of patients crossed over to the dian overall survival of 33.1 months other treatment arm, the meaningfulwith FOLFIRI plus cetuximab, vs

FIRE-3 Subanalysis in All-RAS Wild-Type Patients ■■ In a subanalysis of the FIRE-3 trial, which compared cetuximab vs

bevacizumab with a FOLFIRI backbone, patients with all-RAS wild-type metastatic colorectal tumors had improved survival with cetuximab.

■■ Median overall survival time was 7.5 months longer with cetuximab, but

only in patients with no RAS mutations, including all KRAS and NRAS exons.

■■ Progression-free survival, however, was not improved with cetuximab, vs bevacizumab. Patients with RAS-mutant tumors had longer progressionfree survival with bevacizumab.

25.6 months with FOLFIRI plus bevacizumab, a statistically significant difference of 7.5 months (hazard ratio [HR] = 0.70; P = .011). In RAS-mutant carriers, however, no difference was observed between the regimens: Median overall survival was 16.4 months and 20.6 months, respectively (HR = 1.20; P = .57). In the RAS wild-type patients, there was also no difference between the arms in median progression-free survival, which was approximately 10 months with either treatment (P = .54). Interestingly, for patients with RAS-mutated tumors, median progression-free survival was longer in the opposite arm—12.2 months with bevacizumab vs 6.1 months with cetuximab (P = .004). Response rates within both the RAS wild-type and RAS-mutant patients were similar between the arms.

Surprising Findings Commenting on the study, Josep Tabernero, MD, Director of Vall d’Hebron Institute of Oncology in Barcelona, Spain, said that the findings should not change practice right now, especially considering that the other key endpoints were not significantly different between the treatments. “It is difficult to understand how a treatment that does not increase response rate and progression-free survival in the first-line setting has a

big impact on overall survival. This is something surprising in the field of cancer,” he said. “It is difficult to compare these regimens when we don’t completely understand what is happening in latter lines—especially which treatments patients received in the second- and third-line setting. We hope that the upcoming results of the CALGB-80405 study will provide more light in this important setting” n

Disclosure: Dr. Tabernero is a consultant for Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, and Celgene. He also received honoraria from Amgen, Merck KGaA, Novartis, Roche, and Sanofi, for presentations.

References 1. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013. 2. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.

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The ASCO Post | DECEMBER 1, 2013

PAGE 28

Quality Care Symposium Issues in Oncology

Two Studies Highlight Communication Challenges Facing Medical Oncology By Ronald Piana

n one study presented at ASCO’s second annual Quality Care Symposium in San Diego, patients receiving chemotherapy with palliative care intent were at high risk of side-effect– related hospitalization, which defeats the clinical purpose and adds preventable costs to health care.1 “There is an increasing use of palliative chemotherapy. If risks of toxicity

be hospitalized. The most common cancers among patients who required hospitalization were gastrointestinal (36%) and lung (32%), followed by breast cancer (14%). The chemotherapies were also broadly distributed, with platinum-based regimens being the most commonly used (50%), followed by taxanes (27%), fluorouracil (25%), and camptothecins (19%).

There is an increasing use of palliative chemotherapy. If risks of toxicity of that chemotherapy are underappreciated or misunderstood, the goals of palliative care are undermined. —Ankit J. Kansagra, MD

This study raises important questions for oncologists regarding shared-decision conversations, and why they objectively could be important. —Christine M. Bestvina, MD

of that chemotherapy are underappreciated or misunderstood, the goals of palliative care are undermined,” said lead author Ankit J. Kansagra, MD, a hematology/oncology fellow at Tufts University School of Medicine, Boston.

Nested Case-Control Study Dr. Kansagra and his associates conducted a nested case-control study of adult cancer patients at North Shore Medical Center in Salem, Massachusetts, who received chemotherapy between January 2003 and December 2011. Of the 6,850 adult patients who received chemotherapy, 2,559 (37.3%) had the therapy delivered with palliative intent. Of that group, 230 patients (9%) required treatment-associated hospitalization; 199 of those cases were included in the research. The study also included two matched controls for each case, amounting to 398 patients in the control group who underwent the same lines of therapy but did not need to

Communication Distortions Panel discussant for the session, Robert D. Siegel, MD, of Hartford Hospital in Hartford, Connecticut, noted, “The administration of palliative chemotherapy cannot and should not happen in a void.” He stressed that there is evidence that the intent of palliative chemotherapy is often misconstrued by patients. “However, in this setting there is often a miscommunication in which the patient believes that the palliative treatment is also being given to cure the cancer,” he stressed. Dr. Siegel added, “There are clearly some communication distortions at

Robert D. Siegel, MD

the time of diagnosis leading to the determination of what therapy to deliver and when to deliver it. Identifying the issues underlying this miscommunication would result in better informed patients capable of better assessing the risks and benefits of palliative chemotherapy. This might be the most effective method of diminishing chemotherapy-related hospitalizations. Prior studies have suggested that early introduction of palliative care discussions can lessen patient misconceptions regarding the intent of care.” Dr. Kansagra concluded, “We’ve found that patients receiving palliative chemotherapy are at increased risk of hospitalization. Identifying predictors of severe toxicity may help caregivers and patients make informed decisions about their therapeutic options.”

Study Two: Drug Costs Affect Patient Decisions As a general rule, most insurance plans cover cancer drugs used by Medicare beneficiaries. However, according to results of a cross-sectional survey presented at the ASCO Quality Care Symposium, many of today’s high-cost cancer drugs impose outof-pocket costs on cancer patients that affect their treatment decisions.2 Lead author of this second study Christine M. Bestvina, MD, a resident at Duke University Medical Center in Durham, North Carolina, said, “Nonadherence to medications and chemotherapy because of high copays is common. Those who had previously discussed out-of-pocket costs of cancer care with their oncologists were more likely to report medication non-adherence. This study raises important questions for oncologists regarding shared-decision conversations, and why they objectively could be important. Dr. Bestvina asked the audience, “Can we use discussions of costs in the clinic as potentially a red flag for medication nonadherence when that patient leaves the office?” The survey included 300 insured respondents diagnosed with solid tumors. The most common malignancy was colorectal; 78% of the group had advanced-stage cancer. The median income of the survey group was about

$60,000 per year; 52 (17%) reported a state of “high” or “overwhelming” financial distress. A total of 56 patients (19%) had talked to their oncologists about out-of-pocket costs, and 52% of the patients expressed in the survey a desire to have cost discussions with their physicians. Nonadherence parameters included skipping doses, taking less medication than prescribed in order to make the prescription last longer, or simply not filling the prescription because of cost. A total of 80 patients reported nonadherence to their cancer medications. Of those patients who skipped their medications, 7% skipped chemotherapy doses. Of those who took less than prescribed, 15% did so with a chemotherapy drug. Ten patients reported not filling a chemotherapy prescription because of cost.

Study Limitation Dr. Bestvina commented that the trial was limited by the self-reporting of nonadherence, as well as by the lack of information on temporality. “A better understanding of the timeline, content, and quality of the doctor-patient discussion about the costs of cancer treatments is important,” said Dr. Bestvina. Given the current school of thought that “more information and shared decision-making leads to better outcomes for patients,” it is noteworthy that the connection between more information about out-of-pocket costs is associated with treatment nonadherence, a poorer outcome. Dr. Bestvina said that her study indicated that more work is needed in this difficult-to-navigate clinical scenario. n

Disclosure: Drs. Kansagra, Siegel, and Bestvina reported no potential conflicts of interest.

References 1. Kansagra AJ, Brooks G, Gao JH, et al: Risk factors for the development of chemotherapy-related hospitalization (CRH) in patients treated with palliative intent: Results of a 9-year nested case control study. 2013 Quality Care Symposium. Abstract 3. Presented November 1, 2013. 2. Bestvina CM, Zullig LL, Rushing C, et al: Patient-oncologist cost communication, financial distress, and medication adherence. 2013 Quality Care Symposium. Abstract 2. Presented November 2, 2013.

ASCOPost.com | DECEMBER 1, 2013

PAGE 29

Quality Care Symposium Standardized Approach Improves Palliative Care Services and Outcomes By Caroline Helwick

tandardized criteria for initiating palliative care consultations can substantially improve the care of patients with advanced solid tumors, according to research from Mount Sinai School of Medicine, New York, led by Kerin Adelson, MD, Coordinator for Ambulatory Oncology Quality for the Tisch Cancer Institute.1

Pilot Program At a press briefing in advance of the 2013 ASCO Quality Care Symposium, Dr. Adelson described the 3-month pilot program, which evaluated whether the use of standardized criteria could improve palliative care services and outcomes. Prior to the study, no guidelines were available for identifying which patients with advanced solid tumors most warranted palliative care consultation, she said. “Despite a top-rated palliative care division at Mount Sinai, our solid tumor division utilized palliative care and hospice less than other medical centers. We hypothesized that implementing standardized criteria for palliative care consultation would improve these metrics,” she said.

Criteria Developed From Literature and Guidelines Dr. Adelson and her team developed criteria based on extensive literature review and discussions with oncologists and palliative care specialists. The criteria stipulate that palliative care consultation is warranted for patients with any of the following: stage IV solid tumor, stage III pancreatic or lung cancer, hospitalization within the prior 30 days, prolonged hospitalization (> 7 days), and uncontrolled symptoms, including pain, nausea, shortness of breath, delirium, and psychological distress.

Standardization Leads to Multiple Improvements Over 3 months, 68 patients met the criteria for consultation, and their outcomes were compared to 51 similar patients seen in the 6 weeks prior to intervention (preintervention group). Palliative care consultations increased from 41% to 82%, 30-day readmission rates dropped from 36% to 17%, and use of hospice services rose 14% to 25%, Dr. Adelson reported. Comparing the pilot group’s out-

comes to the aggregate University Health System Consortium data from the previous year, the researchers showed that standardization reduced 30-day readmission rates from 21.7% to 13.5%, and improved the mortality

index from 1.35 to 0.59. “Formalizing criteria for a palliative care consult was easy to implement, highly effective, and led to improvements in multiple quality measures,” Dr. Adelson said. n

Reference 1. Adelson K, et al: Standardized criteria for required palliative care consultation on the solid tumor oncology service. 2013 Quality Care Symposium. Abstract 37. Presented November 1, 2013.

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)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

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

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 | DECEMBER 1, 2013

PAGE 30

Quality Care Symposium Survivorship

Benefits and Controversies in Survivorship Care Plans By Ronald Piana

ince the Institute of Medicine’s (IOM’s) 2005 report, From Cancer Patient to Cancer Survivor: Lost in Translation,1 survivorship plans have received growing attention. In short, a survivorship care plan is the record of a patient’s cancer history and recommendations for follow-up care. At ASCO’s recent Quality Care Symposium, the pros and cons of survivorship plans were debated.2

PRO POSITION Patricia A. Ganz, MD, UCLA Schools of Medicine and Public Health, Los Angeles “For many decades, hospitals have required doctors to prepare a discharge summary for their patients in order to communicate with the outpatient physician what happened during the patient’s hospital stay. It often summarizes lengthy and complex stays,” said Dr. Ganz, adding, “This summary also informs the patient of what care and medications are planned post discharge, so they and their caregivers can plan accordingly.” Dr. Ganz explained that the patient may have been too ill to remember details of the hospital stay and could still be sick at the time of discharge. “Quite frankly, there were no clinical trials to test

Neglected Phase of Cancer Care She then referenced the IOM’s 2005 report, which found that survivorship is a neglected phase of the cancer care trajectory, and there are few guidelines dealing with follow-up care. “The report also found that many survivors are unaware of the late effects of their cancer treatment, so they have no follow-up plan that might help diminish some of the risks they’ll encounter in the future,” said Dr. Ganz, adding that the report also stated that cancer should be viewed as a chronic disease where we focus on prevention, surveillance, intervention, and coordination of care. She continued, “There have been several examples of implementing survivorship care plans into clinical practice—for instance, the ASCO breast cancer registry pilot, in which 20 oncology practices participated in an effort to prospectively create a treatment plan and summary. The study was initiated to see if you could report on quality measures using a treatment and summary care plan. There was some initial grumbling about cost, but most of the providers felt that the summary care plan helped improve communication with patients,” said Dr. Ganz. In another recent study in the Journal of Oncology Practice, a nurse and

[Survivorship] plans help coordination and adherence to patient follow-up and many other important outcome factors for the patient. The time is now for survivorship care plans. —Patricia A. Ganz, MD

the value of care summaries; it evolved over time and became an accredited part of hospital procedures simply because it makes common sense,” said Dr. Ganz. She emphasized that poor communication during the handoff from hospital to outpatient can lead to unnecessary readmissions. “Cancer is different from most chronic diseases. It is incredibly complex, lasting months to years. The treatment is also complex, multimodal, and multidisciplinary. The drugs are highly toxic and expensive, and the treatment is often poorly coordinated in the outpatient setting,” said Dr. Ganz.

social worker were able to successfully deliver treatment summaries and care plans at a cost that was reimbursed, and they identified important patient needs that increased satisfaction with care. “There’s a lot of back and forth about how to do a survivorship care plan, but I really don’t think there’s one way to approach it. We need to start somewhere because we do know that communication with patients can help coordination and adherence to followup. So we cannot let the perfect be the enemy of the good. The time is now for survivorship care plans,” concluded Dr. Ganz.

CON POSITION Eva Grunfeld, MD, DPhil, FCFP, Ontario Institute for Cancer Research and University of Toronto, Canada. Dr. Grunfeld said that she supports the concept of survivorship care plans, noting that she was an early adopter, publishing the first trial evaluating survivorship care plans, the results of which were used to frame her position. “I’m going to focus on the con as controversies rather than the con

“The final controversy is determining whether the complex needs of cancer survivors, who have multiple chronic conditions, are met by survivorship care plans, and will they improve continuity of care,” said Dr. Grunfeld. She referenced a population-based study of survivorship care plans conducted in Ontario that found shortcomings in both addressing the complex needs of survivors and in improving continuity of care.

We need to refine our approach and be able to determine the patients most in need of these plans, and we must be able to link needs to services to give full value to these instruments. —Eva Grunfeld, MD, DPhil, FCFP

as against,” said Dr. Grunfeld, adding, “For instance, several reviews in the literature have found a huge variation in the elements included in survivorship care plans.” In addition, she noted a controversy over variation in determining when to provide the survivorship care plan. “The IOM report originally recommended that the care plan should be started at the end of treatment, while ASCO suggests that it should be an ongoing document, and the UK National Survivorship Initiative recommends beginning it at time of diagnosis,” said Dr. Grunfeld. She continued, “Similarly, there is a huge variation in the format. It could be a face-to-face discussion with a provider, a paper document, or be done electronically. But the most important controversy is determining how to measure the plan’s benefit. We’re an evidence-based culture—we want to know what outcomes are most relevant and who they will benefit,” she said.

Cost-Effectiveness Threshold Dr. Grunfeld commented that while initiating a survivorship care plan is comparatively inexpensive, her study found that in many instances the plans did not meet the statistical cost-effectiveness threshold. “And although most cancer organizations have recommended that survivorship care plans become standard practice, there are many implementation challenges that need to be overcome before that happens,” she said.

“I agree with Dr. Ganz that the time for personalized survivorship care plans has arrived. But when you think about policymakers, managers, and oncology providers who have to deal with the costs and opportunities in an evidence-based environment, I think the value of survivorship care plans is undecided at this point. We need to refine our approach and be able to determine the patients most in need of these plans. And we must be able to link needs to services to give full value to these instruments,” Dr. Grunfeld said.

Conclusions The message distilled from pro and con discussions is that survivorship care plans could be an important part of the continuum of cancer care. But before being fully embraced as standard care, we need to refine the design, implementation, and timing of plans. And as Dr. Grunfeld concluded, in order to make these plans valuable and cost-effective instruments, we need to link needs to services. n

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

References 1. Hewitt M, Greenfield S, Stovall E (eds): From Cancer Patient to Cancer Survivor: Lost in Translation. Bethesda, Maryland, National Academies Press, 2005. 2. Ganz P, Grunfeld E: Survivorship care plans: 2013 Quality Care Symposium. Presented November 2, 2013.

ASCOPost.com | DECEMBER 1, 2013

PAGE 31

Journal Spotlight Gastrointestinal Oncology

Adjuvant Gemcitabine Improves Long-Term Survival in Patients With Resected Pancreatic Cancer By Matthew Stenger

n initial report from the phase III Charité Onkologie (CONKO) 001 trial of adjuvant gemcitabine vs observation in patients with completely resected pancreas cancer showed that gemcitabine treatment was associated with a significant prolongation of disease-free survival.1 As reported in JAMA by Helmut Oettle, MD, PhD, of Charité-Universitätsmedizin Berlin, and colleagues, 11-year follow-up in this trial has shown that adjuvant gemcitabine is associated with improved long-term disease-free survival and overall survival.2

in September 2012. Patients were stratified for tumor stage, nodal status, and resection status. The primary endpoint was diseasefree survival, and secondary endpoints included overall survival, defined as

Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival.

Study Details In this multicenter open-label trial, 354 German and Austrian patients with macroscopically completely removed pancreatic cancer were randomly assigned to receive gemcitabine treatment at 1 g/m2 on days 1, 8, and 15 every 4 weeks for 6 months (n = 179) or observation alone (n = 175). Enrollment occurred between July 1998 and December 2004, and follow-up ended

tus (median, 80 in both), sex (59% and 56% men), primary tumor stage (T2 in 10% in both, T3 in 82% and 83%), nodal status (N0 in 29% and 27%, N1 in 70% and 71%), resection status (R0 in 81% and 85%, R1 in 19% and 15%),

—Helmut Oettle, MD, PhD, and colleagues

the time from date of randomization to death. The majority of patients had T3, N1 disease prior to surgery and had undergone an R0 resection. The gemcitabine and observation groups were generally well matched for age (median, 62 years in both), Karnofsky performance sta-

grade (G2 in 58% and 55%, G3 in 35% and 38%), and histology (adenocarcinoma in 98% and 96%).

Disease-Free Survival Median follow-up was 136 months. As reported in the initial trial publication, median disease-free survival was

13.4 months in the gemcitabine group vs 6.7 months in the observation group (hazard ratio [HR] = 0.55, P < .001). At 5 and 10 years, disease-free survival rates were 16.6% vs 14.3% and 7.0% vs 5.8%, respectively. On multivariate analysis including age, sex, Karnofsky performance status, primary tumor stage, nodal status, and resection status, the effect of gemcitabine treatment remained significant (HR = 0.54, P < .001). Other significant factors were T stage (HR = 1.60, P = .007, for T3-4 vs T1-2) and nodal status (HR = 1.82, P < .001, for N+ vs N0). The effect of gemcitabine was consistent across all stratification subgroups, with heterogeneity tests showing no treatment by subgroup interaction except for a borderline significant interaction reflecting a low hazard ratio in the small subgroup of patients with microscopic residual disease. Hazard ratios were 0.50 (95% confidence interval [CI] = 0.26–0.95) for T1-2 and 0.56 (95% CI = 0.44– continued on page 35

Long-Term CONKO-001 Results: Adjuvant Therapy Improves Survival By Eileen M. O’Reilly, MD

rom 12% to 15% of the approximately 45,000 patients diagnosed with pancreas adenocarcinoma undergo a potentially curative resection each year in North America, translating into roughly 5,000 to 7,000 patients who are candidates for adjuvant therapy. About 80% of these patients will relapse and succumb to their disease with a median survival with adjuvant therapy now approaching 2 years. While the absolute benefit of adjuvant therapy for resected pancreas adenocarcinoma remains a subject of debate, and while there is clear need for improvement, there is no longer any debate that adjuvant therapy improves survival—it clearly does!

Earlier Trials The original historical precedent for adjuvant therapy for resected pancreas adenocarcinoma dates back Dr. O’Reilly is a gastrointestinal medical oncologist at Memorial Sloan-Kettering Cancer Center, New York.

over 25 years to the results of a small phase III trial by the Gastrointestinal Tumor Study Group (GITSG) trial, which showed a benefit to adjuvant fluorouracil (5-FU)-based chemoradiation and subsequent systemic 5-FU over observation.1 A subsequent series of trials from the European Study Group for Pan-

systemic therapy—in this case, bolus 5-FU and leucovorin given on days 1 to 5 monthly for 6 months—improved overall survival over observation in the adjuvant setting. The other main conclusion from the ESPAC-1 trial was that adjuvant chemoradiation not only did not offer any survival benefit, but may have led to inferior outcomes,

Adjuvant therapy for pancreas adenocarcinoma works, with a magnitude of risk reduction similar to the benefit observed for adjuvant therapy in other solid tumor malignancies. —Eileen M. O’Reilly, MD

creatic Cancer (ESPAC) investigators have contributed much to the field. The initial ESPAC-1 trial, reported in 2004,2 provided a clear signal in an adequately powered randomized trial that

possibly in part by delaying systemic therapy. These latter conclusions have been heavily challenged, reflecting concerns regarding the complex ESPAC-1

statistical design, use of older-style split-course radiation, and limited bolus 5-FU exposure, along with other quality control concerns related to surgery, radiation, and chemotherapy. Nonetheless, the notion that adjuvant chemoradiation does not add benefit in the adjuvant setting has been embraced by the non-U.S. pancreatic community, and over the past decade, adjuvant systemic therapy alone has increasingly become a standard option in most parts of the world.

CONKO-001 Study More recently, the initial report of the CONKO-001 study in 20073 and the results of the ESPAC-3 trial4 have firmly entrenched the value of systemic adjuvant therapy for resected pancreas cancer. Specifically, the ESPAC-3 trial compared bolus 5-FU and leucovorin to gemcitabine and concluded that the two systemic options are essentially equivalent. However, the toxicity profile favored continued on page 35

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. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

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

What truly matters to you in 2nd-line mRCC?

EVIDENCE In the phase 3, head-to-head study of exclusively 2nd-line patients with mRCC...

INLYTA was the 1st agent to demonstrate

SUPERIOR EFFICACY to sorafenib

Primary endpoint: PFS HR=0.67 (95% CI: 0.54, 0.81; P<.0001)

6.7

months

4.7

months

median PFS

INLYTA

sorafenib

(n=361)

(n=362)

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily ) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2

95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

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.

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(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. 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) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

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%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (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

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

Hematology Hemoglobin decreased 320 35 <1 316 52 4 Lymphocytes (absolute) decreased 317 33 3 309 36 4 Platelets decreased 312 15 <1 310 14 0 White blood cells decreased 320 11 0 315 16 <1 Chemistry Creatinine increased 336 55 0 318 41 <1 Bicarbonate decreased 314 44 <1 291 43 0 Hypocalcemia 336 39 1 319 59 2 ALP increased 336 30 1 319 34 1 Hyperglycemia 336 28 2 319 23 2 Lipase increased 338 27 5 319 46 15 Amylase increased 338 25 2 319 33 2 ALT increased 331 22 <1 313 22 2 AST increased 331 20 <1 311 25 1 Hypernatremia 338 17 1 319 13 1 Hypoalbuminemia 337 15 <1 319 18 1 Hyperkalemia 333 15 3 314 10 3 Hypoglycemia 336 11 <1 319 8 <1 Hyponatremia 338 13 4 319 11 2 Hypophosphatemia 336 13 2 318 49 16 a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase © 2013 Pfizer Inc.

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) and hypercalcemia (6% for INLYTA versus 2% for sorafenib). 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 September 2013 References: 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. 2. Data on file. Pfizer Inc, New York, NY. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

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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 coadministered, 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 [see Adverse Reactions]. 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. 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 μU/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

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Gemcitabine in Pancreatic Cancer continued from page 31

0.71) for T3-4 subgroups (P = .76 for heterogeneity), 0.57 (95% CI = 0.36– 0.89) for N0 and 0.53 (95% CI = 0.40– 0.68) for N1 subgroups (P = .77 for heterogeneity), and 0.59 (95% CI = 0.46–0.76) for R0 and 0.33 (95% CI = 0.19–0.58) for R1 subgroups (P = .06 for heterogeneity).

Overall Survival As noted by the investigators, since there was a high number of relapses within the first year of the study and since gemcitabine-based therapy was the standard therapy in patients with relapse after resection, the study can be seen as a comparison of immediate vs delayed postoperative therapy with gemcitabine with regard to overall survival. Median overall survival was 22.8 months in the gemcitabine group vs 20.2 months in the observation group (HR = 0.76, P = .01). Overall

Eileen M. O’Reilly, MD, on CONKO-001 continued from page 31

gemcitabine over bolus “Mayo Clinic–style” 5-FU and leucovorin. The now updated and mature survival results from the CONKO-001 trial, reported by Oettle et al in JAMA5 and reviewed in this issue of The ASCO Post, provide long-term outcome data for patients with resected pancreas adenocarcinoma who received gemcitabine adjuvant therapy compared to placebo in the setting of a well-designed contemporary trial. The results provide concrete support for adjuvant gemcitabine, with a doubling in median disease-free survival (13.4 vs 6.7 months) and improved overall survival for gemcitabine vs placebo (hazard ratio = 0.76, 95% confidence interval = 061–0.95, P = .01), along with improved 5-year and 10-year overall survival for the treated group.

Current Options Where do these collective data leave us in 2013? First, adjuvant systemic therapy should be recommended to all patients with resected pancreas adenocarcinoma who have a reasonable postoperative recovery. There are almost no patients in whom adjuvant therapy should not be considered, except perhaps a small subset of patients with resected intraductal papillary mucinous

survival rates at 5 and 10 years were 20.7% vs 12.2% and 10.4% vs 7.7%, respectively. On multivariate analysis including age, sex, Karnofsky performance status, primary tumor stage, nodal status, and resection status, the effect of gemcitabine treatment remained significant (HR = 0.78, P = .03). Other significant factors were T stage (HR =

tent effects across stratification subgroups, with testing for heterogeneity showing no significant treatment by subgroup interactions. Hazard ratios were 0.58 (95% CI = 0.30–1.10) for T1-2 and 0.78 (0.61–0.99) for T3-4 subgroups (P = .39 for heterogeneity), 0.63 (95% CI = 0.40–0.97) for N0 and 0.81 (95% CI = 0.63– 1.06) for N1 subgroups (P = .31 for

Role of Gemcitabine in Pancreatic Cancer ■■ Adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall and disease-free survival among patients with macroscopic complete removal of pancreatic cancer. ■■ The effect of gemcitabine on overall survival was consistent across T stage, nodal status, and resection status subgroups. 1.68, P = .003, for T3-4 vs T1-2) and nodal status (HR = 1.59, P < .001, for N+ vs N0), with age being borderline significant (HR = 1.24, P = .06, for ≥ 65 vs < 65 years). Subgroup analysis showed consis-

heterogeneity), and 0.76 (95% CI = 0.60–0.98) for R0 and 0.66 (95% CI = 0.39–1.13) for R1 subgroups (P = .63 for heterogeneity). The investigators concluded: “Among patients with macroscopic

neoplasia with a small amount of invasive disease, where the utility of adjuvant therapy has not been rigorously studied; in this setting, decisions should be made on a case-by-case basis. Second, either systemic therapy alone with gemcitabine (or 5-FU) or along with adjuvant chemoradiation are acceptable options. Third, the role of adjuvant chemoradiation following resection of pancreas adenocarcinoma remains very much an unanswered question without prospective modern era data to support using or not using such an approach. Opinion

ting following gemcitabine-based therapy. This study incorporates modern principles of chemoradiation delivery, including real-time quality assurance measures. The RTOG 0848 trial has enrolled about one-third of planned patients, so results are not likely to accrue until later this decade.

Looking Ahead Major questions in the adjuvant setting going forward are whether adding a second drug to gemcitabine adds benefit and whether non–gemcitabine-based regimens have a role,

It is hoped that some of the improved outcomes that have been observed in the treatment of metastatic pancreas cancer will translate to the adjuvant setting. is heated in both directions. Several large single-institution retrospective data sets indicate a benefit to adjuvant chemoradiation with improved survival and improved locoregional tumor control over surgery alone. The current ongoing Radiation Therapy Oncology Group (RTOG) 0848 study is designed to provide a definitive answer to the value of chemoradiation in the adjuvant set-

along with further study of neoadjuvant therapy. ESPAC-4 is examining the addition of capecitabine to gemcitabine. A soon-to-open adjuvant study will evaluate albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) and gemcitabine compared to gemcitabine in the adjuvant setting. This trial follows on the recently reported positive results in the metastatic disease setting demonstrating improved

complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting.” n

Disclosure: The trial was supported by Lilly Germany, the German Cancer Society and a grant from the CharitéUniversitätsmedizin Berlin. For full disclosures of the study authors, visit jama. jamanetwork.com.

References 1. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267-277, 2007. 2. Oettle H, Neuhaus P, Hochhaus A, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473-1481, 2013.

survival with addition of nab-paclitaxel to gemcitabine, and in Europe, a trial evaluating FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) compared to gemcitabine is underway. To date, no molecularly targeted agent has been established to have a role in the adjuvant therapy of pancreas adenocarcinoma, although studies are evaluating the addition of erlotinib (Tarceva) to gemcitabine (CONKO-005, RTOG 0848). A randomized phase II study did not suggest any utility for the addition of either bevacizumab (Avastin) or cetuximab (Erbitux) to gemcitabine in the adjuvant treatment of pancreas cancer. Other directions of study in adjuvant pancreas cancer include an evaluation of various immunotherapeutic approaches. One example is that of a phase III trial that has recently completed recruitment with pending results evaluating a “hyperacute” vaccine (algenpantucel-L) using two allogeneic pancreatic cancer tumor cell lines compared to standard therapy. Other immune approaches have evaluated KRAS vaccines.

Conclusions To summarize, adjuvant therapy for pancreas adenocarcinoma works, with a magnitude of risk reduction similar to the benefit observed for adjuvant continued on page 40

The ASCO Post | DECEMBER 1, 2013

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Journal Spotlight Gastrointestinal Oncology

Addition of Nab-Paclitaxel to Gemcitabine Improves Survival in Previously Untreated Metastatic Pancreas Cancer By Matthew Stenger

n a phase III trial reported in The New England Journal of Medicine, Daniel D. Von Hoff, MD, of Translational Genomics Research Institute in Phoenix, and colleagues assessed the addition of albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) to gemcitabine in patients with previously untreated metastatic pancreatic cancer.1 The combination resulted in significantly improved overall survival and progression-free survival but was also associated with increased myelosuppression and peripheral neuropathy.

tinued until disease progression. The primary endpoint was overall survival. The nab-paclitaxel/gemcitabine and gemcitabine groups were generally well balanced for age (median, 62 and 63 years), sex (57% and 60% male), race/ ethnic group (88% and 87% white), geographic region (north America for

In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate.

Study Details In this international open-label trial, 861 patients with Karnofsky performance status ≥ 70 and no previous treatment for metastatic disease were randomly assigned to receive either (1) nab-paclitaxel at 125 mg/m2 followed by gemcitabine at 1,000 mg/ m2 on days 1, 8, and 15 every 4 weeks (n = 431) or (2) gemcitabine alone weekly for 7 of 8 weeks during cycle 1 and then on days 1, 8, and 15 every 4 weeks during cycle 2 and subsequent cycles (n = 430). Patients could have received fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment had been received ≥ 6 months before randomization. Treatment con-

7% in both, and biliary stent in 19% and 6%). In total, 63% of patients were from North America, 15% from Eastern Europe, 14% from Australia, and 9% from Western Europe. The median duration of treatment was 3.9 months (range, 0.1–21.9 months) in the nab-paclitaxel/gem-

—Daniel D. Von Hoff, MD, and colleagues

62% and 63%), Karnofsky performance status (100 in 16% in both, 90 in 42% and 46%, 80 in 35% and 30%), pancreatic tumor location (head in 44% and 42%, body in 31% and 32%), metastatic site (liver in 85% and 84%, lung in 35% and 43%), number of metastatic sites (2 in 47% and 48%, 3 in 32% and 33%, > 3 in 14% and 15%), CA19-9 level (≥ 59 times upper limit of normal in 52% and 53%), and previous therapy (radiation therapy in 4% and 3%, chemotherapy in 5% and 3%, Whipple procedure in

citabine group and 2.8 months (range, 0.1–21.5 months) in the gemcitabine group, with 32% and 15% receiving treatment for ≥ 6 months. In the nabpaclitaxel/gemcitabine group, 41% of patients had reductions in nab-paclitaxel dose and 47% had reductions in gemcitabine dose. In the gemcitabine group, 33% of patients had dose reductions. After discontinuation of study treatment, 38% of nab-paclitaxel/ gemcitabine patients and 42% of gemcitabine patients received subsequent

therapy, with 6% of the gemcitabine group receiving a regimen including nab-paclitaxel.

Improved Overall Survival Median overall survival was 8.5 months in the nab-paclitaxel/gemcitabine group vs 6.7 months in the gemcitabine group (hazard ratio [HR] = 0.72, P < .001). Overall survival rates were 35% vs 22% (P < .001) at 1 year and 9% vs 4% (P = .02) at 2 years. On multivariate analysis including the stratification factors of performance status, presence or absence of liver metastases, and geographic region, the treatment effect remained significant (HR = 0.71, P < .001). Karnofsky performance status and liver metastases status were also independent predictors of survival. When the data were censored at the time of the initiation of subsequent therapy, overall survival was still longer in the nab-paclitaxel/ gemcitabine group (median, 9.4 vs 6.8 months, HR = 0.68, P < .001). Subgroup analyses showed consistent benefit of nab-paclitaxel/ gemcitabine across the majority of prespecified subgroups; patients with more advanced disease generally had the greatest reduction in risk of death, including those with Karnofsky performance status of 70 or 80 (HR =

Has a New Standard of Care for Metastatic Pancreatic Cancer Been Established? By Andrew H. Ko, MD

Andrew H. Ko, MD

or a number of years following the approval of gemcitabine for advanced pancreatic cancer, one phase III clinical trial after the next Dr. Ko is Associate Professor of Medicine at the University of California, San Francisco.

failed to demonstrate a survival benefit of combination chemotherapy compared to gemcitabine alone. Even the one positive study from the mid2000s—the PA.3 trial leading to the approval of erlotinib (Tarceva) in combination with gemcitabine as first-line treatment1—was associated with a very modest improvement in survival, and is often cited as an example of a therapy whose benefit may be statistically significant but not necessarily clinically meaningful.

Expanding Options Thankfully, therapeutic options are now evolving and expanding for patients with advanced pancreatic

cancer. Positive results from the international phase III MPACT trial, reported by von Hoff and colleagues in the September 2013 issue of The New England Journal of Medicine2 and reviewed in this issue of The ASCO Post, have led to the recent FDA approval of albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) in combination with gemcitabine for this disease. The study demonstrated clear (albeit still modest) improvements in overall and progression-free survival and objective response rate of gemcitabine/ nab-paclitaxel compared to gemcitabine monotherapy, accompanied by a predictable and manageable toxicity profile. But do these data now place this

regimen at the forefront of treatment options for this disease, or does it simply represent one of an expanding number of equally viable alternatives?

Gemcitabine/Nab-Paclitaxel vs FOLFIRINOX: Beware Cross-Study Comparisons Inevitable comparisons will be made between gemcitabine/nab-paclitaxel and another combination chemotherapy regimen, FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin). The French trial (PRODIGE 4/ACCORD 11)3 that led to the adoption of FOLFIRINOX as a front-line stancontinued on page 37

ASCOPost.com | DECEMBER 1, 2013

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Journal Spotlight

0.61, 95% confidence interval [CI] = 0.48–0.78), presence of liver metastasis (HR = 0.69, 95% CI = 0.59–0.81), more than three sites of metastatic disease (HR = 0.50, 95% CI = 0.33–0.76), metastatic pancreatic cancer at initial diagnosis, and CA19-9 level ≥ 59 times the upper limit of normal (HR = 0.61, 95% CI = 0.48–0.77).

Progression-Free Survival and Objective Response Median progression-free survival on independent assessment was 5.5 months vs 3.7 months (HR = 0.69, P < .001). Progression-free survival rates at 1 year were 16% vs 9%. On investigator assessment, median progression-free survival was 5.3 vs 3.5 months (HR = 0.61, P < .001). Subgroup analyses showed consistent benefit of nab-paclitaxel/gemcitabine, similar to the overall survival analyses. Response rates were 23% vs 7% (P < .001) on independent review and 29% vs 8%

Andrew H. Ko, MD, on Metastatic Pancreatic Cancer continued from page 36

dard, however, was conducted in a single country, enrolled fewer than half the number of subjects as the MPACT trial, and included only patients with an Eastern Cooperative Oncology Group performance status of 0 or 1. These differences notwithstanding, the control arm (gemcitabine alone) for both trials had essentially identical median survivals (6.8 months for PRODIGE, 6.7 months for MPACT), suggesting that the patient populations for the two studies may have been, on the whole, fairly similar. Although we proceed at our own risk when trying to make cross-study comparisons of this sort (which may be overly simplistic), the magnitude of benefit associated with FOLFIRINOX, with a median survival of 11.1 months, does appear superior to that of gemcitabine/nab-paclitaxel (8.5 months). However, unless and until these results are replicated in a successor study directly comparing these two regimens head to head— an initiative that likely will only be led by national cooperative groups, if at all, rather than by industry—we will be left with a fair degree of uncertainty regarding the optimal choice of first-line therapy in the subset of

(P < .001) on investigator assessment. Disease control rates were 48% vs 33% (P < .001) on independent review. The most common treatment-related nonhematologic adverse events of any grade in the nab-paclitaxel/gemcitabine group were fatigue (54%),

neuropathy was reported). Febrile neutropenia occurred in 3% vs 1% of patients, sepsis in 5% vs 2%, and pneumonitis in 4% vs 1%. Serious adverse events occurred in 50% vs 43% of patients, and fatal adverse events occurred in 4% of both groups.

Role of Nab-Paclitaxel in Pancreatic Cancer ■■ The addition of nab-paclitaxel to gemcitabine significantly increased overall survival, progression-free survival, and response rate in patients with previously untreated metastatic pancreas cancer.

■■ Combination treatment was associated with higher rates of myelosuppression and peripheral neuropathy.

alopecia (50%), and nausea (49%). Treatment-related adverse events of grade 3 or higher reported more frequently in the nab-paclitaxel/gemcitabine group were neutropenia (38% vs 27%), leukopenia (31% vs 16%), fatigue (17% vs 7%), and peripheral neuropathy (17% vs 1%; no grade 4

Peripheral neuropathy led to discontinuation of nab-paclitaxel in 8% of patients and to dose reduction in 10%. Among patients receiving treatment for 4 months (the average treatment duration), the rate of grade 3 neuropathy was 7%. Median time to first occurrence of grade 3 neuropathy was 140

patients who are robust enough to entertain multiple options. Moreover, as we are now faced in this disease with the positive development of having an expanding array of choices, the question of sequencing treatments through mul-

the level of protein expression, mutation of a particular gene, or a multigene panel—that can offer insight into therapies that are particularly effective or, conversely, may be necessary to avoid in any given patient. In their preclinical and phase I/II

Clearly, the MPACT study is not only practicechanging, providing a welcome new addition to our therapeutic armamentarium for pancreatic cancer, but equally importantly, opens up many new exciting avenues for further exploration in a disease that desperately needs it. —Andrew H. Ko, MD

tiple lines, and the need to assess the benefit of each of these (and other) regimens in the second-line setting and beyond, becomes increasingly relevant.

Need for Biomarkers Such unanswered questions highlight one of the key missing pieces in the treatment of pancreatic cancer: that is, the lack of a predictive biomarker to guide us in therapeutic decision-making. To this day, pancreatic cancer lags behind most other malignancies in terms of identification of a useful biomarker—whether it be at

study of gemcitabine/nab-paclitaxel,4 von Hoff and colleagues showed that an albumin-binding protein called SPARC (Secreted Protein Acidic and Rich in Cysteine), when expressed at high levels in the stromal compartment of pancreatic tumors, was associated with better survival in patients treated with the gemcitabine/ nab-paclitaxel combination. Data on SPARC expression and its correlation with patient outcomes in the phase III MPACT trial are eagerly awaited to offer further validation of its potential prognostic and/or predictive utility, as it may further help identify the subset

days; median time to improvement to grade 2 was 21 days and to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% resumed treatment at a reduced dose of nab-paclitaxel at a median of 23 days after onset. The investigators concluded, “In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased…[although] these side effects appear to be reversible.” n

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

Reference 1. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.

of patients who respond particularly well to nab-paclitaxel–based therapy.

Further Considerations Additionally, the positive results associated with nab-paclitaxel raise a whole host of other issues when it comes to both pancreatic cancer clinical research and practical clinical management. Does gemcitabine/nabpaclitaxel now become the new reference standard (ie, the control arm) in randomized phase II/III trial design in the future? And do targeted therapies in clinical development automatically have to be tested in the first-line setting in combination with this twodrug chemotherapy backbone, absent a compelling preclinical rationale? (In this author’s opinion, no.) From a patient management standpoint, noting the small subset of patients with poorer performance status from the MPACT study who still showed a survival benefit from combination therapy, can gemcitabine/nab-paclitaxel be routinely offered even to frailer patients? Finally, is it appropriate to expand the use of this drug to the locally advanced, neoadjuvant, and/or adjuvant settings before we have firmer data to verify its efficacy in these different contexts? (Again, in this author’s opinion: for locally advanced and borderline resectable disease, continued on page 40

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.

The ASCO Post | DECEMBER 1, 2013

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Journal Spotlight

Andrew H. Ko, MD, on Pancreatic Cancer continued from page 37

yes, it seems reasonable; in the postoperative adjuvant setting, not yet.) Clearly, the MPACT study is not only practice-changing, providing a welcome new addition to our therapeutic

armamentarium for pancreatic cancer, but equally importantly, opens up many new exciting avenues for further exploration in a disease that desperately needs it. Disclosure: Dr. Ko has received prior research funding from Celgene to support investigator-initiated clinical trials.

References 1. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin On-

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

col 25:1960-1966, 2007. 2. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013. 3. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011. 4. Von Hoff DD, Ramanathan RK, Borad MJ, et al: Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: A phase I/II trial. J Clin Oncol 29:4548-4554, 2011.

Eileen M. O’Reilly, MD, on CONKO-001 continued from page 35

therapy in other solid tumor malignancies, however, we clearly have much work to do. It is hoped that some of the improved outcomes that have been observed in the treatment of metastatic pancreas cancer will translate to the adjuvant setting, with results from ongoing trials likely to accrue over the next 2 to 5 years. In addition, a major focus going forward will be a more wide-scale investigation of neoadjuvant therapy. n

Disclosure: Dr. O’Reilly is a consultant for Celgene.

References 1. Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: Comparison of combinedmodality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80:751-755, 1988. 2. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:12001210, 2004. 3. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curativeintent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267277, 2007. 4. Neoptolemos JP, Stocken DD, Bassi C, et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA 304:1073-1081, 2010. 5. Oettle H, Neuhaus P, Hochhaus A, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473-1481, 2013.

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Journal Spotlight Gastrointestinal Oncology

Anti–VEGFR-2 Antibody Ramucirumab Prolongs Survival in Previously Treated Advanced Gastric or Gastroesophageal Cancer By Matthew Stenger

ascular endothelial growth factor (VEGF)– and VEGF receptor-2 (VEGFR-2)–mediated signaling and angiogenesis seem to have an important role in the pathogenesis of gastric cancer. In the phase III REGARD trial reported in Lancet, Charles S. Fuchs, MD, MPH, of Dana-Farber Cancer Institute, Boston, and colleagues investigated whether the monoclonal antibody VEGFR-2 antagonist ramucirumab could prolong survival in patients with previously treated advanced gastric 1 cancer. Ramucirumab treatment was associated with significantly prolonged overall survival and progression-free survival, validating VEGFR-2 signaling as an important target in this setting.

sex (71% and 68% male), race (76% and 78% white, 16% and 15% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 28% and 26%, 1 in 72% and 73%), weight loss in previous 3 months (< 10% in 83% in both), and geographic region (North America, Europe, Australia, New Zealand for 69% and 68%; Asia for 8% and 7%; South and Central America, India, South Africa, and Middle East for 25% and 26%). The two arms were also similar in terms of primary tumor location (gas-

Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy.

Study Details This international double-blind trial enrolled 355 patients aged 24 to 87 years with advanced gastric or gastroesophageal junction adenocarcinoma that had progressed after first-line platinum-containing or fluoropyrimidine-containing chemotherapy. Patients were randomly assigned 2:1 to receive best supportive care plus either ramucirumab at 8 mg/ kg intravenously (n = 238) or placebo (n = 117) once every 2 weeks. Patients were enrolled at 119 centers in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Randomization was stratified by weight loss (≥ 10% vs < 10% in the previous 3 months), geographic region (North America, Europe, Australia, and New Zealand vs South and Central America, India, South Africa, and Middle East vs Asia), and location of the primary tumor (gastric vs gastroesophageal junction). The primary endpoint was overall survival. The ramucirumab and placebo groups were generally well matched for age (median, 60 years in both),

—Charles S. Fuchs, MD, MPH, and colleagues`

tric in 75% and 74%), histologic subtype (intestinal in 22% and 30%, diffuse in 40% and 38%, unknown in 38% and 32%), presence of primary tumor (73% and 74%), number of metastatic sites (0–2 in 68% and 61%), measurable disease (92% and 91%), progression-free interval after previous treatment (< 6 months in 65% and 71%), and previous treatment (fluoropyrimidine/platinum in 84% and 75%, fluoropyrimidine/ other systemic agent in 5% and 15%, fluoropyrimidine alone in 7% and 6%, platinum/other systemic agent in 4% in both). More placebo patients had peritoneal metastasis (38% vs 27%).

Overall Survival Outcomes Median overall survival was 5.2 months (interquartile range, 2.3–9.9 months) in the ramucirumab group and 3.8 months (interquartile range,

Ramucirumab in Gastroesophageal Cancer ■■ Ramucirumab treatment significantly prolonged overall and progression-

free survival in patients with advanced gastric or gastroesophageal cancer progressing after platinum- or fluoropyrimidine-containing first-line therapy.

■■ Ramucirumab treatment was associated with a greater frequency of hypertension compared with placebo.

1.7–7.1 months) in the placebo group (hazard ratio [HR] = 0.776, P = .047). Estimated overall survival was 41.8% vs 31.6% at 6 months and 17.6% vs 11.8% at 12 months. ECOG performance status (≥ 1 vs 0), location of the primary tumor (gastroesophageal junction vs gastric), and presence of peritoneal metastases were identified as significant independent predictors of overall survival on a stepwise Cox proportional hazards model; after adjustment for these factors, ramucirumab was still associated with a significant improvement in over-

all survival (HR = 0.774, P = .042). After addition of the predefined stratification factors to the multivariable analysis, the effect of ramucirumab remained significant (HR = 0.767, P = .037). The effect of ramucirumab was consistent across almost all subgroups, including the prespecified stratification factors. Hazard ratios were 0.823 (95% confidence interval [CI] = 0.608–1.114) among patients with gastric cancer and 0.756 (95% CI = 0.472– 1.211) among those with gastroesophageal junction cancer. Outcome did not differ significantly between men and women (P = .063). After discontinuation of study drug, more placebo patients received systemic antineoplastic treatment.

Progression-Free Survival and Response Rates Median progression-free survival was 2.1 months in the ramucirumab group vs 1.3 months in the placebo group (HR = 0.483, P < .0001). Progression-free survival rates were 40.1% and 15.8% at 12 weeks. The effect of ramucirumab on progression-free survival was maintained after adjustment for other significant baseline prognostic factors and was consistent across almost all subgroups.

Objective response was observed in 3% of patients in the ramucirumab group (1 complete response) and 3% of patients in the placebo group, and stable disease was observed in 45% vs 21%, yielding disease control rates of 49% vs 23% (P < .0001). Duration of disease control was significantly longer in the ramucirumab group (median, 4.2 vs 2.9 months, P = .036).

Toxicities Adverse events of any grade occurred in 94% of patients in the ramucirumab group and 88% of patients in the placebo group, with hypertension being more common in the ramucirumab group (16% vs 8%). Ramucirumab was not associated with increased rates of fatigue, decreased appetite, vomiting, anemia, increased bleeding, venous thrombosis, proteinuria, gastrointestinal perforation, fistula formation, or infusion-related reactions. Grade 3 or higher adverse events occurred in 57% vs 58% of patients, with grade 3 hypertension being more common in the ramucirumab group (8% vs 3%). After hypertension, the most common adverse events of grade 3 or higher in the ramucirumab group were fatigue (6% vs 10%), abdominal pain (6% vs 3%), and anemia (6% vs 8%). Grade 3 or higher arterial thromboembolic events were more common in the ramucirumab group (1% vs 0%, P = .55). Death in five ramucirumab patients (2%; due to intestinal perforation in two patients, myocardial infarction, gastric hemorrhage, and pneumonia) and in two placebo patients (2%; due to intestinal perforation and pulmonary embolism) were considered related to study drug. Anti-ramucirumab antibodies were detected in 3% of ramucirumab patients and < 1% of placebo patients. None of these patients had an infusion-related reaction, and no patients developed neutralizing antibodies to ramucirumab.

Conclusion The investigators concluded: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after firstcontinued on page 42

The ASCO Post | DECEMBER 1, 2013

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Journal Spotlight

Ramucirumab continued from page 41

line chemotherapy…. In view of our findings, ramucirumab could be an important treatment option in [these] patients…. Additionally, this novel drug has a mechanism of action and toxic-effect profile that is distinctly different and non-overlapping with standard chemotherapy for oesophagogastric adenocar-

cinoma…. Our results validate the role of VEGFR-2 signalling as an important therapeutic target in advanced gastric and gastro-oesophageal junction adenocarcinoma. Future analyses are needed to identify potential predictive biomarkers for ramucirumab. A recently completed randomised clinical trial (ClinicalTrials. gov, number NCT01170663) has reported a survival benefit when ramucirumab

is added to second-line paclitaxel in patients with advanced oesophagogastric adenocarcinoma, while an ongoing randomised clinical trial (NCT01170663) is assessing a combination of ramucirumab with first-line chemotherapy in this patient population. n Disclosure: The study was funded by ImClone Systems. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. October 3, 2013 (early release online).

Gastric Cancer: Time to Revisit Angiogenesis By David H. Ilson, MD, PhD

Targeted Agents

David H. Ilson, MD, PhD

rogress in the treatment of gastric cancer has lagged behind advances in other solid tumor malignancies. A modest but clear survival benefit with the use of adjuvant therapy combined with surgery has been achieved, including the use of postoperative adjuvant chemotherapy as shown in large-scale trials from Asia, the use of pre- and postoperative chemotherapy from British trials, and the application of combined postoperative chemotherapy and radiotherapy in American trials. For esophageal and gastroesophageal junction adenocarcinoma, combined chemoradiotherapy followed by surgery is emerging as a standard of care in the United States. Progress in the treatment of metastatic gastric cancer, however, has been minimal. The combination of a fluorinated pyrimidine with a platinum agent remains the chemotherapy standard despite decades of research in newer systemic therapies. The advent of oral fluorinated pyrimidines and the use of oxaliplatin have improved therapy convenience and potentially lessened toxicity, but overall survival in advanced gastric cancer has not been significantly improved over the past few decades. Taxanes and irinotecan are used in second-line treatment, with a modest but very limited survival improvement achieved. Dr. Ilson is Attending Physician at Memorial Sloan-Kettering Cancer Center, New York.

The development of targeted therapies in gastric cancer has also been slow. Trastuzumab (Herceptin) has been the only targeted agent shown to improve survival when added to chemotherapy.1 The benefit is limited to the 10% to 20% of patients with HER2-positive or HER2-amplified tumors. Currently available epidermal growth factor receptor (EGFR)targeted agents have repeatedly failed to improve outcome in advanced disease, either in combination with chemotherapy or as single agents.2-4 Furthermore, no biomarker has emerged to potentially identify a subgroup of patients likely to benefit from EGFR-targeted therapies. Esophago-

a poorer prognosis. Unfortunately, the negative trial results for targeted agents have also extended to angiogenesis in gastric cancer. The global AVAGAST trial of the VEGF-A–targeted agent bevacizumab (Avastin) combined with chemotherapy failed to show a survival benefit in first-line treatment.6 However, enthusiasm for further study of antiangiogenic therapies in gastric cancer may now change with publication of the REGARD trial,7 as reviewed in this issue of The ASCO Post. Ramucirumab, a monoclonal antibody that binds to and blocks ligand binding and activation of VEGFR2, was evaluated in this phase III double-blind placebo-controlled trial in

Appropriate biomarker-driven patient selection for new therapies will be the key to new drug development. — David H. Ilson, MD, PhD

gastric adenocarcinoma seems to lack the driving mutations seen in other cancers, with activating mutations in KRAS and EGFR virtually absent. Recent studies from genomic analyses of esophagogastric cancer indicate that amplification rather than mutation of key pathways may be a more common driver of carcinogenesis.5 The search for amplified genes to target with new agents will hopefully lead to the identification of candidate biomarkers to ensure the greatest benefit from new agents.

Antiangiogenic Agents Angiogenesis is a key pathway in esophagogastric cancer, with increased levels of blood and tissue vascular endothelial growth factor (VEGF) correlating with a more advanced stage of disease and with

patients with metastatic gastric and gastroesophageal junction adenocarcinoma progressing on first-line platinum or fluorinated pyrimidine chemotherapy. Overall survival in the REGARD trial was modestly but significantly improved with ramucirumab, with the hazard ratio for a benefit (0.78) in the ballpark of benefit seen for trials comparing second-line chemotherapy to best supportive care (0.66–0.67).8,9 Progression-free survival and disease control were also improved with ramucirumab, although no significant tumor responses were seen. Toxicity of therapy above placebo was limited to grade 3 hypertension, an expected class effect for antiangiogenic therapy.

Supportive Data The positive results for the RE-

GARD trial are supported by the recent press release report of results from the RAINBOW trial. This trial also indicated a survival benefit for the combination of ramucirumab plus paclitaxel vs paclitaxel alone as secondline therapy. Ramucirumab therefore appears be active both as monotherapy and when added to chemotherapy. Ramucirumab represents the first targeted agent to demonstrate singleagent activity in a non–biomarker-selected population in advanced gastric cancer, and it is the first antiangiogenic therapy to show a survival benefit in this disease. This, in concert with the favorable toxicity profile, indicates that this agent will likely become a part of second-line therapy options in advanced gastric cancer. First-line data in combination with FOLFOX (leucovorin, fluorouracil, oxaliplatin) are still pending as of this publication. Biomarkers for antiangiogenic therapy have yet to be established in gastrointestinal cancers. VEGF-A levels, in conjunction with levels of the receptor neuropilin, may be potential candidate biomarkers in gastric cancer. The AVAGAST bevacizumab phase III trial indicated that patients with either relatively high VEGF-A levels or relatively low neuropilin levels achieved a survival benefit with the addition of bevacizumab.10 These biomarkers also appeared to have prognostic value, with inferior survival in these patients.

Future Progress Appropriate biomarker-driven patient selection for new therapies will be the key to new drug development. The benefits of newer and likely costly therapies will certainly be modest, and likely to have an actual impact on a relative minority of patients when unselected popula-

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Journal Spotlight

tions are treated. The dramatic success of biomarker selection of patients with EGFR-mutated or ALK gene-rearranged non–small cell lung cancer, and more recently in BRAFmutant melanoma, needs to be duplicated in esophagogastric adenocarcinoma. n

placebo-controlled, phase 3 trial. Lancet October 3, 2013 (early release online). 8. Kang JH, Lee SI, Lim do H, et al: Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care versus best supportive care. J

Clin Oncol 30:1513-1518, 2012. 9. Cook N, Marshall A, Blazeby JM, et al: Cougar-02: A randomized phase III study of docetaxel versus best supportive care in patients with relapsed esophagogastric cancer. J Clin Oncol 31(suppl):Abstract 4023, 2013.

10. Van Cutsem E, de Haas S, Kang YK, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30: 21192127, 2012.

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

References 1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2 positive advanced gastric or gastroesophageal junction cancer (TOGA): A phase 3 open label randomized controlled trial. Lancet 376:687-697, 2010. 2. Waddell T, Chau I, Cunningham D, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated esophagogastric cancer (REAL-3): A randomized open label phase 3 trial. Lancet Oncol 14:481489, 2013. 3. Lordick F, Kang YK, Chung HC, et al: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomized open label phase 3 trial. Lancet Oncol 14:490-499, 2013. 4. Dutton SJ, Blazeby JM, Petty RD, et al: Patient reported outcomes from a phase III, randomized, double-blind placebo controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy: Cancer Oesophagus Group (COG). J Clin Oncol 30(suppl 34):Abstract 6, 2012. 5. Dulak AM, Schumacher SE, van Lieshout J, et al: Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 72:4383-4393, 2012. 6. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer, a randomized double blind placebo controlled phase III trial. J Clin Oncol 29:3968-3976, 2011. 7. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre,

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The ASCO Post | DECEMBER 1, 2013

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FDA Update

New Medical Device Treats Urinary Symptoms Related to Benign Prostatic Hyperplasia

he U.S. Food and Drug Administration has authorized the marketing of the UroLift system, a permanent implant to relieve low or blocked urine flow in men age

50 and older with benign prostatic hyperplasia. As men age, the prostate can become enlarged, also known as benign prostatic hyperplasia. When the

prostate is enlarged it can restrict or block urine flow. The UroLift system relieves the urine flow by pulling back the prostate tissue that is pressing on the urethra.

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FDA Update

More than half of all men in their 60s and as many as 90% of men in their 70s and 80s have some symptoms of benign prostatic hyperplasia, such as more frequent urination with hesitant, interrupted, or weak stream and urgency and leaking. Severe benign prostatic hyperplasia can lead to serious problems over time, such

as strain on the bladder, urinary tract infections, bladder or kidney damage, bladder stones, and incontinence. Current treatment options to relieve symptoms associated with benign prostatic hyperplasia include drug therapy or surgical procedures including removal of the enlarged part of the prostate.

“The UroLift provides a less invasive alternative to treating [benign prostatic hyperplasia] than surgery,” said Christy Foreman, Director of the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. “This device also may offer relief to men who cannot tolerate available drug therapies.”

Clinical Studies The FDA’s review of the UroLift system included data from two clinical studies of men with benign prostatic hyperplasia implanted with two or more UroLift sutures. The first study included 64 men between the ages of 53 and 83, and the second study in-

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continued on page 46

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FDA Update

Medical Device Treats Urinary Symptoms continued from page 45

cluded 210 men between the ages of 49 and 86. Both studies showed that physicians successfully inserted UroLift in 98% of participants. The studies also measured participant urine flow and ability to empty the blad-

der, and throughout the study period, found a 30% increase in urine flow and a steady amount of residual urine in the bladder. Study participants answered validated questionnaires about their benign prostatic hyperplasia–related symptoms and quality of life, reporting a decrease in symptoms and an increase in quality of life in the 2 years following treatment.

Minor adverse events reported included pain or burning during urination, blood in the urine, frequent or urgent need to urinate, incomplete emptying of the bladder, and decreased urine flow. Investigators did not report any serious device-related adverse events. The FDA reviewed the UroLift

system through its de novo classification process, a regulatory pathway for some novel low-to-moderate risk medical devices that are not substantially equivalent to an already legally marketed device. The UroLift System is manufactured by NeoTract Inc of Pleasanton, California. n

FDA Grants Ofatumumab Breakthrough Therapy Designation for Previously Untreated CLL

he U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for ofatumumab (Arzerra) in combination with chlorambucil (Leukeran) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not received prior treatment and are inappropriate for fludarabinebased therapy. Ofatumumab, a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing

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parts of the small and large extracellular loops, is not approved or licensed anywhere in the world for use in this treatment setting. Breakthrough Therapy Designation is the newest of the FDA’s programs aimed at accelerating the development and review times of drugs for serious or life-threatening conditions. The Breakthrough Therapy designation was based on the results from an international, multicenter, randomized phase III clinical trial in more than 400 patients with previously untreated CLL. The full study results have been submitted for presentation at the 2013 American Society of Hematology Annual Meeting in December. Ofatumumab is being developed under a codevelopment and commercialization agreement between Genmab and GlaxoSmithKline. n

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Future of Oncology Supportive Care

Improving Fertility Options for Patients With Cancer A Conversation With Teresa K. Woodruff, PhD By Jo Cavallo

Teresa K. Woodruff, PhD

even years ago, Teresa K. Woodruff, PhD, coined the term “oncofertility” to describe the melding of two medical specialties, oncology and reproductive endocrinology, with the goal of maximizing the reproductive potential of patients with cancer. Today, with Dr. Woodruff’s establishment of the Oncofertility Consortium—an interdisciplinary initiative designed to explore the reproductive future of cancer survivors—there are more than 60 cancer centers nationwide dedicated to incorporating fertility preservation strategies into oncology treatment. More effective and targeted chemotherapeutics, which has led to improved survival rates for patients with cancer, has also presented more opportunities for oncologists to offer patients fertility preservation options at the time of diagnosis. For male adolescents and men, such options include cryopreservation of sperm or testicular tissue. Although fertility preservation in female adolescents and women is more complicated, advancements in cryopreservation of oocytes, embryos, and ovarian tissue are resulting in more successful pregnancies. The ASCO Post recently spoke with Dr. Woodruff, Chief of the Division of Fertility Preservation, Department of Obstetrics and Gynecology, and Thomas J. Watkins Professor of Obstetrics & Gynecology at Northwestern University Feinberg School of Medicine in Chicago, about the progress being made in fertility preservation.

Past Progress Please talk about the progress that has been made in fertility preservation in oncology patients, especially in young adults.

Over the past 5 years, we have seen tremendous progress. Advancements in cryopreservation of ovarian tissue, for example, have led to more than 25 babies born to women who had a cancer that threatened their fertility. In addition, many more young patients are now being referred to fertility specialists by their oncologists soon after their diagnosis, which has resulted in a rise in the number of young women who have gone through traditional fertilitysparing options like in vitro fertilization (IVF). For young women who aren’t eligible for an ovarian tissue transplant or IVF, we are making continual progress on in vitro grown ovarian follicles and in building artificial ovaries to develop oocytes into mature eggs. Using these methods, we have had live births in mice and we now have embryos implanted in monkeys. For young men, sperm can be collected before cancer treatment begins and then frozen and stored. For patients with low sperm counts, a procedure known as Onco-TESE (oncologic testicular sperm extraction), in which tes-

bers of ovarian follicles, so maintaining reproductive potential is better. For women approaching their late 30s, although their ovarian potential is already declining, it is not gone, and in many cases we can remove tissue and isolate the eggs, which can then be cryopreserved for implantation following cancer therapy and remission. We don’t understand everything about the reproductive potential of cancer patients, but we do have options now for all these age ranges. We have also developed a strategy for cancer survivors to have nonbiologic options as well—for example, adoption. When we started the oncofertility program, we didn’t realize how hard it was for women with a cancer diagnosis to adopt a child. We investigated the adoption process and found that adoption organizations weren’t familiar with the increasing number of cancer survivors due to more effective therapies. Now we have a group of 12 adoptive services that are oncofertility friendly, so more survivors have both biologic and nonbiologic options for having children.

Over the next 10 years, I can see fertility referrals from oncologists rising to between 85% and 90%, and fertility referrals will become nearly automatic for anyone under age 40. —Teresa K. Woodruff, PhD

ticular tissue is removed and sperm extracted, frozen, and then stored, is also effective in preserving male fertility. So I think both the present and future are looking very bright for fertility interventions for patients with cancer.

Age Considerations Is fertility preservation more achievable in younger cancer patients than older cancer patients? It depends. For prepubertal boys and girls, it is a matter of removing testicular or ovarian tissue and we do not have much experience with that method in such young boys. For pubertal boys and young men, sperm banking is very easy and effective. For girls of pubertal age to age 18, the procedure is to remove ovarian tissue, which at that age is filled with large num-

Novel Strategy for Chemotherapy Delivery Please talk about the research you and your husband [Thomas V. O’Halloran, PhD, Morrison Professor of Chemistry and Director of the Chemistry of Life Processes Institute at Northwestern University] are conducting with a new chemotherapy delivery system. The system administers drugs to tumors in microscopic bubbles, or nanobins, sparing the reproductive organs.1 Our goal is to eliminate the need for oncofertility. One way to do that would be to deliver existing or new chemotherapeutics so that they don’t produce off-target effects on hair and ovarian follicles, so you don’t lose your hair and you don’t lose ovarian function. We tested delivering a nanoscale

formulation of arsenic trioxide in a murine lymphoma model in the hope that the drug would be delivered to the vascular cancer tissue and not have toxic effects on other organs, including the reproductive organs. It turned out that the nanobins really did target just the cancer cells, and we were thrilled because the study suggests that nanobin techniques could be used not just for new-generation chemotherapeutics but for existing chemotherapeutics as well.

Looking Ahead How will the field of oncofertility change over the next decade? First, we are going to be able to diagnose the disease earlier, and we are going to have smarter drugs that target the disease more effectively and have fewer off-target effects. As those advances develop, we will have less need for the field of oncofertility, which is our goal. Second, there will be continued increases in the rate of fertility referrals by oncologists. They will become as commonplace as the rate of referrals to other specialists such as genetic counselors. Over the next 10 years, I can see fertility referrals from oncologists rising to between 85% and 90%, and fertility referrals will become nearly automatic for anyone under age 40. Third, the progress we have seen over the past 5 years—including the birth of 25 babies through ovarian tissue transplants in patients after cancer treatment—will continue to grow. The next step is to have live births from isolating the immature eggs housed within ovarian tissue follicles, maturing them in the laboratory, freezing the eggs until they are ready for in vitro fertilization, and then implanting them following cancer treatment. If successful, this method would provide a new option for women who have too much disease within their ovary because it would eliminate the chance of transferring cancer cells from the transplanted tissue back into the patient. n Disclosure: Dr. Woodruff reported no potential conflicts of interest.

Reference 1. Ahn RW, Barrett SL, Raja MR, et al: PLoS One, 8(3):e58491, 2013.

NOW INDICATED

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

ignite survival in first-line mPAC Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to

patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may

substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

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

0.2

P<0.0001b

0.1 0.0 0

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

Patients at risk

A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

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

B:14.25”

T:14”

S:13”

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%),

headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages. For more information, please visit www.abraxane.com. ABRAXANE® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-ABR130068a

Geriatric • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary for metastatic adenocarcinoma of the pancreas; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level

ABRAXANE (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

600

Discontinue

If additional dose reduction required

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day Day 1 Day 8

ANC Platelet count ABRAXANE / Gemcitabine (cells/mm3) (cells/mm3) < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at No dose reduction next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis lower dose level or diarrhea

4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/Gemcitabined Gemcitabine Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421) System Organ Class General disorders and administration site conditions

Gemcitabine (N=402)

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Skin and subcutaneous tissue disorders

Alopecia

212 (50%)

6 (1%)

21 (5%)

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%)

Nervous system disorders

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

3 (1%)

Dysgeusia

68 (16%)

33 (8%)

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%) 6 (1%)

Gastrointestinal disorders

Metabolism and nutrition disorders

52 (12%)

18 (4%)

28 (7%)

Cough

72 (17%)

30 (7%)

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

1 (<1%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

Depression

51 (12%)

1 (<1%)

24 (6%)

B:14.25”

T:14”

S:13”

Hypokalemia Respiratory, thoracic and mediastinal disorders

Psychiatric disorders a

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal. Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema

Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

The ASCO Post | DECEMBER 1, 2013

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Announcements

National Human Genome Research Institute Names First Director of Division of Genomics and Society

awrence C. Brody, PhD, has been selected to be the first Director of the newly established Division of Genomics and Society at the National Human Genome Research Institute (NHGRI). Dr.

Brody, a genetics and genomics researcher, is currently Chief of the Genome Technology Branch B:7.5” within NHGRI’s intramural research T:7”program, and the Chief Scientific Officer of the trans-NIH CenS:6.5”

ter for Inherited Disease Research. Dr. Brody’s expertise and interests are wide-ranging, from human genetics and genomics to the public understanding of science. As a bench scientist, he

Lawrence C. Brody, PhD

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

ABRAXANE PANCREATIC

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_PANC_HCP_BSv006 9_2013

T:10”

B:10.5”

S:9.5”

played an instrumental role in early and important discoveries about the BRCA1 gene. His research efforts have regularly included studying the practical implications of genomic advances. Moreover, on multiple occasions, he worked closely with the U.S. Solicitor General in the drafting and editing of legal briefs and in the preparation of oral arguments for the gene patenting case that went before the U.S. Supreme Court earlier this year. “Dr. Brody brings an extraordinary and diverse body of accomplishments and expertise to lead this newly created division,” said NHGRI Director Eric D. Green, MD, PhD. “His perspective as a bench scientist combined with a demonstrated long-term interest in the intersection of science and society makes him uniquely qualified to lead this critical part of NHGRI’s research program.” “It is an exciting time for genetics and genomics, but with that comes the responsibility to examine and address the many important societal implications of these research advances. With improvements in technology as the driving force, genomics can increasingly be used in clinical settings in a way that was simply not possible a decade ago,” Dr. Brody said. “Because genomics is moving closer to our daily lives, we need to better understand its societal impact. Issues such as consent, privacy, and access to genomic information will continue to grow in importance. We need to increasingly pursue research to understand these issues and to engage relevant stakeholders, including the general public, in the discussions.” Dr. Brody received a Ph.D. in human genetics from Johns Hopkins University, Baltimore. He was a Howard Hughes Medical Institute (HHMI) Research Associate from 1990 to 1993 and an HHMI postdoctoral fellow at Johns Hopkins University and the University of Michigan, Ann Arbor, during that time. He joined NHGRI in 1993. n

ASCOPost.com | DECEMBER 1, 2013

PAGE 53

Direct from ASCO

Philanthropy Spotlight Why We Give: ASCO Staff Members on Why They Support the Conquer Cancer Foundation Lynne Blasi, Director, Patient Education and Advocacy, ASCO Why do you choose to support the Conquer Cancer Foundation? I support the Conquer Cancer Foundation because of the tremendous impact it has across so many vital areas. From funding grants for young researchers with innovative ideas,

Lynne Blasi

helping to educate oncologists so they can stay current on new developments in care and treatment, to making sure patients and families around the world have access to accurate, oncologist-approved information, the Foundation covers all the bases. As a long-time donor, the Foundation is at the top of my list of organizations to support. How does the Conquer Cancer Foundation support your work at ASCO? I oversee ASCO’s patient education and advocacy programs, and the Foundation’s ongoing, generous support of Cancer.Net, ASCO’s patient website, and our print patient education materials has made it possible to reach millions of people with lifesaving information and resources for support when they need it most. Thanks to the Foundation, we’ve been able to grow the patient education program and ensure that it continues to meet the needs of ASCO members and the patients we all serve.

Doug Pyle, Senior Director, International Affairs, ASCO Why do you choose to support the Conquer Cancer Foundation? I suppose for many of the same reasons that my work at ASCO means so much to me. Like pretty much everyone, I’ve been touched personally

by cancer. My dad, who ironically was a hematologist/oncologist in Boston, died of a brain tumor when I was young. My mom is a cancer survivor. So for me it is a real privilege to work

programs, the International Cancer Corps, which enables ASCO member volunteers to help improve cancer care delivery at hospitals in developing countries. I could go on.

evated my support of the Conquer Cancer Foundation.

Eileen Melnick, Director, Grants & Awards, Conquer Cancer Foundation Why do you choose to support the Conquer Cancer Foundation? I donate and support the Conquer

at ASCO, to have a chance to do my best each day to improve the lives of cancer patients around the world. And for me to be able to support the Foundation in its work adds another dimension to this same privilege. How does the Conquer Cancer Foundation support your work at ASCO? The Foundation has been a pioneering supporter of ASCO’s international mission and remains crucial to achieving our goals. The International Development and Education Award (IDEA), which for 10 years has been helping young oncologists in low- to middle-income countries, has been supported by the Foundation from the beginning. We are now seeing these “young” oncologists take leadership positions at ASCO and in

Doug Pyle

their own national oncology societies. The Foundation’s Long-Term International Fellowship, started with my department, enables oncologists like these to study with a mentor in North America and “builds bridges” for research collaborations. The Foundation also supports one of our newer

Aaron Tallent, Manager, Policy Communications, ASCO Why do you choose to support the Conquer Cancer Foundation? I give to organizations based on my research of them and my belief that the money I donate will go towards

Aaron Tallent

combatting issues that are important to me. When you look at the cancer doctors and/or researchers that the Conquer Cancer Foundation has supported over the years, you can be confident that the donations you make are planting seeds that will improve cancer care. How does the Conquer Cancer Foundation support your work at ASCO? I manage the communication efforts for CancerLinQ, which is supported by the Conquer Cancer Foundation. CancerLinQ is ASCO’s multiphase initiative to build a learning health system in cancer care and truly has the potential to transform the way cancer is understood and treated. It is an inspiring project that has only el-

Eileen Melnick

Cancer Foundation because I believe in our mission. Four years ago, conquering cancer took on a more personal meaning to me when my mother was diagnosed with cancer. Sadly, she passed away, but there are many who have survived this devastating disease due to the important progress against cancer over the past four decades. Much work remains to be done to conquer cancer and the Foundation needs support more than ever, no matter how small. How does the Conquer Cancer Foundation support your work at ASCO? The Conquer Cancer Foundation raises funds that support the Grants and Awards Program, which has identified and supported the best and brightest clinical and translational researchers for 30 years. As the Director of this program, I take great pride in ensuring that donors’ investments in cancer research creates hope for breakthroughs in the future.

Jeannine Salamone, Associate Director, Patient Education and Advocacy, ASCO Why do you choose to support the Conquer Cancer Foundation? The Conquer Cancer Foundation provides people with cancer and their loved ones with information to continued on page 55

The ASCO Post | DECEMBER 1, 2013

PAGE 54

Direct from ASCO

A New Gift to Add to Your List—One to Conquer Cancer

onquering cancer requires the commitment, talent, and resources of all members of our community. It requires the innovation of researchers and the insight of clinicians, the courage of our worldwide community of patients and survivors, and it requires the generosity of everyone who believes in a world free from the fear of cancer. This year, as you plan your year-end giving, consider a tax-deductible gift to the Conquer Cancer Foundation. Your support will make a difference in the lives of people living with cancer and those who care for and about them. Together, we can: • Fund breakthrough research and advance new discoveries in cancer care and treatment • Put up-to-the minute, accurate can-

cer information directly into the hands of patients and caregivers, so that they can be empowered in their care and survivorship • Support cutting-edge training and professional development for oncology practitioners • Improve the standard of care worldwide—particularly in developing nations—by promoting international communication, collaboration, and education among cancer practitioners The Conquer Cancer Foundation funds research focused on finding new therapeutics to conquer cancer and is also committed to funding research that other organizations may not, such as in palliative care, rare cancers, pediatric cancers, and high-risk areas. With government support of research becoming increasingly tenuous, support from donors like you is needed more than ever before to help

Want to learn more about the researchers your gift supports?

Visit www.conquercancerfoundation.org/researcherspotlights to see videos of featured researchers discussing their work and the impact of their Conquer Cancer Foundation grant.

young oncology researchers get their start and to continue to advance the practice of oncology worldwide. As the end of the year approaches, we hope that you will join us in building a world free from the fear of cancer

Sunshine Act Reporting: ASCO Encourages Members to Get Prepared, Stay Educated

n August 1 of this year, requirements of the Physician Payments Sunshine Act, or Open Payments, went into effect. The legislation, passed as part of the Patient Protection and Affordable Care Act, was designed to create greater transparency around financial relationships between physicians, teaching hospitals, and manufacturers by posting relevant information to a public, searchable website. Although the first public report of information will not come out until September 30, 2014, it is important that oncologists begin to learn about the legislation now. ASCO is committed to providing ongoing information to help its members prepare for and understand what interactions with manufacturers will appear on the Centers for Medicare & Medicaid Services (CMS) public website.

Key Dates Beginning on August 1, manufacturers of covered drugs, biologics

and medical devices and supplies began gathering information on payments or other transfers of value that they make to physicians and teaching hospitals. This information, along with information on physicians who hold certain ownership interests, will be submitted to CMS annually and updated on a public website. In early 2014, it is anticipated that CMS will launch a physician portal that will allow physicians to sign up to receive an alert when information about them has been submitted. Physicians can then review submitted information and contact the manufacturer is there is a dispute in the accuracy of the report. Physicians can also ask any applicable manufacturer for a presubmission review of information to ensure that submitted information is accurate and complete. Manufacturers must report data from 2013—gathered from August 1 to December 31—to CMS on March 31, 2014. CMS has estimated that physicians will have access to the

2013 reports in June 2014 in order to seek correction or modification of the information. On September 30, 2014, the first reports will become available to the public.

Effect on ASCO Activities As this legislation goes into effect, certain interactions with ASCO that are indirect transfers from a manufacturer may be publicly reported on the CMS website, such as the acceptance of grants and awards or attending certain events, ASCO will not report these indirect transfers directly to CMS, but is required to report them to the manufacturer, which is then required to report to CMS. ASCO is committed to communicating with members in advance if any ASCO or Conquer Cancer Foundation activity could result in a report so that members can opt out if they choose. Most of the typical interactions members have with the Society re-

main nonreportable. Members can continue to attend the ASCO Annual Meeting or other thematic meetings throughout the year, can continue subscribing or paying for access to ASCO journals or publications, and can accept faculty roles at accredited continuing medical education meetings without creating a reportable event. In addition, members can also volunteer for ASCO Committees and can continue to make personable charitable contributions to the Conquer Cancer Foundation. If you would like to find out more details about Open Payments or what activities related to ASCO requiring public disclosure by a manufacturer or company, please visit www.asco.org/about-asco/ physician-payments-sunshine-act. ASCO will continue to update this website as any new information becomes available. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | DECEMBER 1, 2013

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Philanthropy Spotlight Why We Give continued from page 53

help them make informed decisions about their care. I turned to Cancer. Net 13 years ago when I was first diagnosed with breast cancer. I am in-

port of the Conquer Cancer Foundation, we started a patient advocate scholarship program in 2007, awarding scholarships to cancer advocates so that they may attend ASCO meetings to attain the education, knowledge, and skills essential to their par-

Direct from ASCO

ticipation and engagement in cancer research, education, and support. It has been an honor to manage this program from its inception and I am grateful to the Conquer Cancer Foundation for its ongoing support of this vital program.

GE Healthcare Clarient Diagnostic Services

Jeannine Salamone (right) and Jacqueline Mazzilli (left)

credibly proud to support the Foundation that helped me become an advocate for myself as well as for others, like my twin sister, Jackie, who is currently undergoing treatment for breast cancer. How does the Conquer Cancer Foundation support your work at ASCO? I work on the Patient Education and Advocacy team in ASCO’s Communications and Patient Information Department. Our Editorial Board and editorial staff provide patients and caregivers with trusted cancer education through Cancer.Net as well as a wealth of printed publications and resources. Additionally, with the sup-

Save the Date

Clarient

Consulting Service The Link Between Complex Breast Cancer Cases and Comprehensive Diagnosis Expertise and Experience

Reduce Patient Anxiety

Clarient partners with clinicians to help diagnose 30,000 breast cancer cases per year. Our world class experts provide a consulting service that provides a link between complex breast cancer cases and comprehensive diagnosis including prognostic and predictive biomarkers. Our experts include:

No two breast cancer patients are the same. Every patient wants to know about their own individual risk of recurrence, and they want to know quickly. Clarient Insight®Dx Mammostrat® can provide unique biological information about your patient’s risk assessment in 48-72 hours.

Dr. Craig Allred Dr. Noel Weidner

Commitment to Cancer Patients

Dr. Ken Bloom Dr. Neil Goldstein

Partnership

2014 Gastrointestinal Cancers Symposium January 16-18, 2014 Moscone West Building San Francisco, California

We strive to help provide clarity to the complexities of cancer by using the most appropriate technologies to partner with physicians to manage cancer cases. We perform testing that provides insight into the likely drivers of a cancer so that patients can receive therapies that will work best for them, while avoiding therapies that are unlikely to be effective.

GE is committing $1 billion in dedicated cancer-related research and development in addition to helping clinicians deliver care to 10 million patients by 2020. In September 2011, GE created the healthymagination Challenge to identify and accelerate ideas to advance breast cancer early detection and diagnostics, and ultimately help save lives affected by breast cancer.

© 2013 General Electric Company — All rights reserved. GE, the GE Monogram, and imagination at work are trademarks of General Electric Company. GE Healthcare, a division of General Electric Company. Clarient Diagnostic Services, Inc. is a division of General Electric Company. Clarient InsightDx Mammostrat is a trademark of General Electric Company.

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The ASCO Post | DECEMBER 1, 2013

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Direct from ASCO

More Than 200 Practices Now QOPI® Certified for Delivering High-Quality Cancer Care

SCO and its affiliate, the Quality Oncology Practice Initiative (QOPI®) Certification Program (QCP™), have announced that more than 200 practices have received certification. Since its start in 2010, the QOPI Certification Program has evaluated individual outpatient oncology practice performance in areas that affect patient care and safety. Certified outpatient oncology practices/ institutions meet the highest national standards in quality and safety for cancer care delivery. “QOPI’s growth over the past 3 years is remarkable with a doubling of QOPI-certified practices across the country in less than 2 years,” said ASCO President Clifford A. Hudis, MD, FACP. “Through their certification, these practices have shown a commitment to providing treatment that meets the highest national standards and to continuous improvement. This is a testament to our ASCO members’ focus on quality.”

QOPI Certification Program The QOPI Certification Program, launched in 2010, builds on ASCO’s Quality Oncology Practice Initiative by assessing the practice’s compliance with certification standards based on the ASCO/Oncology Nursing Society Standards for Safe Chemotherapy Administration. To become certified, practices must attain a benchmark

quality score on certification measures in QOPI and attest that they comply with 20 QCP standards. Practices that participate receive detailed reports that indicate their performance on over 160 quality metrics including key certification quality measures as well as a structured onsite review which offers insights into specific areas for improvement. The QCP addresses the call from the Institute of Medicine to close the quality gap by aligning evidence-based guidelines and consensus-driven standards with requirements for oncology practices to develop and maintain structural safety components (ie, policy and procedures that ensure a practice’s performance). More than 200 practices have earned the QCP seal, a way for cancer centers to demonstrate commitment to high-quality patient care. The first step towards achieving QOPI certification is participation in QOPI data collection. Practices and institutions must then undergo an extensive review by a team of ASCO professionals and oncology physicians and nurses at least once every 3 years. For a list of certified practices, please visit http://qopi.asco.org/ certifiedpractices.htm. n © 2013. American Society of Clinical Oncology. All rights reserved.

Save the Date

Your Patients Can Learn More with Videos on Specific Cancer Topics

n www.cancer.net/videos, your patients can view ASCO members discussing many different cancer topics. By using the drop-down menu on that page, patients can choose from several categories of videos. Topics include the basics of cancer care, tests and treatments, side ef-

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

fects, and survivorship. There are also videos on the latest cancer research news and videos targeted toward family members, friends, caregivers, and young adults with cancer. 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 Improving Pediatric Hematology/Oncology Care in the Emergency Department by Jill C. Beck

The National Cancer Institute–American Society of Clinical Oncology Cancer Trial Accrual Symposium: Summary and Recommendations by Andrea M. Denicoff, et al

Effect of Medical Oncologists’ Attitudes on Accrual to Clinical Trials in a Community Setting by Carol P. Somkin, et al

Is Physician Employment by Health Systems an Answer? by Alice G. Gosfield

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

Using Quality Oncology Practice Initiative Metrics for Physician Incentive Compensation by Grace Makari-Judson, et al

ASCOPost.com | DECEMBER 1, 2013

PAGE 57

In the Clinic Hematology

Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia 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 November 1, 2013, obinutuzumab (Gazyva) was approved for use in combination with chlorambucil (Leukeran) in the treatment of previously untreated chronic lymphocytic leukemia (CLL).1,2 Approval was based on results of an open-label trial showing improved progression-free survival with the combination of obinutuzumab plus chlorambucil vs chlorambucil alone in patients with previously untreated CD20-positive CLL. The study also included a rituximab (Rituxan) plus chlorambucil group; comparative data for the two combination groups are not yet available. In the trial, 356 patients with coexisting medical conditions or reduced renal function (creatinine clearance < 70 but ≥ 30 mL/min) were randomly assigned 2:1 to receive obinutuzumab at 1,000 mg on days 1, 8, and 15 of the first cycle and day 1 of five subsequent 28-day cycles plus oral chlorambucil at 0.5 mg/kg on day 1 and 15 of each cycle (n = 238) or chlorambucil alone (n = 118). After a very high incidence of infusion-related reactions during the first dose in obinutuzumab recipients, the first obinutuzumab dose was divided into 100 mg on day1 and 900

OF NOTE After binding to CD20 antigen on pre B- and mature B-lymphocytes, obinutuzumab mediates Bcell lysis and activates intracellular death signaling pathways. mg on day 2 of the first cycle for the last 45 study patients treated. Patients received glucocorticoid, acetaminophen, and antihistamine premedication prior to initial obinutuzumab infusions and subsequently as needed. Patients with active infection, positive hepatitis B virus (HBV) serology (HBsAg- or anti-HBc–positive,

patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable), positive hepatitis C serology, or immunization with live virus vaccine within the prior 28 days were excluded from the study. Patients had a median age of 73 years, 60% were male, 95% were Caucasian, 68% had creatinine clearance < 70 mL/min, 76% had multiple coexisting medical conditions, and 22%, 42%, and 36% were Binet stage A, B, and C, respectively. In total, 81% of the combination group and 67% of the chlorambucil-alone group received all six cycles of treatment. Median progression-free survival on independent review was 23.0

OF NOTE Obinutuzumab carries a boxed warning for HBV reactivation and progressive multifocal leukoencephalopathy, both of which have resulted in death. mine should be given before the first two doses. Thereafter, acetaminophen should be given before all doses, antihistamine premedication should be given to all patients with an infusionrelated reaction ≥ grade1 during the prior infusion, and glucocorticoid premedication should be given to all pa-

Obinutuzumab for CLL ■■ The monoclonal antibody obinutuzumab (Gazyva) has been approved

for use in combination with chlorambucil (Leukeran) to treat previously untreated chronic lymphocytic leukemia (CLL).

■■ Obinutuzumab is given by intravenous infusion at a dose of 100 mg on day 1 and 900 mg on day 2 of the first treatment cycle, and at 1,000 mg on day 8 and 15 of cycle 1 and day 1 of the subsequent five 28-day cycles.

months in the combination arm vs 11.1 months in the chlorambucil-alone arm (hazard ratio = 0.16, P < .0001). The overall response rate was 75.9% vs 32.1%, with complete response in 27.8% vs 0.9%, and median duration of response was 15.2 vs 3.5 months.

How It Works Obinutuzumab is a monoclonal antibody targeting the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. After binding to CD20, obinutuzumab mediates B-cell lysis by engaging immune effector cells, directly activating intracellular death signaling pathways, and activating the complement cascade. Immune effector cell activities include antibody-dependent cellular cytotoxicity and antibodydependent cellular phagocytosis.

How It Is Given Obinutuzumab is given via intravenous infusion at a dose of 100 mg on day 1 and 900 mg on day 2 of the first treatment cycle, and at 1,000 mg on day 8 and 15 of cycle 1 and day 1 of the subsequent five 28-day cycles. Premedication with a glucocorticoid, acetaminophen, and antihista-

tients with an infusion-related reaction ≥ grade 3 during the prior infusion or a lymphocyte count > 25 × 109/L. Tumor lysis syndrome should be anticipated, and premedication with an antihyperuricemic beginning 12 to 24 hours before the start of therapy and adequate hydration for tumor lysis syndrome prophylaxis should be provided, particularly in patients with high tumor burden or high circulating absolute lymphocyte count (> 25 × 109/L). Electrolyte abnormalities should be corrected, supportive care provided, and renal function and fluid balance monitored. Since hypotension may occur during infusion, withholding of antihypertensive treatment for 12 hours before and 1 hour after administration should be considered. Patients with neutropenia should receive antimicrobial prophylaxis throughout the treatment period, and antiviral and antifungal prophylaxis should be considered. Blood counts should be routinely monitored.

Safety Profile The most common adverse events of any grade in the pivotal trial’s combination-group patients were infusion-

related reactions (69% vs 0% in chlorambucil alone group), neutropenia (40% vs 18%), and thrombocytopenia (15% vs 7%). The most common grade 3 or 4 adverse events were infusion-related reactions (21% vs 0%), neutropenia (34% vs 16%), thrombocytopenia (11% vs 3%), and anemia (4% vs 5%). Infusion-related reaction symptoms included dyspnea, hypotension, nausea, vomiting, chills, flushing, and pyrexia. The most common grade 3 or 4 hematologic abnormalities were neutropenia (46% vs 27%), lymphopenia (40% vs 2%), leukopenia (36% vs < 1%), and thrombocytopenia (14% vs 11%), and the most common grade 3 or 4 chemistry abnormalities were hyponatremia (8% vs 2%) and hyperkalemia (5% vs 2%). The incidence of infection was similar in the two groups, with infection occurring in 38% of the combination group and grade 3 or 4 infection occurring in 9% (none fatal). Grade 3 or 4 tumor lysis syndrome occurred in 2% of the combination group and in 0% of the chlorambucil-alone group. Anti-obinutuzumab antibodies were detected in 13% of combination-group patients; the clinical significance of these antibodies is not known. Obinutuzumab carries a boxed warning for HBV reactivation, which has resulted in fulminant hepatitis, hepatic failure, and death in some cases, and for progressive multifocal leukoencephalopathy, which has resulted in death. Obinutuzumab also has warnings/precautions for infusion-related reactions, tumor lysis syndrome, neutropenia, thrombocytopenia, and immunization. Patients should be monitored for infection, platelet counts, and bleeding. Management of hemorrhage may require blood product support. Patients should not receive live virus vaccines prior to or during obinutuzumab treatment. n References 1. U.S. Food and Drug Administration: Gazyva (obinutuzumab). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm373263.htm. 2. GAZYVATM (obinutuzumab) injection for intravenous infusion prescribing information. Genentech, Inc, November 2013. Available at www.accessdata.fda.gov/dr ugsatfda_docs/ label/2013/125486s000lbl.pdf.

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

NOW AVAILABLE

GRANIX is a new option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

The ASCO Post | DECEMBER 1, 2013

PAGE 60

News Breast Cancer

With Genetic Discoveries, Breast Cancer Complexity Grows By Caroline Helwick

ncologists are getting a handle on BRCA1/2 in breast cancer, becoming more adept at treating and counseling patients with these mutations. But the BRCA mutation is only

one example of a host of genetic variations that can increase breast cancer risk, according to James M. Ford, MD, Associate Professor of Medicine and Genetics and Director of Clinical Can-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

cer Genetics Program at Stanford University School of Medicine, Palo Alto. With next-genome sequencing and genome-wide association studies will come new paradigms for genetic

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

testing and counseling, said Dr. Ford, who discussed the topic at the Best of ASCO Meeting in Los Angeles.

Penetrance Matters BRCA1/2 mutations are high-penetrance mutations that are very rare but confer a greatly elevated risk of breast cancer. Less is known about the moderate-penetrance gene mutations, such as those found in the Fanconi anemia pathway, associated with a two- to threefold increased breast cancer risk. Even less has been established regarding the lowpenetrance mutations, which are common in the population but confer only a minimal increased risk. “The completion of many genomewide association studies is yielding information about the moderate- and lowpenetration mutations,” said Dr. Ford. “These studies have identified common genetic changes—mostly SNPs [single nucleotide polymosphisms]—in a high proportion of the population, but their effect size is small. This knowledge is helping us close in on the unexplained heritability in cancer.” BRCA1/2 mutations account for about 25% of familial breast cancers, and a small percentage are explained by SNPs, TP53, and PTEN alterations, with a smattering due to half a dozen or so other rare mutations. Approximately 65% of familial breast cancer risk remains unexplained. The goal of genetic testing is to render either a clearly positive answer (showing disease association) or negative answer (no sequence change consistent with the mutation). However, in 5% to 20% of cases (depending on ethnicity) the result is a “variant of uncertain significance.” These are changes in sequences that cannot be determined to be deleterious. “If you multiple the risk of a variant by the number of genes we will be looking at on multiplex panels—up to 40 or so—you can see the challenge in interpreting these results,” Dr. Ford said.

Familial Syndromes and Testing The National Comprehensive Cancer Network revised its guidelines this year for BRCA1/2 mutation testing to advise screening when there is a: • Family member with known BRCA1/2 mutation • Personal history of breast cancer with:

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—Triple-negative

age ≤ 60

breast cancer and

— Onset at age ≤ 45 (7% prevalence) — Onset at age ≤ 50 if two primaries,

or ≥ 1 affected close relative ≤ 50 — Onset at any age, if ≥ 2 close relatives with breast/ovarian cancer —High-risk ethnicity, such as Ashkenazi (20%–25% prevalence) • Personal history of ovarian cancer (10%–15% prevalence) • Personal history of male breast cancer (12%–16% prevalence) • Close family member meeting the above criteria While the BRCA-associated hereditary breast and ovarian cancer syndrome is certainly the most common familial breast cancer syndrome, there are others that clinicians should be familiar with and that help guide screening. More and more susceptibility loci are being described as genetic testing becomes more sophisticated. Family studies have revealed the rare to very rare, high-risk alleles to include TP53, PTEN, CDH1, and STK11, which are observed in far less than 1% of the population but convey a relative risk of 10.0 or higher. The rare, moderaterisk alleles, found by sequencing studies, appear to be BRIP1, ATM, PALB2, and CHEK2; they occur in about 1% of the population and carry a relative risk of around 2.0. The common,

low-risk alleles, identified on genomewide association studies, include 6q, TOX3, FGFR2, 2q, MAP3K1, LSP1, Sp, 8q, AKAP9, and CASP8. These are observed in about 25% to 50% of the population, but the relative risk ranges from 1.1 to 1.5. “What is unclear is whether the risks associated with these multiple SNPs, when they occur within a single patient, are additive,” he said. The recommendation for genetic testing is also informed by breast can-

• Lobular breast cancer with a family history of gastric cancer: Consider CDH1 testing for hereditary diffuse gastric cancer syndrome. • Breast cancer plus mucocutaneous lesions, macrocephaly, endometrial cancer, nonmedullary thyroid cancer: Consider PTEN testing for Cowden syndrome. • Microsatellite-high breast cancer and family history of colorectal or endometrial cancer: Consider mismatch repair gene testing for Lynch syndrome.

If you multiple the risk of a variant by the number of genes we will be looking at on multiplex panels—up to 40 or so—you can see the challenge in interpreting these results. —James M. Ford, MD

cer molecular phenotype and certain patient characteristics. Dr. Ford might advise testing under the following circumstances: • Triple-negative breast cancer and age ≤ 60: Consider BRCA1/2 testing. • Triple-positive and age ≤ 35: consider p53 testing for Li-Fraumeni syndrome

Genetic Syndromes in Breast Cancer ■■ BRCA1/2 mutations are only the most common example of genetically driven breast cancer.

■■ With genome-wide association studies and next-generation

sequencing, new mutations of moderate and low penetrance are being identified, but the optimal management and screening strategies for these remain unclear.

■■ The breast cancer risk associated with BRCA mutations varies according to additional genetic modifiers that an individual patient may harbor. These can help refine an individual’s risk and guide management.

Risk Modifiers Can Help Refine Treatment Not all BRCA-associated breast cancers carry the same magnitude of risk, according to research done by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a global collaboration. The group has stored more than 15,000 BRCA1/2 samples from which they have begun to identify modifiers from common alleles. CIMBA has concluded that certain genetic factors can modify the individual risk of a BRCA mutation carrier. Depending on the particular mutations identified, aside from BRCA, risk may be greater or lesser than the oft-quoted numbers, he said. Ten influential genes or regions have been found to modify risk associated with BRCA1, and 12 have been found for BRCA2. These modifiers occur at a frequency ranging from 7% to

52% and carry hazard ratios ranging from 0.75 to 3.18. “These modifiers are multiplied against a very high baseline risk, and they can be used to stratify patients at relatively low risk (21%–50%) from those at extraordinarily high risk (81%–100%),” he explained. “These can help us with risk assessment and counseling regarding screening and prophylactic surgeries. We determine the individual risk, as compared with the population risk.”

Future Directions Increasingly, more susceptitility loci and modifier genes will be identified through advanced SNP array technology, and the challenge of interpreting the data and incorporating it into clinical management will be formidable, Dr. Ford concluded. Multiplex panels, which examine 20 to 40 genes, are arriving in the clinic and are capable of revealing moderatepenetrance genes. But there are currently concerns about their implementation, as the proper way to deal with incidental findings and uncertainty is unknown, and as yet there is no clear strategy for counseling patients regarding the results. “How will we discuss these test results with patients within a reasonable time frame?” he asked. “And how will we interpret and deal with nonsyndromic changes, and variants of uncertain significance, which we cannot identify as deleterious or not? The role of professional judgment will be indispensable.” n

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

Reference 1. Ford JM: Hereditary cancer genetics and syndromes: New and noteworthy in 2012-2013. Best of ASCO Los Angeles. Education Session. Presented August 17, 2013.

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Announcements

University of Chicago Names Ernst Lengyel, MD, PhD, Chair of Obstetrics and Gynecology

rnst Lengyel, MD, PhD, was recently named Chair of the Department of Obstetrics and Gynecol-

Early Career Dr. Lengyel completed his basic science and medical school training at the University of Munich and the University of Texas MD Anderson

Cancer Center, where he performed his residency in obstetrics and gynecology. After his fellowship in gyneS:6.75” cologic oncology at the University of California, San Francisco (UCSF)/

Stanford, he served at UCSF for a year as a junior faculty member before joining the University of Chicago as Assistant Professor of Obstetrics and Gynecology. n

COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

Ernst Lengyel, MD, PhD

ogy at the University of Chicago. He succeeds Arthur Haney, MD, who served as Chair of the Department of Obstetrics and Gynecology since April 2003. Under the leadership of Dr. Haney, the Department developed strong educational and clinical programs. Dr. Haney will remain an active member of the faculty.

Research Interests Dr. Lengyel joined the University of Chicago in 2004 and since that time his work has included studies into the biology of how ovarian cancer spreads to other sites and the use of novel drugs for its treatment. His laboratory was the first to culture metastatic ovarian cancer cells in a three-dimensional environment, similar to how these cells would grow in the body, and the first to use high-throughput drug screening in this model. Dr. Lengyel’s current research is focused on finding new drugs for the treatment of ovarian cancer and on the interactions between ovarian cancer cells and their surrounding environments. “Ernst Lengyel has demonstrated wisdom and dedication as a caring physician and as a scientist,” said Kenneth Polonsky, MD, Executive Vice President for Medical Affairs at the University of Chicago and Dean of the Biological Sciences Division and the Pritzker School of Medicine. “He is a meticulous gynecologic surgeon and an innovative investigator who has done pioneering research on the spread of ovarian cancer and its impact on surrounding tissues,” Dr. Polonsky added.

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

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ASCO Launches Formal Development of CancerLinQ™ System SCO recently announced that it has initiated development of the full CancerLinQ™ system, a groundbreaking health information technology (HIT) initiative to achieve higher-quality, higher-value cancer care with better outcomes for patients. The announce-

ment was made at a White House Office of Science and Technology Policy event at The Ronald Reagan Building and International Trade Center in Washington, DC. S:6.75” The multiphase development process will encompass a series of succes-

sively more powerful quality improvement tools for physicians, with the first components becoming available by early 2015. ASCO’s move into the full build follows the successful completion of the CancerLinQ™ prototype, which demonstrated the feasibility of a

HIT-based learning health system . “ASCO’s prototype left no doubt that a learning health system in cancer care is possible,” said ASCO President, Clifford A. Hudis, MD, FACP. “With development of the full system now underway, continued on page 64

PROD

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

months

11.2

ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

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Please see brief summary of full Prescribing Information on next page.

COMETRIQ.com

DATE

SIGNOFF

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit fda.gov/medwatch or call 1-800-FDA-1088.

Disk release

Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

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we believe we can enhance our contributions to better, smarter patient care within the next 18 months. By the time CancerLinQ™ is complete, we expect it will revolutionize cancer care and serve as a model for other areas of medicine.” The first components of CancerLinQ™ will center on providing next-generation quality measurement that builds

on ASCO’s Quality Oncology Practice Initiative (QOPI®). Future components will encompass more powerful quality improvement tools, real-time clinical decision support, and analysis of thousands of patient experiences to create a continuous cycle of learning. ASCO is currently defining the functional requirements for the full system and will be issuing a

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

request for proposals in early 2014. ASCO also continues to seek financial support for CancerLinQ™ through the Conquer Cancer Foundation. To date, the Foundation has raised $7.8 million in major commitments, including generous contributions from Amgen; Chan Soon-Shiong Family Foundation; Genentech BioOncol-

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. 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 safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

ogy™; Helsinn Therapeutics (US), Inc; Lilly; Novartis Oncology; Susan G. Komen®; and numerous individual supporters including: Raj Mantena, RPh, Thomas G. Roberts, Jr, MD, and Susan M. DaSilva, NP. n See page 65 for information about the CancerLinQ Advisory Committee.

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

ASCOPost.com | DECEMBER 1, 2013

PAGE 65

Announcements

Amy P. Abernethy, MD, PhD, to Chair CancerLinQ™ Advisory Committee

SCO has announced that Amy P. Abernethy, MD, PhD, FACP, has agreed to chair a new CancerLinQ™ Advisory Committee within the Institute for Quality, an ASCO affiliate dedicated to innovative quality improvement programs, that will guide this multiphase

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

effort. The advisory committee consists of leaders in a wide range of relevant fields, including oncology, health outcomes, epidemiology, and health information technology. The committee will advise on the design and implementation of the full system throughout its

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg 34 54 Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

development. Dr. Abernethy, a medical oncologist and palliative medicine physician, is a tenured Associate Professor in Duke University Schools of Medicine and Nursing, Director of the Duke Center for Learning Health Care in the Duke

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are 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 COMETRIQ, 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. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

Clinical Research Institute, and Director of the Duke Cancer Care Research Program in the Duke Cancer Institute. “CancerLinQ™ truly has the potential to transform the way we understand and treat cancer,” said Dr. Abernethy. “I am excited to be part of a project where

CancerLinQ™ truly has the potential to transform the way we understand and treat cancer. —Amy P. Abernethy, MD, PhD, FACP

we can improve the quality of cancer care for all patients by learning from each of them.” The Institute will also be establishing additional, sector-specific subcommittees of external advisors to provide more perspectives as CancerLinQ™ is developed and implemented. Future groups will include patient and physician advisory subcommittees, as well as a technology advisory subcommittee. CancerLinQ™ is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. CancerLinQ™ is a project of ASCO’s Institute for Quality. For more information, please visit: www.asco. org/cancerlinq. n

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The ASCO Post | DECEMBER 1, 2013

PAGE 66

JCO Spotlight Hematology

Rituximab Does Not Improve Outcome in B-Cell Lymphoma With Skeletal Involvement, but Radiotherapy Benefit Found By Matthew Stenger

n a retrospective analysis of German High-Grade Non-Hodgkin Lymphoma Study Group trials reported in the Journal of Clinical Oncology, Gerhard Held, MD, of Saarland University Medical School in Homburg, and colleagues assessed the impact of rituximab (Rituxan) and radiotherapy on outcome in patients with aggressive B-cell lymphoma and skeletal involvement.1 The analysis showed that the addition of rituximab to chemotherapy did not improve outcome but suggested that radiotherapy was associated with improved outcome.

Study Details The analysis included nine consecutive German High-Grade NonHodgkin Lymphoma Study Group studies in which patients with diffuse large B-cell lymphoma received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHEOP (CHOP and etoposide) -like regimens with or without rituximab. Event-free survival and overall survival were assessed in patients with vs without skeletal involvement and in those who did or did not receive rituximab. Analyses were also performed in populations of the two largest trials comparing CHOP regimens with and without rituximab—the MabThera International Trial (MInT), which was conducted in young good-prognosis patients, and the Rituximab With CHOP Over 60 Years (RICOVER-60) Study.

Analysis in Entire Population Of the total of 3,840 patients, 2,814 patients (73.3%) were treated without and 1,026 patients (26.7%) were treated with rituximab, and 292 (7.6%) had skeletal involvement. Of the 292 patients with skeletal involvement, 61 (20.9%) were treated with and 231 (79.1%) without rituximab. The frequency of skeletal involvement was higher in patients not receiving rituximab than in those receiving rituximab (8.2% vs 5.9%). Median time of observation was 41 months in the entire group and 44 months in patients with skeletal involvement. Among the 2,814 patients treated without rituximab, there was no signif-

icant difference between 231 patients with and 2,583 patients without skeletal involvement in 3-year event-free survival (55% vs 59%, P = .341) or overall survival (69% vs 75%, P= .070). Among the 1,026 patients treated with rituximab, the 61 patients with skeletal involvement had significantly worse 3-year event-free survival than the 965 patients without skeletal involvement (57% vs 72%, P= .002) and borderline worse 3-year overall survival (74% vs 82%, P= .055). Since skeletal involvement was associated with adverse International Prognostic Index (IPI) prognostic factors, a multivariable analysis was performed adjusting for IPI risk factors.

Rituximab in Diffuse Large B-Cell Lymphoma ■■ On multivariate analysis, the addition of rituximab to chemotherapy did not improve event-free or overall survival in patients with diffuse large B-cell lymphoma and skeletal involvement.

■■ In the MInT and RICOVER-60 trials, the addition of rituximab to CHOP

significantly improved event-free and overall survival in patients without skeletal involvement but not in those with skeletal involvement.

■■ Radiotherapy to affected sites was associated with significantly improved event-free survival in patients with skeletal involvement.

and 1,136 without skeletal involvement), the addition of rituximab to CHOP improved event-free survival (HR in MInT = 0.4, P<. 001; HR in RICOVER-60 = 0.6, P< .001) and overall survival (HR in MinT = 0.4, P<

Our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. —Gerhard Held, MD, and colleagues

In this analysis, hazard ratios (HRs) for event-free survival in patients with skeletal involvement were 0.9 (P = .173) in patients not receiving rituximab vs 1.4 (P = .131) in those receiving rituximab, and hazard ratios for overall survival were 0.9 (P = .328) vs 1.0 (P = .945).

.001; HR in RICOVER-60 = 0.7, P = .002) in patients without skeletal involvement but did not improve eventfree survival (HR in MinT = 1.4, P = .444; HR in RICOVER-60 = 0.8, P = .449) or overall survival (HR in MInT = 0.6, P= .449; HR in RICOVER-60 = 1.0, P = .935) in those with skeletal involvement.

Outcomes in MInT and RICOVER-60 Trials

Radiotherapy Analysis

In the combined MInT and RICOVER-60 studies, 1,013 patients received CHOP with and 1,022 without rituximab. In multivariable analysis adjusting for IPI prognostic factors, hazard ratios for event-free survival in patients with skeletal involvement were 0.8 (P = .181) in those not receiving rituximab vs 1.5 (P = .048) in those receiving rituximab, and hazard ratios for overall survival were 0.7 (P = .083) vs 1.1 (P = .828). In multivariate analysis of the individual MInT (51 patients with and 772 without skeletal involvement) and RICOVER-60 trials (86 patients with

The analysis of the effect of radiotherapy was restricted to 161 patients with skeletal involvement who achieved a complete or partial response after the end of immunotherapy/chemotherapy, because patients achieving less than a partial response went off protocol to receive salvage chemotherapy. Compared with 29 patients not receiving radiotherapy to sites of skeletal involvement, the 133 who received radiotherapy had significantly better 3-year event-free survival (75% vs 36%, P < .001) and nonsignificantly better 3-year overall survival (86% vs 71%, P = .064).

Since patients who did not receive radiotherapy had worse prognostic factors than those who received radiotherapy, a multivariable analysis adjusting for IPI risk factors and bulky disease was performed. In this analysis, radiotherapy was still associated with significantly better event-free survival (HR = 0.3, P = .001) and nonsignificantly better overall survival (HR = 0.5, P = .111). Radiotherapy appeared to have a beneficial effect in both limited- and advanced-disease stages; hazard ratios were 0.4 (P = .146) for event-free survival and 1.2 (P = .864) for overall survival among 78 patients with stage I or II disease and 0.3 (P = .001) for event-free survival and 0.4 (P = .059) for overall survival among 83 with stage III or IV disease. The investigators concluded Rituximab failed to improve the outcome of patients with diffuse large Bcell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials. n Disclosure: The study was supported by Deutsche Krebshilfe. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Held G, Zeynalova S, Murawski N, et al: Impact of rituximab and radiotherapy on outcome of patients with aggressive Bcell lymphoma and skeletal involvement. J Clin Oncol. September 23, 2013 (early release online).

ASCOPost.com | DECEMBER 1, 2013

PAGE 67

JCO Spotlight

German Analysis in Diffuse Large B-Cell Lymphoma: Hypothesis-Generating Rather Than Definitive? By Brad Kahl, MD

n their retrospective analysis of German High-Grade Non-Hodgkin Lymphoma Study Group trials reported in Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, Held and colleagues assessed the effects of rituximab (Rituxan) and radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement.1 The analysis, which included nine consecutive studies in which patients with diffuse large B-cell lymphoma received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHEOP (CHOP and etoposide) -like regimens with or without rituximab, suggested that radiotherapy but not the addition of rituximab to chemotherapy was associated with improved outcome.

Key Findings For the 231 patients with vs 2,583 patients without skeletal involvement who were treated without rituximab, there was no difference in 3-year event-free survival (55% vs 59%, P = .341) or overall survival (69% vs 75%, P = .070). For the 61 patients with and 965 patients without skeletal involvement who were treated with rituximab, those with skeletal involvement had worse 3-year eventDr. Kahl is Skoronski Chair of Lymphoma Research and Associate Professor, University of Wisconsin School of Medicine and Public Health, and Associate Director for Clinical Research, UW Carbone Cancer Center, Madison.

free survival (57% vs 72%, P = .002) and borderline worse 3-year eventfree survival (74% vs 82%, P = .055). The analysis of radiotherapy was restricted to 161 patients with skeletal involvement who had complete

tients with skeletal involvement are not improved by the addition of rituximab is unclear. Perhaps rituximab, a relatively big molecule, has difficulty obtaining appropriate biodistribution to bony sites of involvement. Perhaps

The authors have generated a provocative publication, with results that fly in the face of commonly held beliefs regarding the benefit of rituximab and the role of radiation in advanced-stage diffuse large B-cell lymphoma. —Brad Kahl, MD

or partial response after immunotherapy/chemotherapy, because patients with less than partial response went on to receive salvage chemotherapy. Compared with 29 patients not receiving radiotherapy to sites of skeletal involvement, the 133 who received radiotherapy had better 3-year eventfree survival (75% vs 36%, P < .001) and marginally better 3-year eventfree survival (86% vs 71%, P = .064). These findings led the authors to conclude, “Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement.” Precisely why outcomes of pa-

these findings are not “real” and simply statistical noise based on the relatively small numbers. There were only 61 patients in the data set who had bony involvement and who received R-CHOP. I suggest that these observations be viewed as hypothesis-generating rather than as definitive. In the meantime, I will continue to include rituximab in my diffuse large B-cell lymphoma patients who have bony involvement.

Experiment Within the Experiment The dramatic improvement in outcomes for patients who received post–rituximab/chemotherapy radiation is an interesting observation. It is

important to note that the radiation vs no radiation observation is not the result of random assignment. Rather, the protocols suggested that all patients with bony involvement receive consolidation radiation therapy, but it was merely a suggestion. As a result, an experiment within the experiment emerged, and 133 patients received radiation while 29 did not. Because there may have been biases built into the recommendation to receive radiation, this observation should also be viewed as hypothesis-generating. The authors suggest that positronemission tomography (PET) imaging post-therapy may be a useful tool to sort out who benefits from radiation post–rituximab/chemotherapy. It might, and it should be studied prospectively. Because of issues with bone remodeling post-therapy and potential for false-positive PET scans, this will need to be done very carefully. The authors have generated a provocative publication, with results that fly in the face of commonly held beliefs regarding the benefit of rituximab and the role of radiation in advanced-stage diffuse large B-cell lymphoma. n

Disclosure: Dr. Kahl is on the advisory board and receives research funding from Genentech and Roche.

Reference 1. Held G, Zeynalova S, Murawski N, et al: Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. September 23, 2013 (early release online).

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PAGE 70

Announcements

CTCA Names National Director for HIPEC Research

ancer Treatment Centers of America (CTCA) has announced the appointment of Jesus Esquivel, MD, as the National Director of Hyperthermic Intraperitoneal Chemotherapy (HIPEC). In this position Dr. Esquivel will oversee the organization’s national HIPEC research.

Dr. Esquivel’s past experience includes positions in Social Service in Mexico, as Attending Physician of General and Oncology Surgery at Kaiser Permanente, and as Director of Peritoneal Surface Malignancies at St. Agnes Health Care Hospital in Baltimore, Maryland. Additionally, Dr.

Jesus Esquivel, MD

Esquivel has been an Assistant Professor of Gynecologic Oncology at Johns Hopkins School of Medicine and Adjunct Member of the United States Military Cancer Institute. Dr. Esquivel performed his fellowship at the Washington Cancer Institute for Gastrointestinal Surgical Oncology. n

BRIEF SUMMARY for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The TAFINLAR® (dabrafenib) capsules for oral use median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg). The following is a brief summary only; see full prescribing information for complete product information. Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from 4 CONTRAINDICATIONS analyses of Trial 1 [see Clinical Studies (14) of full Prescribing Information]. Trial 1, a multi-center, None. international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable 5 WARNINGS AND PRECAUTIONS or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily 5.1 New Primary Cutaneous Malignancies (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63). The trial excluded patients TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, with abnormal left ventricular ejection fraction or cardiac valve morphology (≥Grade 2), corrected and melanoma. In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) QT interval ≥480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate occurred in 7% (14/187) of patients treated with TAFINLAR and in none of the patients treated with dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated dacarbazine. Across clinical trials of TAFINLAR (n = 586), the incidence of cuSCC was 11%. The median with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those patients who developed a cuSCC, was 60% male, 99% white, and had a median age of 53 years. The most commonly occurring adverse reactions (≥20%) in patients treated with TAFINLAR were, in approximately 33% developed one or more cuSCC with continued TAFINLAR. The median time order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and between diagnosis of the first cuSCC and the second cuSCC was 6 weeks. palmar-plantar erythrodysesthesia syndrome (PPES). In Trial 1, the incidence of new primary malignant melanomas was 2% (3/187) for patients The incidence of adverse events resulting in permanent discontinuation of study medication in receiving TAFINLAR while no chemotherapy-treated patient was diagnosed with new primary Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The malignant melanoma. most frequent (≥2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, PPES (3%), chills (3%), fatigue (2%), and headache (2%). and for up to 6 months following discontinuation of TAFINLAR. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma Table 3. Selected Common Adverse Reactions Occurring in ≥10% (All Grades) or ≥2% In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and (Grades 3 or 4) of Patients Treated with TAFINLARa increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm TAFINLAR Dacarbazine evidence of BRAF V600E mutation status prior to initiation of TAFINLAR [see Indications and Usage N = 187 N = 59 (1) and Dosage and Administration (2.1) of full Prescribing Information]. 5.3 Serious Febrile Drug Reactions All Grades All Grades Primary System Organ Class In Trial 1, serious febrile drug reactions, defined as serious cases of fever or fever of any severity Grades 3 and 4b Grades 3 and 4 Preferred Term accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another (%) (%) (%) (%) identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with TAFINLAR and Skin and subcutaneous tissue disorders in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) Hyperkeratosis 37 1 0 0 was 28% in patients treated with TAFINLAR and 10% in patients treated with dacarbazine. In patients 2 NAf Alopecia 22 NAf treated with TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days) and the median duration of fever was 3 days (range: 1 to 129 days). Palmar-plantar erythrodysesthesia syndrome 20 2 2 0 Withhold TAFINLAR for fever of 101.3°F or greater or for any serious febrile drug reaction and evaluate Rash 17 0 0 0 for signs and symptoms of infection. Refer to Table 1 for recommended dose modifications for Nervous system disorders adverse reactions [see Dosage and Administration (2.3) of full Prescribing Information]. Prophylaxis with antipyretics may be required when resuming TAFINLAR. 32 0 8 0 Headache 5.4 Hyperglycemia General disorders and administration site conditions Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent 28 3 10 0 Pyrexia therapy can occur with TAFINLAR. In Trial 1, five of 12 patients with a history of diabetes required more Musculoskeletal and connective tissue disorders intensive hypoglycemic therapy while taking TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values 6% (12/187) in patients treated with TAFINLAR compared to none at of advertiser’s Advertisement notwasdisplayed in digital edition request Arthralgia 27 1 2 0 the dacarbazine-treated patients. Back pain 12 3 7 0 Monitor serum glucose levels as clinically appropriate during treatment with TAFINLAR in patients Myalgia 11 0 0 0 with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. Neoplasms benign, malignant and unspecified (including cysts and polyps) 5.5 Uveitis and Iritis 27 0 2 0 Papillomac Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR across clinical trials. d,e 7 4 0 0 cuSCC Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Gastrointestinal disorders Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, and eye pain). 11 2 14 0 Constipation 5.6 Glucose-6-Phosphate Dehydrogenase Deficiency Respiratory, thoracic, and mediastinal disorders TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in 12 0 5 0 Cough patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients Infections and infestations with G6PD deficiency for signs of hemolytic anemia. 5.7 Embryofetal Toxicity 10 0 3 0 Nasopharyngitis Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant a Adverse drug reactions, reported using MedDRA and graded using CTCAE version 4.0 for woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the assessment of toxicity. human exposure at the recommended clinical dose. If this drug is used during pregnancy or if the b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). patient becomes pregnant while taking this drug, the patient should be apprised of the potential c Includes skin papilloma and papilloma. hazard to a fetus [see Use in Specific Populations (8.1)]. d Advise female patients of reproductive potential to use a highly effective non-hormonal method Includes squamous cell carcinoma of the skin and keratoacanthoma. e of contraception during treatment and for 4 weeks after treatment since TAFINLAR can render Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. f hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they NA = not applicable become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (8.6)]. Table 4. Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in Trial 1 [Between Arm Difference of 6 ADVERSE REACTIONS ≥5% (All Grades) or ≥2% (Grades 3 or 4)] The following adverse reactions are discussed in greater detail in another section of the label. • New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)] Dabrafenib DTIC • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] N = 187 N = 59 • Serious Febrile Drug Reactions [see Warnings and Precautions (5.3)] All Grades All Grades • Hyperglycemia [see Warnings and Precautions (5.4)] Grades 3 and 4 Grades 3 and 4 • Uveitis and Iritis [see Warnings and Precautions (5.5)] (%) (%) (%) (%) 6.1 Clinical Trials Experience Hyperglycemia 50 6 43 0 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 14 2 Hypophosphatemia 37 6a 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. Increased Alkaline phosphatase 19 0 14 2 The safety of TAFINLAR was evaluated in 586 patients with BRAF V600 mutation-positive unresectable Hyponatremia 8 2 3 0 or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily as monotherapy until disease progression or unacceptable toxicity, including 181 patients treated aGrade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

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Announcements

Mount Sinai Health System Appoints New Director and Faculty to Division of Gynecologic Oncology

eter R. Dottino, MD, has been appointed Director of the Division of Gynecologic Oncology in the Department of Obstetrics, Gynecology and Reproductive Medicine at

the Mount Sinai Health System in New York. He also holds an appointment as Associate Clinical Professor at the Icahn School of Medicine at Mount Sinai.

Dr. Dottino is Director of the Group for Women and Co-Director with John A. Martignetti, MD, of the Ovarian Cancer Translational Research Laboratory at Mount Sinai.

Other clinically important adverse reactions observed in <10% of patients (N = 586) treated with with moderate to severe hepatic impairment may have increased exposure. An appropriate TAFINLAR were: dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3) of full Prescribing Information]. Gastrointestinal Disorders: Pancreatitis. 8.8 Renal Impairment Immune System Disorders: Hypersensitivity manifesting as bullous rash. No formal pharmacokinetic trial in patients with renal impairment has been conducted. Dose Renal and Urinary Disorders: Interstitial nephritis. adjustment is not recommended for patients with mild or moderate renal impairment based 7 DRUG INTERACTIONS on the results of the population pharmacokinetic analysis. An appropriate dose has not been 7.1 Effects of Other Drugs on Dabrafenib established for patients with severe renal impairment [see Clinical Pharmacology (12.3) of full Drugs that Inhibit or Induce Drug-Metabolizing Enzymes: Dabrafenib is primarily metabolized Prescribing Information]. by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or 10 OVERDOSAGE decrease, respectively, concentrations of dabrafenib [see Clinical Pharmacology (12.3) of full There is no information on overdosage of TAFINLAR. Prescribing Information]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is 13 NONCLINICAL TOXICOLOGY recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when risk of cutaneous squamous cell carcinomas in patients in clinical trials. taking strong inducers. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) Drugs that Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump or the mouse lymphoma assay, and was not clastogenic in an in vivo rat bone marrow inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its micronucleus test. bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric In a combined female fertility and embryofetal development study in rats, a reduction in pH-altering agents on the systemic exposure of dabrafenib. When TAFINLAR is coadministered with fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of dabrafenib may exposure at the recommended dose based on AUC). A reduction in the number of ovarian be decreased and the effect on efficacy of TAFINLAR is unknown. corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately 7.2 Effects of Dabrafenib on Other Drugs three times the human exposure at the recommended dose based on AUC). Dabrafenib induces CYP3A4 and may induce other enzymes including CYP2B6, CYP2C8, CYP2C9, Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a and three times the human exposure at the recommended dose based on AUC, respectively. substrate of CYP3A4) by 61% and 74%, respectively [see Clinical Pharmacology (12.3) of full Prescribing 13.2 Animal Toxicology and/or Pharmacology Information]. Coadministration of TAFINLAR with other substrates of these enzymes, including Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and (approximately five times the human exposure at the recommended dose based on AUC) or loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor greater, when administered for up to 4 weeks. Adverse effects consisted of coronary arterial patients for loss of efficacy if use of these medications is unavoidable. degeneration/necrosis and hemorrhage, as well as cardiac atrioventricular valve 8 USE IN SPECIFIC POPULATIONS hypertrophy/hemorrhage. 8.1 Pregnancy 17 PATIENT COUNSELING INFORMATION Pregnancy Category D See FDA-approved patient labeling (Medication Guide). Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered Inform patients of the following: to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses 3 times greater • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If for whom treatment with TAFINLAR is indicated [see Dosage and Administration (2.1) of full this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the Prescribing Information]. patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.7)]. Advertisement not displayed in digital edition atof advertiser’s request • TAFINLAR increases the risk developing new primary cutaneous malignancies. Advise Animal Data: In a combined female fertility and embryofetal development study in rats, patients to contact their doctor immediately for any new lesions or changes to existing developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in lesions on their skin [see Warnings and Precautions (5.1)]. thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately 3 times the human exposure • TAFINLAR causes pyrexia including serious febrile drug reactions. Instruct patients to contact their at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the doctor if they experience a fever while taking TAFINLAR [see Warnings and Precautions (5.3)]. human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more development and reduced fetal body weight. intensive hypoglycemic treatment. Advise patients to contact their doctor to report 8.3 Nursing Mothers symptoms of severe hyperglycemia [see Warnings and Precautions (5.4)]. It is not known whether this drug is present in human milk. Because many drugs are present in • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase human milk and because of the potential for serious adverse reactions from TAFINLAR in nursing (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.6)]. into account the importance of the drug to the mother. • TAFINLAR can cause fetal harm if taken during pregnancy. Instruct female patients to use 8.4 Pediatric Use non-hormonal, highly effective contraception during treatment and for 4 weeks after The safety and effectiveness of TAFINLAR have not been established in pediatric patients. treatment. Advise patients to contact their doctor if they become pregnant, or if pregnancy is 8.5 Geriatric Use suspected, while taking TAFINLAR [see Use in Specific Populations (8.1)]. One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR and 40 (21%) • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. TAFINLAR [see Use in Specific Populations (8.3)]. 8.6 Females and Males of Reproductive Potential • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Contraception: Populations (8.6)]. Females • TAFINLAR should be taken either at least 1 hour before or at least 2 hours after a meal [see Advise female patients of reproductive potential to use highly effective contraception during Dosage and Administration (2.1) of full Prescribing Information]. treatment and for 4 weeks after treatment. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective. Advise TAFINLAR is a registered trademark of GlaxoSmithKline. patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.7), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Males Effects on spermatogenesis have been observed in animals. Advise male patients of the GlaxoSmithKline Research Triangle Park, NC 27709 potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. ©2013, GlaxoSmithKline. All rights reserved. 8.7 Hepatic Impairment TFR: 1BRS No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Revised: May 2013 Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary ©2013 GlaxoSmithKline group of companies. secretion are the primary routes of elimination of dabrafenib and its metabolites, patients All rights reserved. Printed in USA. TAF025R0 September 2013

He previously served as the Director of Gynecologic Oncology at Mount Sinai and also is one of the founders of the Ovarian Cancer Research Fund, a United States charity funding ovarian cancer research.

New Faculty Rudy Albert Segna, MD, named Associate Director of Gynecologic Oncology, and Ann Marie Beddoe, MD, named Director of the Gynecologic Oncology Chemotherapy

Left to right: Peter Dottino, MD, Ann Marie Beddoe, MD, and Rudy Albert Segna, MD

Infusion Service join Dr. Dottino at Mount Sinai as faculty members. Dr. Dottino received his medical degree at Georgetown Medical School in Washington, DC, and completed his chief residency at Downstate Medical Center/Kings County Hospital, and a fellowship in gynecologic oncology at The Mount Sinai Hospital. Dr. Segna was awarded his medical degree at New York University School of Medicine, and completed a chief residency at the Naval Medical Center in San Diego, and a fellowship at Mount Sinai. He also served as the Director of Gynecologic Oncology and the Colposcopy Service at the Naval Medical Center in Portsmouth, Virginia. Dr. Beddoe has been Assistant Professor in Gynecologic Oncology at Mount Sinai, and previously served as the Director of the Gynecologic Oncology Services at City Hospital in Elmhurst, New York. She was awarded her medical degree from the State University of New York Downstate Medical School, where she also completed residency training and a fellowship. Dr. Beddoe completed a fellowship in clinical nutrition at Memorial Sloan Kettering Cancer Center in New York. n

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Journal Spotlight Breast Cancer

No Survival Benefit of Adjuvant Ibandronate in High-Risk Early Breast Cancer: Potential Activity in Low-Estrogen Patients By Matthew Stenger

PhD, Chairman of the German Breast Group in Neu-Isenberg and Professor of Gynecology at the University of Frankfurt, Germany, and colleagues compared adjuvant oral ibandronate bisphosphonate therapy with observation in women with high-risk early breast cancer.1 The study found no survival benefit of the addition of ibandronate to dose-dense chemotherapy. Gunter von Minckwitz, MD, PhD

Study Details

he effect of bisphosphonate treatment in early breast cancer is controversial, with some data indicating survival benefit in the adjuvant

In the open-label, 2×2 factorial design GAIN trial, patients with nodepositive early breast cancer were randomly assigned between June 2004 and August 2008 to adjuvant dose-

Two years of adjuvant treatment with ibandronate after dose-dense chemotherapy had acceptable adverse effects but did not improve survival in patients with high-risk breast cancer.… Future meta-analyses on an individual patient data level may reliably reveal subgroups in which this approach has the most efficacy. —Gunter von Minckwitz, MD, PhD, and colleagues

setting. In a study reported in the Journal of Clinical Oncology (German Adjuvant Intergroup Node-Positive Study, GAIN), Gunter von Minckwitz, MD,

dense chemotherapy with either ECTX (epirubicin and cyclophosphamide for 4 2-week courses followed by 10 courses of paclitaxel combined

Adjuvant Ibandronate in Early Breast Cancer ■■ Ibandronate treatment was not associated with significant differences in disease-free survival or overall survival compared with observation.

■■ Almost one-third of patients aged younger than 40 years with hormone receptor–positive disease were receiving hormone therapy.

■■ A trend toward improved disease-free survival in patients younger than 40 years and older than 60 years was observed, suggesting activity of ibandronate in patients with low estrogen levels.

with weekly capecitabine) or ETC (3 courses of epirubicin, followed by 3 courses of paclitaxel and by 3 courses of cyclophosphamide, all given at 2-week intervals) and randomized 2:1 to ibandronate at 50 mg/d (n = 2,015) or observation (n = 1,008) for 2 years. The primary endpoint was disease-free survival. The ibandronate and observation groups were well matched for age (median, 49 and 50 years), body mass index, postmenopausal status (52% and 53%), tumor stage (eg, pT2 in 56% in both), tumor laterality (unilateral in 97% in both), histologic type (ductal invasive in 77% in both), tumor grade (G2 in 49.5% and 52%, G3 in 47% and 44%), pN status (pN1 in 38% and 37%, pN2 in 35% and 36%, pN3 in 27% in both), hormone receptor status (positive in 76.5% and 78%), HER2 status (negative in 78% in both), triple-

negative status (15% in both), surgery type (breast conservation in 55.5% and 57%), and endocrine adjuvant treatment (tamoxifen alone in 37% and 38%, aromatase inhibitor with/ without tamoxifen in 28% and 26%, and luteinizing hormone-releasing hormone and tamoxifen in 5.6% and 6.1%). Both groups had a median of five involved axillary nodes. A total of 85 of 161 patients receiving adjuvant luteinizing hormone-releasing hormone and tamoxifen were younger than age 40 years, with this total representing 31.5% of patients in this age group with hormone receptor–positive disease.

No Improvement in Disease-Free Survival In total, 78% of ibandronate patients completed treatment as planned, with 6% discontinuing treat-

Where Is Adjuvant Bisphosphonate Therapy Now? By Debu Tripathy, MD

he adjuvant use of bisphosphonates in breast cancer continues to yield seemingly contradictory data despite a sound biologic basis and smaller pilot studies suggesting that dampening bone turnover with bisphosphonates can lessen the bone reservoir of micrometastases.1,2 Early adjuvant trials with the weaker earliergeneration non-amino bisphosphonate clodronate, though not all consistent, provided promising data and suggested that this issue would be settled quickly with adequately powered studies.3-5 Dr. Tripathy is Professor of Medicine, Keck School of Medicine and USC/Norris Comprehensive Cancer Center, University of Southern California.

All things considered, adjuvant bisphosphonate therapy—and its accompanying real but small rate of osteonecrosis of the jaw and other side effects—is not quite ready for broad application. —Debu Tripathy, MD

A decade later, larger pivotal trials continue to show mixed results, although their larger sizes have raised new hypotheses. For example, the benefit of adjuvant zoledronic acid may be significant in low-estrogen environments—either with ovarian ablation or in the postmenopausal

subset as observed in the ABCSG-12, AZURE, and ZO-FAST trials.6-8

GAIN Trial The GAIN Trial tested the oral amino-bisphosphonate ibandronate for 2 years in patients not restricted by menopausal or hormone receptor

status and for whom chemotherapy was appropriate adjuvant treatment. An unplanned Bayesian futility analysis was added to the planned interim analysis, showing it was unlikely that a difference would be seen after the target number of events. No difference in disease-free survival was seen with ibandronate at the time of this prespecified analysis, but subset analysis revealed a trend toward benefit in younger patients (most of whom had ovarian blockade in the case of hormone receptor–positive disease) as well as in those over age 60. However, no difference was seen in the estrogen receptor–positive subset. There were not enough events in subsets continued on page 74

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Journal Spotlight

ment due to progression or death and 16% discontinuing for other reasons. After a median follow-up of 38.7 months, there was no difference in disease-free survival between the ibandronate group and the observation group (hazard ratio [HR] = 0.945, 95% confidence interval [CI] = 0.768–1.161, P = .589); this prompted release of efficacy data by the independent data monitoring committee due to failure of the difference to cross the futility boundary after 50% of the required disease-free survival events were observed. There was also no difference in overall survival between the two groups (HR = 1.040, P = .803). Bone metastases were found in 31% of ibandronate patients and 38% of observation patients.

Improvement Trend in Younger and Older Patients Univariate analysis showed that age, tumor and nodal stage, hormone receptor status, grade, and menopausal status but not body mass index, histologic tumor type, or HER2 status were prognostic for disease-free survival. In multivariate analysis, the same factors except age and menopausal status remained significant. Analysis adjusted by baseline factors confirmed that ibandronate did not improve diseasefree survival (HR = 0.912, P = .395) or overall survival (HR = 0.980, P = .899). Ibandronate was not associated with significant improvement in disease-free survival in any subgroup examined. A trend toward improved disease-free survival was observed with ibandronate in patients aged less than 40 years (HR = 0.70, 95% CI = 0.44–1.13), many of whom were receiving hormone therapy, and in those aged more than 60 years (HR = 0.75, 95% CI = 0.49–1.14, P = .093 for interaction).

Adverse Events Patients in the ibandronate group had an excess of adverse events of any grade (22% vs 15%, P < .001) and of at least grade 3 (5.3% vs 2.9%, P = .003). The excess was observed in the system categories of infection, cardiac, gastrointestinal, hepatobiliary, and general condition. Osteonecrosis of the jaw was reported in two ibandronate patients. No ibandronate-related deaths were observed. The investigators concluded:

[Two] years of adjuvant treatment with ibandronate after dose-dense chemotherapy had acceptable adverse effects but did not improve survival in patients with high-risk breast cancer. Post hoc subgroup analyses support the hypothesis that adjuvant bisphosphonate activity is restricted to patients with low estrogen levels, either because

of medical ovarian suppression or definite menopause. Future meta-analyses on an individual patient data level may reliably reveal subgroups in which this approach has the most efficacy. n Disclosure: The study was supported by Amgen, Germany, Bristol-Myers Squibb, Germany, and Roche, Germany. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. von Minckwitz G, Möbus V, Schneeweiss A, et al: German Adjuvant Intergroup Node-Positive Study: A phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer. J Clin Oncol 31:3531-3539, 2013.

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Journal Spotlight

Debu Tripathy, MD, on Bisphosphonate Therapy continued from page 72

of interest—for example, postmenopausal patients with hormone receptor–positive tumors—to verify the findings of other studies.

ABCSG-12 Trial The ABCSG-12 trial is the only contemporary trial to show a benefit in its primary endpoint in the overall population. It remains unclear whether the benefit in a low-estrogen state also requires hormone receptor–posi-

tive breast cancer. In fact, one randomized neoadjuvant zoledronic acid study showed a disease-free and overall survival benefit in the estrogen receptor–negative subset only.9 Nevertheless, in the general population of early-stage breast cancer patients,

recent meta-analyses of randomized zoledronic acid studies (either as adjuvant therapy or to inhibit bone loss) have shown no impact on disease-free or overall survival. That said, the first cited study did show benefits for the postmenopausal subsets in disease-free (including both distant and locoregional disease) and overall survival.10,11

Further Considerations Given the known pitfalls of subset analyses, what are we to make of the collective data on adjuvant bisphosphonates? Is there enough support to change practice in the case of ovarian blockade or menopause for hormoneresponsive breast cancer? Some have postulated that these findings could be explained by estrogen-mediated effects on the bone microenvironment via transforming growth factor (TGF)-β family members and the receptor activator of nuclear factor-kappaB (RANK) signaling system, both of which affect bone modeling.12 Additionally, zoledronic acid may have direct effects on cancer cells as evidenced by higher complete pathologic complete response rates seen in both randomized groups and uncontrolled series of patients on bisphosphonate therapy.13,14 A small randomized biomarker trial demonstrated enhanced tumor recovery of cell proliferation and apoptosis and lowered post-treatment serum vascular endothelial growth factor (VEGF) with zoledronic acid.15 Explanations for this effect include direct inhibition of the mevalonic acid pathway and subsequent inhibition of the prenylation (and activation) of signal transduction proteins involved in growth factor receptor pathways.16

Conclusion All things considered, adjuvant bisphosphonate therapy—and its accompanying real but small rate of osteonecrosis of the jaw and other side effects—is not quite ready for broad application. Ideally, corroborating data from trials designed with specific subsets of patients may answer the many questions regarding the optimal agent, receptor subtype, and estrogenic milieu (eg, menopausal status, use of tamoxifen or aromatase inhibitors). n Disclosure: Dr. Tripathy reported no potential conflicts of interest. continued on page 75

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Announcements

Ocular Melanoma Research Fellowship Opportunity Announced

he American Association for Cancer Research (AACR) and the Ocular Melanoma Foundation (OMF) are pleased to announce a new partnership to provide a grant opportunity for researchers focused on ocular melanoma, which is diagnosed in approximately 2,000 adults in the United States each year.

Ocular/Uveal Melanoma Research The AACR-Ocular Melanoma Foundation Fellowship represents a joint effort to encourage and support a postdoctoral or clinical research fellow to conduct ocular/uveal melanoma research and to establish a successful career path in ophthalmology, ocular oncology, uveal melanoma cancer biology, or a similar field. “Rare diseases can often get overlooked because of low incidence or a lack of awareness, so the AACR is very pleased to be collaborating with the OMF to provide a fellowship op-

Debu Tripathy, MD, on Bisphosphonate Therapy continued from page 74

References 1. Aft R, Naughton M, Trinkaus K, et al: Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: An open label, randomised, phase 2 trial. Lancet Oncol 11:421–428, 2010. 2. Solomayer EF, Gebauer G, Hirnle P, et al: Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol 23:22712277, 2012. 3. Diel IJ, Jaschke A, Solomayer EF, et al: Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: A long-term follow-up. Ann Oncol 19:2007-2011, 2008. 4. Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled

portunity that will enable a talented young investigator to conduct research related to ocular melanoma,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “While advances have been made in recent years against metastatic melanoma of the skin, no effective treatments have been forthcoming for metastatic ocular melanoma, and more research is urgently needed to accelerate progress against this disease.” “We are delighted to be partnering with the AACR in rolling out this grant program and see it as a fantastic vehicle for identifying and catalyzing the next generation of uveal melanoma innovators,” said OMF Chairman Grant Allen. “It’s these promising young researchers who will be identifying effective systemic treatment for ocular melanoma and true cancer cures in the future and, as the only organization funding ocular melanoma research, we are honored to support these individuals today.”

trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002. 5. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 43:650-656, 2004. 6. Gnant M, Mlineritsch B, Stoeger H, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12:631641, 2011. 7. Coleman RE, Marshall H, Cameron D, et al: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:1396-1405, 2011. 8. Coleman R, de Boer R, Eidtmann H, et al: Zoledronic acid (zoledronate) for postmenopausal women with early

No effective treatments have been forthcoming for metastatic ocular melanoma, and more research is urgently needed to accelerate progress against this disease. —Margaret Foti, PhD, MD (hc)

Applications Due December 17, 2014 The fellowship will provide $50,000 over the 1-year term, which will begin July 1, 2014. The recipient will formally accept the grant at the AACR Annual Meeting 2014, held April 5-9, in San Diego, California. The proposed research may be basic, translational, or clinical in nature and must have direct, primary applicability and relevance to ocular/uveal melanoma, or, if applicable to cutaneous melanoma as well, be focused primarily on uveal mela-

breast cancer receiving adjuvant letrozole (ZO-FAST study): Final 60-month results. Ann Oncol 24:398-405, 2013. 9. Aft RL, Naughton M, Trinkaus K, et al: Effect of (neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer. Br J Cancer 107:7-11, 2012. 10. Yan T, Yin W, Zhou Q, et al: The efficacy of zoledronic acid in breast cancer adjuvant therapy: A meta-analysis of randomised controlled trials. Eur J Cancer 48:187-195, 2012. 11. Valachis A, Polyzos NP, Coleman RE, et al: Adjuvant therapy with zoledronic acid in patients with breast cancer: A systematic review and meta-analysis. Oncologist 18:353-361, 2013. 12. Hadji P, Coleman R, Gnant M, et al: The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis. Ann Oncol 23:2782-2790, 2012.

noma and its specific cancer biology. Interested investigators may visit http://bit.ly/18b6W2H for further details. Applications must be submitted by noon ET, Tuesday, Dec. 17, 2013, using the proposal central website. (https:// proposalcentral.altum.com/). A hard copy with original signatures must be mailed to the AACR at 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106, Attn: Hanna Hopfinger. Additional inquiries may be directed to grants@aacr.org. n

13. Coleman RE, Winter MC, Cameron D, et al: The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: Exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 102:10991105, 2010. 14. Chavez-Macgregor M, Brown E, Lei X, et al: Bisphosphonates and pathologic complete response to taxane- and anthracycline-based neoadjuvant chemotherapy in patients with breast cancer. Cancer 118:326-232, 2012. 15. Winter MC, Wilson C, Syddall SP, et al: Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer—a randomized biomarker pilot study. Clin Cancer Res 19:2755-2765, 2013. 16. Rogers MJ, Gordon S, Benford HL, et al: Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88:2961-2978, 2010.

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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NewYork-Presbyterian/Columbia University Medical Center Opens Irving Radiation Oncology Center

ewYork-Presbyterian/Columbia University Medical Center has opened its new Irving Radiation Oncology Center, part of the medical center’s Herbert Irving

Comprehensive Cancer Center. The 12,500-square-foot facility provides precision radiation therapies and advanced diagnostic imaging for children and adults with cancer. 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

New Imaging Technology The center’s new imaging technology offers cancer treatments that more precisely target tumors and spare healthy cells from unnecessary

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

radiation exposure. “This new technology offers greater customization and allows for a dramatically reduced treatment course, from weeks to days,” says K.S. Clifford Chao, MD, Radia(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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tion Oncologist-in-Chief at NewYorkPresbyterian/Columbia and NewYork-Presbyterian/Weill Cornell.

Serene Environment for Patients The Irving Radiation Oncology Center is an extension of the hospital’s existing radiation oncology • 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

space, which has also been renovated, and is housed on the lower level of the Morgan Stanley Children’s Hospital. The center was designed to be open and filled with natural light. A large skylight provides sunlight to the reception and waiting area to create a serene environment for all visitors. (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)]

“NewYork-Presbyterian Hospital is immensely grateful to Herbert and Florence Irving for their commitment of more than 30 years to cancer research and patient care and for their latest gift to support this stateof-the-art radiation oncology center,” said Steven J. Corwin, MD, CEO of NewYork-Presbyterian Hospital. 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.

“Their generosity has transformed cancer care at our medical center and has touched the lives of countless patients. The Irving Radiation Oncology Center will continue this tradition, delivering outstanding, compassionate care in a modern, welcoming, and patientcentered environment.” n

The ASCO Post | DECEMBER 1, 2013

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Palliative Care in Oncology Living With Cancer: The Role of Palliative Care in Long-Term Survivorship Care A Conversation With Mary McCabe, RN, MA By Jo Cavallo

ccording to data from the Surveillance, Epidemiology, and End Results Program (SEER) and the U.S.

Census Bureau registries,1 there are currently about 13.7 million cancer survivors in the United States, and that

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

number is projected to grow to 18 million by 2022. In addition, 64% of this population has survived 5 years or

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

Mary McCabe, RN, MA

more, 40% have survived 10 years or more, and 15% have survived 20 years or more. For some of these survivors, however, having a cancer diagnosis and treatment will result in myriad physical and psychosocial issues—including chronic pain, sleep disorders, anxiety and depression, and cognitive difficulties—long after active treatment is over. While the term “palliative care” used to be synonymous with end-oflife care, the increase in the number of people surviving cancer for many years past their original diagnosis or living with cancer as a chronic disease has risen so dramatically, the term has been expanded to encompass a spectrum of care for survivors of any age and at any stage of illness, said Mary McCabe, RN, MA, Director of the Cancer Survivorship Program at Memorial SloanKettering Cancer Center in New York. The ASCO Post talked with Ms. McCabe about the changing role of palliative care in long-term survivorship care plans.

Important Relationship What place does palliative care have in long-term survivorship care plans? Very often people think that palliative care and survivorship care are unrelated and are even at opposite ends of the oncology care spectrum. But if one thinks about the definition of palliative care as focusing on symptom management, then it really does have a link to survivorship care. The two terms are very, very important in relation to each other, and if you think about the essentials of palliative care, including attention to both physical and psychosocial symptoms and the need for interdis-

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Palliative Care in Oncology ciplinary care, then palliative care and survivorship care are very related.

Educational Process Is the understanding of when to use palliative care changing, especially since ASCO and other organizations are recommending that the concept be integrated into standard oncology care early after a cancer diagnosis? Yes, palliative care is about symptom management, and there is an educational process that has to take place so that people begin to think about it in that way. We need to focus on addressing symptoms that a patient either self-reports or that physicians or nurses identify when they have an interaction with the patient. Clinicians should elicit that information by asking questions regarding any symptoms and qualityof-life concerns the patient may be experiencing and not wait for the patient to bring them up voluntarily. When we think about survivorship, it’s important to acknowledge that there are several types of at-risk groups in need of palliative care symptom management. For example, we know that a pediatric cancer survivor who has had very intensive therapy is going to have a lot of chronic problems post-treatment, so linking a good assessment of those problems with interventions is important. Patients who have undergone a stem cell transplant are another at-risk group. Elderly patients are an additional group to pay close attention to. Soon, 76% of cancer survivors will be over the age of 60, and these individuals are going to have coexisting problems that may be exacerbated by their treatment. We need to monitor them and provide interventions. In addition, we need to focus on the socioeconomically disadvantaged population with limited resources.

We need to figure out how we can efficiently provide these survivors with the same quality of post-treatment care and plan their care so that it minimizes the morbidity they may experience.

GUEST EDITOR

Essential Components What are the essential components of palliative care? Symptom and pain management as well as attention to psychosocial issues are all important components. And discussions of goals of care are very important at any time along the survivorship care continuum. The other important component is determining which provider can be the most helpful, for example, in the management of pain symptoms during or after treatment. Chronic pain has been underappreciated in the successfully treated patient. Fatigue is another common problem for many cancer survivors. Although it is not really possible to pre-

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. In July 2013, Dr. Von Roenn was named ASCO’s Senior Director of Education, Science and Professional Development Department. n

they are telling us about changes in memory and/or in their ability to multitask.

Coordination of Care Who is the appropriate medical professional to address the palliative care needs of cancer survivors? There are many factors that determine who is the right provider to address specific concerns, including the type of symptom the survivor is experiencing and how far

It is not sufficient for patients to have successfully completed treatment. It is the successful completion of treatment and living well post-treatment that are the ultimate goals.” —Mary S. McCabe, RN, MA

vent or completely treat cancer-related fatigue because it is caused by a number of factors, but just acknowledging that it exists and recommending some possible interventions—for example, taking short naps throughout the day or engaging in light exercise—at least legitimizes the problem for patients. Cognitive dysfunction, known as chemobrain in the lay press, is also an extremely important problem to identify, acknowledge, and offer interventions for, to reduce the problem. It is important to reassure patients and legitimize what

out the survivor is from treatment. There are some symptoms that the oncologist may feel very comfortable addressing, especially if they are consequences of the treatment. Other symptoms or problems, such as depression, may require a referral to another specialist, and there are some issues the primary care physician may feel comfortable treating, such as chronic pain. One of the most important aspects of symptom management is for the patient to know who is responsible

for treating a specific condition. After all, coordination of care is the reason there is such an emphasis on care planning for survivors. In the short-term, the oncologist may feel responsible for care of the post-treatment patient, but over time, as care for that patient is transitioned to the primary care physician, any residual issues related to the cancer and its treatment need to be communicated to the primary care physician. A care plan needs to include some identification of who is ultimately going to be responsible for the management and alleviation of particular problems. Although the emphasis on palliative care is important, the key issue really is the focus on identifying and managing symptoms in the post-treatment patient and acknowledging that it is not sufficient for patients to have successfully completed treatment. It is the successful completion of treatment and living well post-treatment that are the ultimate goals. n

Disclosure: Ms. McCabe reported no potential conflicts of interest.

Reference 1. De Moor JS, Marlotto AB, Parry C, et al: Cancer survivors in the United States: Prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev 22:561570, 2013.

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Journal Spotlight Breast Cancer

Response-Guided Chemotherapy continued from page 1

Clinical response was determined preferably by sonography or another clinical method if investigators considered this more appropriate. No patients received trastuzumab during neoadjuvant or adjuvant treatment. Baseline characteristics were well balanced between patients receiving response-guided chemotherapy (TAC × 8 or TAC-NX) and those receiving conventional chemotherapy (TAC × 6), except for grade, with fewer undifferentiated tumors noted in the response-guided groups. The frequencies of HER2-positive (29.8%) and triple-negative (22.6%) tumors were higher than in the average breast cancer population, reflecting selection of tumors most sensitive to and in need of neoadjuvant chemotherapy.

Disease-Free Survival Improvements Median follow up was 62 months. Disease-free survival was significantly longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio [HR] = 0.78, P = .026) and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR = 0.59, P = .001). Diseasefree survival was similar in the two response-guided groups and shorter in the two groups receiving TAC × 6,

particularly in early nonresponders. Overall, disease-free survival was significantly longer in the responseguided groups than in the conventional groups combined (HR = 0.71, P = .0003). On multivariate analysis, the hazard ratio was unchanged (HR = 0.71, P = .001).

Overall Survival Outcomes Early responders receiving TAC × 8 had a borderline significant increase in

observed in hormone receptor–positive patients, 5-year follow-up might have been too short to show more pronounced effects on overall survival, which is longer in such patients.

Subgroup Analyses Disease-free survival was significantly longer after response-guided vs conventional therapy in patients with hormone receptor–positive tumors (HR = 0.56, 95% confidence inter-

Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy. —Gunter von Minckwitz, MD, PhD, and colleagues

overall survival compared with those receiving TAC × 6 (HR = 0.76, P = .060), whereas nonresponders receiving TACNX had no significant improvement compared with those receiving TAC × 6 (HR = 0.85, P = .432). Overall, response-guided therapy was associated with a significant but marginal overall survival benefit vs conventional therapy (HR = 0.79, P = .048). The investigators speculated that because the treatment effect was mainly

Response-Guided Neoadjuvant Therapy in Breast Cancer ■■ Overall, response-guided neoadjuvant therapy was associated with a significant improvement in disease-free survival and a marginal but significant improvement in overall survival.

■■ Response-guided therapy appeared to be most effective in patients with hormone receptor–positive disease.

val [CI] = 0.44–0.73) and those with HER2-negative tumors (HR = 0.63, 95% CI = 0.49–0.81). By phenotype, disease-free survival was significantly longer with response-guided therapy in luminal A (hormone receptor–positive, G1 or G2) disease (HR = 0.55, 95% CI = 0.37–0.82), luminal B (hormone receptor–positive, G3) disease (HR = 0.40, 95% CI = 0.20–0.79), and luminal B (G3; HER2-positive) disease (HR= 0.56, 95% CI = 0.33–0.96), but not in HER2-positive (nonluminal) or triple-negative disease. Pathologic complete response did not predict many of the observed survival effects, but was significantly predictive of improved disease-free survival in triple-negative (HR = 6.67, P < .001), HER2-positive (nonlumi-

nal) (HR = 5.24, P < .001), and luminal B (HER2-negative) tumors (HR = 3.74, P = .018). Other subgroups with significantly prolonged disease-free survival with response-guided therapy were age ≥ 40 years (HR = 0.73), clinical T stage 1 to 3 (HR = 0.70), clinical tumor size < 40 mm (HR = 0.62) and ≥ 40 mm (HR = 0.79), positive clinical node status (HR = 0.66), ductal or other (nonlobular) histology (HR = 0.73), and tumor grade 3 (HR = 0.65). The investigators concluded: This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptorpositive tumors…. The GeparTrio study provides the first demonstration of the advantage of neoadjuvant chemotherapy over adjuvant chemotherapy because response-guided treatment can only be conducted when the tumor is available for the monitoring of response. Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy. These findings must now be prospectively tested but can be used to guide the design of future trials. n Disclosure: The study was supported by Amgen, Chugai, Roche, and sanofi-aventis. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. von Minckwitz G, Blohmer JU, Costa SD, et al: Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 31:3623-3630, 2013.

Response-Guided Neoadjuvant Therapy for Breast Cancer: A Promising Model Warranting Additional Investigation By Roisin M. Connolly, MB, BCh, and Vered Stearns, MD

eparTrio was an innovative phase III trial conducted by the German Breast Group, enrolling over 2,000 women with early breast Dr. Connolly is Assistant Professor of Oncology, and Dr. Stearns is Professor of Oncology, Breast Cancer Research Chair in Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.

cancer who were candidates for neoadjuvant chemotherapy. Patients with evidence of early response, defined as reduction in clinical tumor size by 50% or more, following two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) were randomized to conventional vs intensification arms for a total of six or eight cycles of the combination (TAC × 6 and TAC × 8, respectively). The response-

guided treatment intensification did not lead to improvement in pathologic complete response rates, the primary endpoint of the study (21% and 23.5% for TAC × 6 and TAC × 8, respectively). Moreover, the longer duration of chemotherapy was associated with a higher degree of toxicity.1,2 Patients without an early response after two cycles of TAC were randomized to conventional four additional

cycles of TAC or to an investigational arm consisting of vinorelbine and capecitabine (NX). Pathologic complete response rates in early nonresponders was low in both arms (approximately 6%).

Role of Pathologic Complete Response Pathologic complete response following neoadjuvant chemotherapy is

ASCOPost.com | DECEMBER 1, 2013

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Journal Spotlight

an accepted primary endpoint in clinical trials, as it is associated with improved disease-free survival and overall survival.3,4 It is intriguing, therefore, that the exploratory analysis of longterm survival of the GeparTrio trial indicated that disease-free survival was significantly longer in early responders receiving TAC × 8 than in those receiving TAC × 6, and in early nonresponders receiving TAC-NX than in those receiving TAC × 6. Compared to the conventional groups combined, response-guided therapy was associated with a significantly longer disease-free survival and with a significant but marginal overall survival benefit. This observation may relate, in part, to inadequate follow-up for the predominantly hormone receptor–positive population enrolled in the study. In an exploratory post hoc subgroup analysis, response-guided therapy was most effective in patients with hormone receptor–positive disease. It has been recognized that pathologic complete response is not an appropriate surrogate for survival in all breast cancer subtypes. Indeed, the U.S. Food and Drug Administration (FDA) released a Draft Guidance to Industry in 2012 outlining a pathway to accelerated approval for neoadjuvant breast cancer therapies.5 This guidance supports the use of pathologic complete response as a regulatory endpoint for new drug development in HER2-positive and triple-negative but not hormone receptor–positive breast cancer. Furthermore, final approval of an agent or a combination based on a neoadjuvant treatment strategy is dependent on the provision of additional supportive data, including the results of adjuvant studies that are ongoing or planned at the time of accelerated approval.

Other Clinical Trial Designs While results from GeparTrio support the hypothesis that responseguided treatment strategies may be beneficial for early breast cancer patients receiving neoadjuvant chemotherapy, this approach is “not ready for prime time” for a number of reasons, including the exploratory nature of the analysis, which was not powered to show differences in survival. In addition, the subgroup analysis that suggested a benefit to response-guided treatment in hormone receptor–positive patients was

not preplanned. Other limitations include lack of anti-HER2 therapy in patients with HER2-positive tumors and subtype designation based on immunohistochemical analysis and histologic grading. Dr. von Minckwitz and colleagues correctly conclude that a prospective validation of the results is required prior to adopting the approach, and that the results may guide the design of future studies. In addition to response-guided strategies, other clinical trial designs in the neoadjuvant setting have been used in order to improve both shortand long-term outcomes for breast cancer patients. For example, in Ge-

high-risk early breast cancer. However, it is clear that there are many patients who do not require or will not benefit from this aggressive approach. The challenge is how to reduce the number of agents or duration of treatment administered to some women with stage II/III breast cancer. Advances have been made in personalizing therapy for breast cancer over the past several years, with prospective/retrospective studies suggesting a role for gene-expression signatures such as Oncotype DX as a prognostic marker in patients with hormone receptor–positive disease who have been treated with endocrine

Predictors of pathologic complete response at baseline and early in the treatment course may be most valuable in limiting the administration of unnecessary and aggressive therapies to breast cancer patients. —Roisin M. Connolly, MB, BCh, and Vered Stearns, MD

parSixto, higher pathologic complete response rates were observed when carboplatin was added to an anthracycline/taxane–based backbone compared to anthracycline/taxane alone, although the more-intensive regimen was also associated with increased toxicity.6 Cancer and Leukemia Group B (CALGB) 40603 investigators are also evaluating the value of adding platinum agents to an anthracycline/taxane approach in a similar patient population, and results are eagerly awaited. Novel agents may also be added to the standard anthracycline/taxane–based backbone in an effort to improve outcomes for high-risk patients.

Personalizing Therapy Most of the studies conducted to date in the neoadjuvant setting involve intensifying therapy in order to improve outcomes in patients with

agents.7 Patients with a high recurrence score appear to be the ones most likely to derive benefit from the addition of chemotherapy, and those with a low score may be better served by entering into clinical trials attempting to overcome resistance to endocrinebased strategies. Similar prognostic and predictive tools are needed for women with hormone receptor–negative or HER2-positive disease. Clinical trials in patients with hormone receptor–positive and HER2positive disease should also aim to identify subpopulations of patients who may be treated with targeted therapy alone, avoiding chemotherapy, through innovative study designs. Prior to initiating large-scale studies, investigators should also consider smaller neoadjuvant studies using surrogate biomarkers of response to assess magnitude of effects in specific populations. Early biomarkers

(for example functional imaging or blood- or tissue-based biomarkers as early as 1 or 2 weeks following treatment initiation) have the potential to identify a group of women who can be spared additional futile, toxic, and costly therapies, and who can be transitioned to an alternative regimen or proceed with local therapy.

Conclusions In summary, studies in the neoadjuvant setting should be specific to tumor subtype and may include standard and/or novel targeted therapies. For patients with triple-negative and HER2-positive breast cancer, pathologic complete response is an acceptable primary endpoint and surrogate for long-term outcomes. The neoadjuvant approach is more challenging for patients with hormone receptor– positive disease, due to the lack of correlation with pathologic complete response and long-term outcome. Predictors of pathologic complete response at baseline and early in the treatment course may be most valuable in limiting the administration of unnecessary and aggressive therapies to breast cancer patients. Until additional data are available, investigators should continue to follow practice guidelines clinically and FDA guidance as they design new trials. n Disclosure: Dr. Connolly has received grants for clinical trial conduct from Novartis and Puma Biotechnology. Dr. Stearns has received grants for clinical trial conduct from Abbott, Abraxis (Celegene), Medimmune, Merck, Novartis, and Pfizer.

References 1. von Minckwitz G, Kummel S, Vogel P, et al: J Natl Cancer Inst 100:542-551, 2008. 2. von Minckwitz G, Kummel S, Vogel P, et al: J Natl Cancer Inst 100:552-562, 2008. 3. Wolmark N, Wang J, Mamounas E, et al: J Natl Cancer Inst Monogr 30:96-102, 2001. 4. Kong X, Moran MS, Zhang N, et al: Eur J Cancer 47:2084-2090, 2011. 5. U.S. Food and Drug Administration: Guidance for Industry. Available at www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed November 4, 2013. 6. von Minckwitz G, Schneeweiss A, Salat C, et al: ASCO Annual Meeting. Abstract 1004. Presented June 3, 2013. 7. Dowsett M, Cuzick J, Wale C, et al: J Clin Oncol 28:1829-1834, 2010.

The ASCO Post | DECEMBER 1, 2013

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Journal Spotlight Breast Cancer

Alliance Trial Evaluates Sentinel Node Surgery After Neoadjuvant Chemotherapy for Node-Positive cN1 Breast Cancer By Matthew Stenger

entinel lymph node surgery provides reliable nodal staging information and is associated with less morbidity than axillary lymph node dissection in patients with clinically node-negative (cN0) breast cancer. The American College of Surgeons Oncology Group (ACOSOG) Z1071 (Alliance) trial examined the falsenegative rate of sentinel node surgery for staging the axilla after neoadjuvant chemotherapy in women who presented with node-positive cN1 breast cancer. As reported in the Journal of the American Medical Association by Judy C. Boughey, MD, of the Mayo Clinic, and colleagues, the false-negative rate

was found to be 12.6% in women with two or more sentinel nodes examined—slightly higher than the 10% rate

Study Details The trial enrolled 756 women who had clinical T0-4, N1-2, M0 breast

Our trial found that both the use of dual-agent mapping and recovery of more than two sentinel lymph nodes were associated with a lower likelihood of false-negative sentinel node findings. —Judy C. Boughey, MD, and colleagues

expected with sentinel lymph node surgery in women with cN0 disease.1

cancer and received neoadjuvant chemotherapy. Following chemotherapy,

patients underwent both sentinel node surgery and axillary node dissection. Sentinel node surgery using both blue dye and a radiolabeled colloid mapping agent was encouraged. The primary endpoint was the falsenegative rate of sentinel node surgery after chemotherapy in women who presented with cN1 disease, with the study evaluating the likelihood that the rate in patients with two or more sentinel nodes examined would be greater than the 10% rate expected with sentinel node surgery in women who present with cN0 disease. Of 663 evaluable patients with cN1 disease, 30% had HER2-positive continued on page 88

EXPERT POINT OF VIEW

n an editorial accompanying the article by Boughey et al, Monica Morrow, MD, and Chau T. Dang, MD, of Memorial Sloan-Kettering Cancer Center, New York, question whether sentinel lymph node biopsy can be considered a part of standard management in patients with initial clinically node-positive disease. They point out that the finding in the Boughey et al study that the falsenegative rate of sentinel node sampling dropped below 10% only when three or more sentinel nodes were removed is similar to the findings of the SENTINA trial, in which initially node-positive patients had to be clinically node-negative after neoadjuvant chemotherapy in order to undergo sentinel lymph node biopsy. In addition to the findings of the SENTINA trial suggesting that false-negative rates are not improved by selecting patients with clinically node-negative disease following neoadjuvant chemotherapy for sentinel lymph node biopsy, the two studies together clearly show that only when at least three lymph nodes are harvested during sentinel node biopsy is the false-negative rate for patients initially presenting with clinically nodepositive disease comparable to that in patients initially presenting with clinically node-negative disease who undergo sentinel lymph node procedures after chemotherapy or in pa-

tients who have sentinel lymph node biopsy prior to chemotherapy. Nevertheless, they point out, “Whether the random removal of additional nodes for patients with fewer than 3 [sentinel nodes] results in equivalent false-negative results is uncertain, and random sampling cannot be advocated as standard management.”

Importance of False-Negative Rates? Drs. Morrow and Dang go on to question the assumption that falsenegative rates > 10% for sentinel node biopsy is important, noting that a large experience with sentinel node biopsy in patients having surgery before chemotherapy shows an incidence of clinical nodal recurrence substantially lower than the false-negative rate. As examples, they cite the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial, in which the false-negative rate of sentinel node biopsy was 9.8% and only 0.7% of patients developed their first recurrence of cancer in the axilla, and the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, in which almost all patients received systemic therapy and radiotherapy and in which 27% of patients receiving sentinel lymph node biopsy had axillary lymph node cancer that was

Because there is no information regarding long-term local cancer control or survival for patients initially presenting with clinically node-positive disease who receive neoadjuvant therapy, but have a 20% to 30% rate of residual cancer in the axilla following [sentinel node] biopsy, we do not believe that [sentinel node] biopsy, regardless of the number of [sentinel nodes] removed, can be considered standard management for these patients. —Monica Morrow, MD, and Chau T. Dang, MD

not removed during surgery but only 0.9% had their first cancer recurrence in the axilla. This 27% figure is similar to the 31% false-negative rate after the removal of one sentinel node in the Boughey et al study. As the commentators stated, “The patients who did not have [axillary lymph node dissection] in the ACOSOG Z0011 study did not experience an excess of distant metastases and death … strongly arguing that undetected microscopic cancer in patients presenting with clinically node-negative disease does not result in a clinically important

increase in recurrences despite being left in place.”

Further Considerations Finally, the commentators point out that decisions about using systemic therapy after neoadjuvant therapy are not dependent upon identifying residual cancer in lymph nodes when all the planned chemotherapy is given preoperatively to maximize the cancer response. They note that identification of residual lymph node cancer may be important in trials of new agents in continued on page 88

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 | DECEMBER 1, 2013

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Journal Spotlight

Sentinel Node Surgery continued from page 86

disease, 45% had hormone receptor–positive/HER2-negative disease, and 23.5% had triple-negative disease. Most had clinical T2 disease (56%), invasive ductal carcinoma (89%), core needle axillary biopsy (61%), anthracycline plus taxane chemotherapy (75%), and no palpable axillary adenopathy after chemotherapy (84%). In total, 92% completed neoadjuvant chemotherapy. Of 651 patients with cN1 disease undergoing sentinel node surgery, 4% had mapping with blue dye only, 17% with radiolabeled colloid only, and 79% with both radiolabeled colloid and blue dye, as recommended by the protocol.

False-Negative Rate of 12.6% Of the 663 patients, 649 underwent chemotherapy followed by both sentinel node surgery and axillary node dissection. A sentinel lymph node could not be identified in 46 patients (7.1%), and only one sentinel node was removed in 78 patients (12.0%). Of the remaining 525 patients with two or more sentinel nodes removed, no cancer was identified in the axillary nodes of 215 patients, yielding a pathologic complete nodal response of 41.0% (95% confidence interval [CI] = 36.7%–45.3%). In the remaining 310 patients, re-

Monica Morrow, MD, and Chau T. Dang, MD continued from page 86

which post-neoadjuvant treatment decisions may depend on detection of residual disease. However, in considering what information can be derived from an initial sentinel node biopsy, they maintain that it must be recognized that patients with residual cancer after neoadjuvant therapy have some level of resistance to systemic therapy. Such patients might require more aggres-

sidual nodal disease was confined to sentinel nodes in 108 (20.6%), confined to nodes removed with axillary node dissection in 39 (7.4%), and present in nodes from both procedures in 163 (31.1%). Thus, sentinel node findings were false-negative in 39 of the 310 patients with residual nodal

vs 20.3% with single agent) and by examination of at least three sentinel nodes (P = .007, false-negative rate = 9.1% for ≥ 3 sentinel nodes vs 21.1% for 2). Multivariate analysis showed that after accounting for the number of sentinel nodes examined (2 vs ≥ 3), no other factors were significant in ex-

Role of Sentinel Node Biopsy ■■ Among women with cN1 breast cancer receiving neoadjuvant

chemotherapy who had two or more sentinel nodes examined, the falsenegative rate was not found to be ≤ 10%.

■■ Use of dual-agent mapping and recovery of more than two sentinel nodes were associated with a lower likelihood of false-negative sentinel node findings.

■■ The findings suggest that surgical technical factors are important to

minimize the false-negative rate when performing sentinel lymph node surgery in this setting. Additionally, selection of patients with the greatest likelihood of pathologic nodal response is recommended.

A bivariable analysis showed that the likelihood of false-negative sentinel node findings was significantly reduced when mapping was performed with the combination of blue dye and radiolabeled colloid (P = .05, falsenegative rate 10.8% with combination

plaining variability in the likelihood of a false-negative finding. The trial included 26 women with cN2 disease with at least two sentinel nodes excised followed by axillary node dissection. Among these, 12 had no residual nodal disease, yielding a pathologic complete nodal response rate of 46.1% (95% CI = 26.6%– 66.6%). Among the remaining 14, residual nodal disease was found only in sentinel nodes in six patients and in both sentinel nodes and nodes excised

sive local therapy such as complete axillary lymph node dissection or axillary radiation therapy. In this regard, Drs. Morrow and Dang state, “Because there is no information regarding long-term local cancer control or survival for patients initially presenting with clinically node-positive disease who receive neoadjuvant therapy, but have a 20% to 30% rate of residual cancer in the axilla following [sentinel node] biopsy, we do not believe that [sentinel node] biopsy, regardless of

the number of [sentinel nodes] removed, can be considered standard management for these patients.” It may be that in the future, identification of residual disease after neoadjuvant therapy will change subsequent systemic management, in which case prognostic information obtained from residual nodal disease after neoadjuvant therapy is likely to become increasingly important in determining the need for additional therapy. “If that is true,” concluded the commentators, “re-

disease, yielding a false-negative rate of 12.6% (90% Bayesian credible interval = 9.85%–16.05%).

Reduced Likelihood of False-Negatives

on axillary node dissection in eight patients, yielding a false-negative rate of 0% (95% CI = 0%–23.2%). The investigators concluded: [O]ur trial found that both the use of dualagent mapping and recovery of more than 2 [sentinel lymph nodes] were associated with a lower likelihood of false-negative [sentinel node] findings. Among women with cN1 breast cancer who received neoadjuvant chemotherapy and had 2 or more [sentinel nodes] examined, the false-negative rate was 12.6% … with [sentinel node] surgery and exceeded the prespecified threshold of 10%. Given this acceptability threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of [sentinel node] surgery as an alternative to [axillary node dissection] in this patient population. n

Disclosure: The study was supported by a grant from the National Cancer Institute awarded to ACOSOG. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Boughey JC, Suman VJ, Mittendorf EA, et al: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: The ACOSOG Z1071 (Alliance) clinical trial. JAMA 310:1455-1461, 2013.

search in ways to improve the performance of [sentinel node] biopsy after neoadjuvant therapy is needed for this approach to become a viable management strategy.” n

Disclosure: Dr. Morrow and Dr. Dang reported no potential conflicts of interest.

Reference 1. Morrow N, Dang CT: Editorial. Sentinel node biopsy after neoadjuvant chemotherapy: A new standard for patients with axillary metastases? JAMA 310:1449-1450, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Mary McCabe, RN, MA, on Palliative Care in Long-Term Survivorship see page 82

Noah D. Kauff, MD, on BRCA Mutations and Hysterectomy see page 108

Visit The ASCO Post online at ASCOPost.com

Grant Achatz, on Surviving Stage IV Squamous Cell Carcinoma of the Tongue see page 111

ASCOPost.com | DECEMBER 1, 2013

PAGE 89

Announcements

University of Michigan Cancer Center Founding Director to Step Down

ax S. Wicha, MD, has announced he will step down as Director of the University of Michigan Comprehensive Cancer Center where he has served for the past 27 years. Dr. Wicha founded University of Michigan’s Cancer Center in 1986 and shep-

herded it to its first National Cancer Institute Cancer Center designation in 1988. Dr. Wicha will continue both his clinical practice and his active research lab, which has grown to include about 30 people. His team’s cancer stem cell research has advanced into testing of

Max S. Wicha, MD

anti-stem cell compounds in clinical trials as potential new therapies for advanced cancer. A national search will be conducted to identify a new Cancer Center director. Dr. Wicha will remain as Director until his successor is named. n

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The ASCO Post | DECEMBER 1, 2013

PAGE 90

Health-Care Policy

Improving Quality Measurement in Cancer Care: Policy Recommendations By Ronald Piana

uality measurement—how we assess cost and effectiveness of cancer care—cannot be separated from policy decisions that have a profound influence on the overall healthcare system. At the recent ASCO Quality Care Symposium, Jennifer L. Malin, MD, PhD, Medical Director for Oncology at WellPoint, Inc, Thousand Oaks, California, noted that many in the oncology community first began thinking about quality measurement with the release of IOM’s 1999 report on the quality of cancer care.1 “The IOM report highlighted the gaps in quality of cancer care for our patients. Although the extent wasn’t fully known, the report underscored the need for us to use a core set of quality measures to assess quality,” said Dr. Malin.

Increased Urgency “Now some 14 years later, with IOM’s new report, “Delivering HighQuality Cancer Care: Charting a New Course for a System in Crisis” we see an increased urgency on this issue with the call for a national quality reporting program with meaningful quality measures including patient outcomes,” said Dr. Malin. She commented that one component of the reporting program should be aligning reimbursement to reward affordable, patient-centered care. “Foremost to this discussion, it’s important to understand that patientcentered care establishes a partnership among practitioners, patients, and their families to ensure that the decisions respect patients’ wants, needs, and preferences and that patients have the education to make and participate in their own care,” said Dr. Malin. She explained, “Quality improvement centers around the science and application of measures to get better outcomes. And then there is accountability and transparency, the way that we ensure that our patients have access to the highest quality of care possible,” said Dr. Malin, adding, “But the

most important aspect of improving the cancer care system is the implementation of rigorous quality measurement instruments and payment systems that are associated with quality as opposed to volume. A number of initiatives have changed the overall ecosystem, bringing us to a place where most of us are fluent in the language of quality measurement.”

Quality Measurement Initiatives Dr. Malin looked at the results of several quality measurement initiatives such as ASCO’s Quality Oncology Practice Initiative (QOPI®). “QOPI probably gives us the broadest view

tive radiologic strategies from oncology practice. ASCO joined the ABIM Foundation’s initiative in 2012 and recently released its list of top recommendations for 2013. “They advise against using cancer-directed therapy for solid tumor patients with low-performance status. They recommend not performing [positron-emission tomography (PET), computed tomography (CT)], and radionuclide bone scans in staging patients with early prostate cancer at low risk of metastases. And they advocate not using PET, CT, and radionuclide scans in early breast cancer, also at low risk for metastases,” said Dr. Malin.

The most important aspect of improving the cancer care system is the implementation of rigorous quality measurement instruments and payment systems that are associated with quality as opposed to volume. —Jennifer L. Malin, MD, PhD

of today’s quality measures. On some metrics, such as adherence to adjuvant therapy, there’s very high compliance, but we don’t see much change over time, which most likely indicates a ceiling effect,” said Dr. Malin. The measures in supportive care showed a different picture. “We see more variation in supportive care in terms of how we’re treating symptoms, but again, there is little variation over time that shows an upward trend of quality. So we must ask ourselves why there is such little change in the clinical outcomes we measure,” said Dr. Malin. She pointed to the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely ® campaign as another initiative to cull ineffec-

She used a study led by Bruce E. Hillner, MD,1 to highlight the QOPI report. “The data in Bruce Hillner’s study underscore the top Choosing Wisely recommendations on overuse of imaging. They looked at scanning patterns in patients across five cancer groups, running the gamut from diagnostic to surveillance. It’s hard to imagine that in some tumor types, more than 50% to 70% of patients received multiple imaging tests within a very short period of time,” said Dr. Malin. “We tend to think of unnecessary imaging in terms of costs, but I would argue that this is not very patient-centered care because it places a burden on patients and caregivers to go back and forth for imaging studies that for

the most part are unnecessary,” said Dr. Malin. “Moreover, looking at some of the outcomes and issues that current measurement strategies have identified, we see a lack of adaptability to discriminate variations in quality, which limits their utility for public reporting or pay-for-performance,” said Dr. Malin.

Improving Outcomes “Quality measurement is an iterative process, but the end goal is improving outcomes. You can have a measure indicating that 60% of cancer patients have their pain needs addressed, but the question becomes, how do you move that needle so that 100% of patients are as pain-free as possible? So the hard work that takes us from where we are to where we want to go is using a measure and then initiating quality improvement strategies,” noted Dr. Malin. She concluded, “We need measures that take into account the waste in the system. Not doing things that are unnecessary is as important for the system as doing the things that are necessary. And to enable accountability and transparency, we have to report our quality measures in a way that our stakeholders can best use the data. Measures need to be specific enough to distinguish high-quality care from mediocre or poor care. Most important, they need to capture the patient experience.” n

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

References 1. Malin J: Policy recommendations to improve quality measurement. 2013 Quality Care Symposium. Presented November 1, 2013. 2. Hillner BE, Tosteson AN, Song Y, et al: Growth in the use of PET for six cancer types after coverage by Medicare: Additive or replacement? J Am Coll Radiol 9:33-41, 2012.

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2013–2014 Oncology Meetings December Sixth AACR International Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved December 6-9 • Atlanta, Georgia For more information: www.aacr.org 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.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

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org Current Controversies in the 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 Gastrointestinal Cancers Conference December 13-15 • Antalya, Turkey For more information: www.igicc2013.org

January 2014

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

AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer January 6-9 • San Diego, California For more information: www.aacr.org 2014 Gastrointestinal Cancers Symposium January 16-18 • San Francisco, California For more information: www.gicasym.org

2013–2014

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

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

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 Gynecological Oncology 2014 Winter Meeting February 20-22 - Breckenridge, Colorado For more information: www.sgo.org

Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 – Phoenix, Arizona For more information: www.surgonc.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/

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

American Association for Cancer Research: RAS Oncogenes: From Biology to Therapy February 24-27 - Lake Buena Vista, Florida For more information: www.aacr.og

24th Annual Interdisciplinary Breast Cancer Conference March 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/

March 2014 Genitourinary Cancers Symposium: Celebrating 10 Years January 30-February 1 • San Francisco, California For more information: www.gucasym.org

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

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

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/

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 WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. 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 WARNINGS 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 MONTHS

PFS (%)

60 50

12.4 MONTHS

40 30

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.

20 10 0

P+H+D Pl+H+D

• 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

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk IRF = independent review facility; 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 WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • 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 PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD) • In Study 1, for patients with MBC, 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 in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETAtreated group and in 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 in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% 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 LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions • PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, 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

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

• 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

37.6 MONTHS

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

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

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

84 67

33 22

9 4

0 0

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 • 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

Hypersensitivity Reactions/Anaphylaxis

• In Study 1, 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 Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI- CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

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 • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

PER0001010504

Printed in USA.

10/13

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

• In MBC, 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 may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. September 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.

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical

Cosmos Communications K

1 ej

Body System/ Adverse Reactions

25.5 1.1 16.0 2.1 5.3 0.0 25.5 0.0 8.5

0.0

67.0 0.0 28.7 1.1 54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 0.0 8.5

0.0

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

Table 3 Summary of Adverse Reactions ≥ 10% in Study 3 (Cont) Body System/ Adverse Reactions

PTZ + T + D Ptz + T + FEC following FEC PERJETA + TCH followed by n=75 n=76 Ptz + T + D Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

Eye disorders Lacrimation increased 12.5 Psychiatric disorders Insomnia 11.1 Investigations ALT increased 6.9

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

0.0

5.3

0.0

7.9

0.0

13.3

0.0

21.1

0.0

2.7

0.0

10.5

3.9

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

ASCOPost.com | DECEMBER 1, 2013

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Journal Spotlight Head and Neck Cancer

Spanning a Spectrum of Issues Related to Head and Neck Cancers By Charlotte Bath

ive recent articles in JAMA Otolaryngology–Head & Neck Surgery1-5 span a spectrum of issues related to head and neck cancers. These include risk factors, concentration of care to teaching hospitals, avoiding venous thromboembolism, and encouraging patients to eat and do swallowing exercises to maximize chances of returning to a regular diet after treatment.

HPV Is a Major Risk Factor More than 90% of head and neck surgeons responding to an online survey said that they discussed risk factors for head and neck cancer, and specifically human papillomavirus (HPV), with their patients.1 “The relationship of human papillomavirus to oropharyngeal carcinogenesis is now well established, with 40% to 80% of cases of oropharyngeal squamous cell carcinoma in the United States estimated to be related to HPV,”

the authors stated. The incidence of oropharyngeal squamous cell carcinoma has also been increasing, “a trend now attributed to the HPV epidemic,” they added, rising 225% between 1988 and 2004 in the United States. The survey was available online to all 1,081 members of the American Head and Neck Society and had an overall response rate of 27.5%. Most of those responding (80.4%) were fellowship-trained head and neck surgeons, and most (78.1%) practiced in the United States. Less than 50% of survey respondents reported discussing the importance of the HPV vaccination for preadolescents. The most common reason for not mentioning it, selected from the survey list by 38.7% of respondents, was “Vaccine is not appropriate for most adults so my patients are not interested.” The next most common reason, chosen by 16.7%, was “Safety and effectiveness of

vaccine are not yet proven.” The article pointed out that there are two HPV vaccines licensed by the U.S. Food and Drug Administration, Gardasil and Cervarix, both effective against HPV type 16, as well as other types. The Centers for Disease Control and Prevention currently recommends routine HPV vaccination for girls and boys aged 11 to 12 years, but the threeshot series can be started as early as age 9. “Catch-up immunization is recommended to age 26 years for women and age 21 years for men,” the authors wrote. “With more than 90% of HPVpositive [oropharyngeal squamous cell carcinoma] attributable to HPV 16, it is possible that the HPV vaccination will have an impact on [prevention of the disease]; currently, however, there is no evidence that HPV vaccines are effective against oral HPV infection.” Among survey respondents with daughters, 68.9% indicated that they

Cosmos Communications K

intend to or have had their children vaccinated. For those with sons, the percentage was 55.8%. “This is in spite of the young average age of the respondents’ children, which would indicate that for many, vaccination would still be possible,” the authors noted.

Dental Caries Not a Risk Factor An inverse relationship between dental caries and head and neck squamous cell carcinoma was “an unexpected finding” of a case control study involving 399 patients with newly diagnosed primary head and neck squamous cell carcinoma and 221 controls. The finding was unexpected, the investigators explained, “because dental caries has been considered a sign of poor oral health.”2 The study included all patients seen at the Roswell Park Cancer Institute Department of Dentistry and Maxilcontinued on page 98

The ASCO Post | DECEMBER 1, 2013

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Journal Spotlight

Head and Neck Cancers continued from page 97

lofacial Prosthetics between June 15, 1999, and September 14, 2007, except those who had a history of cancer, dysplasia, or immunodeficiency, or were younger than 21. Among the patients with head and neck squamous cell carcinoma, 37.8% had oropharyngeal squamous cell carcinoma, 36.6% had oral cavity squamous cell carcinoma, and 25.6% had laryngeal squamous cell carcinoma. Compared to controls, patients with head and neck squamous cell carcinoma had a significantly lower mean number of teeth with caries, crowns, endodontic treatments, and fillings, but more missing teeth. After adjustment for age at diagnosis, sex, marital status, smoking status, and alcohol use, those in the upper third in the number of caries, crowns, and endodontic treatments were less likely to have head and neck squamous cell carcinoma than those in the lower third. “Missing teeth was no longer associated with [head and neck squamous cell carcinoma] after adjustment for confounding,” the researchers reported. The inverse relationship between dental caries and head and neck squamous cell carcinoma persisted even among those who had never smoked and never drank alcohol. The association remained significant among patients with oral cavity and oropharyngeal squamous cell carcinoma but not among those with laryngeal squamous cell carcinoma. Two other objective measures of long-standing caries history—endodontic treatments and crowns—were also inversely associated with head and neck squamous cell carcinoma. “This supports the validity of the association between dental caries and [head and neck squamous cell carcinoma], suggesting that it is not likely a chance finding,” the authors commented. “Caries is a dental plaque-related disease. Lactic acid bacteria cause demineralization (caries) only when they are in dental plaque in immediate contact with the tooth surface. The presence of these otherwise beneficial bacteria in saliva or on mucosal surfaces may protect the host against chronic inflammatory diseases and [head and neck squamous cell carcinoma]. We could think of dental caries as a form of collateral damage and develop strategies to reduce its risk while preserving the beneficial effects of the lactic acid bacteria,” the study concluded.

Increasing Concentration of Care “Head and neck oncologic care is increasingly being regionalized to teaching hospitals and academic centers,” concluded an analysis of all inpatient admissions with a primary head and neck cancer diagnosis contained within the Nationwide Inpatient Sample during the years 2000, 2005, and 2010.3 Over the years, “as expected, and in keeping with a slowly increasing aging population, there were an increasing number of inpatient hospital stays for head and neck cancer,” representing a percentage increase of approximately 29%, the investigators found. They also “found a relative concentration or ‘regionalization’ of inpatient head and

admitted to a teaching institution for 2010 vs 2000. The percentage of cases in hospitals with a large number of beds also increased from 69.2% in 2000 to 71.4% in 2005 and 73.3% in 2010. The primary expected payer distribution did not change significantly over the study years, holding at about 39.6% for Medicare, 33.3% for private insurance, 17.4% for Medicaid, and 9.7% classified as other. “On the positive side, regionalization of head and neck cancer care to teaching institutions is likely to offer significant individual patient and societal benefit, although such benefits will need to be confirmed over time,” the authors wrote. The benefits would come from the support staff, adjunct

Five Recent Findings in Head and Neck Cancer ■■ More than 90% of head and neck surgeons responding to an online

survey said that they discussed risk factors for head and neck cancer, and specifically human papillomavirus, with their patients.

■■ An inverse relationship between dental caries and head and neck squamous cell carcinoma was an unexpected finding of a case control study.

■■ Head and neck cancer care is increasingly being regionalized to teaching

hospitals and academic centers, according to an analysis of inpatient admissions in the Nationwide Inpatient Sample during 2000, 2005, and 2010.

■■ Hospitalized patients not routinely receiving anticoagulation therapy

after surgery for head and neck cancer are at increased risk of venous thromboembolism, according to results of a prospective study.

■■ Patients who eat and perform preventive swallowing exercises during radiotherapy or chemoradiotherapy for pharyngeal cancers have the highest rate of return to a regular diet and the shortest gastronomy dependence, per a retrospective observational study.

neck cancer care evolving by the year 2010, such that almost 80% of inpatient cancer care occurred at teaching hospitals.” The percentage of admissions to teaching hospitals rose from 61.7% in 2000 to 64.2% in 2005 to 79.8% in 2010, a statistically significant increase (P < .001). “Multivariate logistic regression analysis determined that the increase in proportion of cases at teaching hospitals over the calendar years of the study, particularly for the shift in proportion from 2005 to 2010, remained significant even when adjusting for hospital region, hospital bed size, and expected source of payment (P < .001),” the researchers reported. The adjusted odds ratio for a head and neck cancer case being admitted to a teaching institution for 2005 vs 2000 was 1.1 (95% confidence interval [CI] = 0.7–1.7), compared with 2.5 (95% CI = 1.6–3.7) for a case being

services, and familiarity with recovery for complex head and neck surgical procedures at teaching hospitals and anticipated improved quality and outcomes resulting from high volumes for less commonly performed procedures. “However, this trend of concentration of care also compels us to reconsider the goals of basic otolaryngology–head and neck surgical training,” the authors stated. “The observed regionalization of complex head and neck cases logically requires revision of what constitutes the basic body of knowledge needed to certify the majority of trainees in otolaryngology vs the more specialized body of knowledge (a step below fellowship education) needed for more-focused, highvolume care.”

Risk of Venous Thromboembolism Hospitalized patients not routinely receiving anticoagulation therapy fol-

lowing surgery for head and neck cancer are at increased risk of venous thromboembolism, according to results of a prospective study of 100 consecutive patients hospitalized at a tertiary care academic surgical center.4 Researchers measured new cases of venous thromboembolism within 30 days of surgery among patients hospitalized for at least 4 days. The overall incidence of venous thromboembolism was 13%, including 8 patients with clinically significant venous thromboembolism (7 with deep venous thrombosis and 1 with pulmonary embolism) and 5 with asymptomatic lower-extremity superficial venous thromboembolism detected on ultrasonographic evaluation alone. “Of note, only 4 of the clinically significant [venous thromboembolisms] provoked any signs or symptoms. So it is likely that only these 4 (50%) would have been discovered in the absence of our rigorous prospective [venous thromboembolism] screening,” the researchers stated. Among the 14% of patients who received some form of postoperative anticoagulation therapy, the rate of bleeding complications (30.1%) was higher than that in patients without anticoagulation therapy (5.6%, P = .01). The mean age of the study participants was 63.5 years. Most participants had a history of smoking (73%) and had a diagnosis of squamous cell carcinoma (78%). “Participants underwent a variety of head and neck cancer surgical procedures, including 80% who had some form of microvascular reconstruction.” As expected, the investigators noted, these patients had moderate functional impairment and moderate to high risk for venous thromboembolism on risk assessment. “Compliance with [venous thromboembolism] guidelines has historically been poor among otolaryngologists presumably because patients are often able to ambulate soon after surgery, and the potential consequences of airway compromise from bleeding or hematoma are catastrophic. Furthermore, there is relatively little data supporting the use of routine postoperative anticoagulation in head and neck surgery patients,” the investigators noted. “Our results support the use of routine [venous thromboembolism] chemoprophylaxis in patients with head and neck cancer admitted for more than 72 hours after surgery,” the researchers concluded. “Importantly, these data establish a baseline

ASCOPost.com | DECEMBER 1, 2013

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Journal Spotlight

[venous thromboembolism] rate in high-risk head and neck cancer surgery patients that can serve as a benchmark for future prospective trials of [venous thromboembolism] chemoprophylaxis and risk stratification.”

Eat and Exercise Patients who eat and adhere to preventive swallowing exercises while being treated with radiotherapy or chemoradiotherapy for pharyngeal cancers “have the highest rate of return to a regular diet and the shortest duration of gastronomy dependence,” according to a retrospective observational study at The University of Texas MD Anderson Cancer Center in Houston. The study included 497 patients treated with definitive radiotherapy or chemoradiotherapy for pharyngeal cancer. At the conclusion of that treatment, 74% maintained oral intake, 40% full and 34% partial, and 58% reported adherence to swallowing exercises.

Maintenance of oral intake during radiotherapy or chemoradiotherapy and swallowing exercise adherence “were independently associated with better long-term diet after [radiotherapy or chemoradiotherapy] (P = .045 and P < .001, respectively) and shorter duration of gastrostomy dependence (P < .001 and P = .007, respectively) in models adjusted for tumor and treatment burden,” the researchers reported. “Swallowing is the top functional priority rated by patients with head and neck cancers before and after treatment and is a driver of quality of life in survivors,” the authors noted. “Proactive swallowing therapy is prescribed to provide maximal use of the swallowing mechanism during treatment. Two goals can be given to patients under a ‘use it or lose it’ paradigm: eat and exercise.” The benefits of maintaining oral intake during radiotherapy and chemoradiotherapy and swallowing exercise adherence have been previously dem-

onstrated, the authors continued, “but to our knowledge, the independent effects of these efforts have not been reported to date. In this study, we found that both swallowing goals—eat and exercise—were independently associated with significantly better swallowing-related end points,” they wrote. “In addition, subgroup analyses suggested dose-dependent benefits. That is, these data imply that patients who either eat or exercise fare better than those who do neither, and swallowing end points are best among those who both eat and exercise,” they noted. n

Disclosure: For full disclosures of the study authors, visit archotol.jamanetwork.com.

References 1. Malloy KM, Ellender SM, Goldenberg D, et al: A survey of current practices, attitudes, and knowledge regarding human papillomavirus-related cancers and vaccines among head and neck surgeons.

JAMA Otolaryngol Head Neck Surg. August 29, 2013 (early release online). 2. Tezal M, Scannapieco FA, Wactawski-Wende J, et al: Dental caries and head and neck cancers. JAMA Otolaryngol Head Neck Surg. September 12, 2013 (early release online). 3. Bhattacharyya N, Abemayor E: Changing patterns of hospital utilization for head and neck cancer care: Implications for future care. JAMA Otolaryngol Head Neck Surg. September 12, 2013 (early release online). 4. Clayburgh DR, Stott W, Cordiero T, et al: Prospective study of venous thromboembolism in patients with head and neck cancer after surgery. JAMA Otolaryngol Head Neck Surg. September 26, 2013 (early release online). 5. Hutcheson KA, Bhayani MK, Beadle BM: Eat and exercise during radiotherapy or chemoradiotherapy for pharyngeal cancers: Use it or lose it. JAMA Otolaryngol Head Neck Surg. September 19, 2013 (early release online). European Cancer Congress

Novel EGFR Inhibitor Added to Radiotherapy Fails to Improve Outcomes in Head and Neck Cancer By Alice Goodman

he addition of zalutumumab, an investigational epidermal growth factor receptor (EGFR) inhibitor, to primary chemoradiotherapy did not increase locoregional control or improve survival at 3 years in patients with squamous cell carcinoma of the head and

lutumumab had good activity in head and neck squamous cell carcinoma when combined with radiotherapy. The Danish Head and Neck Cancer Group (DAHANCA) 19 trial was conducted to determine whether the addition of zalutumumab during radiotherapy could im-

Zalutumumab/Chemoradiotherapy for Head and Neck Cancer ■■ The addition of the EGFR inhibitor zalutumumab to chemoradiotherapy

failed to improve locoregional disease control, disease-free survival, and overall survival compared with chemoradiotherapy alone in advanced head and neck squamous cell cancer.

■■ Patient p16 status, usually a strong prognostic factor in head and neck cancer, was not related to outcomes with zalutumumab.

neck compared with chemoradiotherapy alone, according to the first results of a randomized phase III trial reported at the Presidential Session of the 2013 European Cancer Congress in Amsterdam.

prove outcome in patients with head and neck squamous cell carcinoma, explained lead author Jesper G. Eriksen, MD, of Odense University Hospital, Denmark.

Study Background

The study enrolled 619 patients with biopsy-verified head and neck squamous cell cancer from November 2007 to June 2012. Sites of cancer were oropharynx (69%), hypopharynx (12%), larynx (15%), and oral cavity (4%). Patients were stratified by tumor site, stage (89% stage III/IV), human papillomavirus/p16 status (75% of oropha-

Cetuximab (Erbitux), an older EGFR inhibitor, is approved by the U.S. Food and Drug Administration for head and neck squamous cell carcinoma. When added to radiotherapy, cetuximab improves overall survival and locoregional disease control in this setting. Preclinical study suggested that za-

DAHANCA 19 Design

EXPERT POINT OF VIEW

ormal discussant of the Danish Head and Neck Cancer Group (DAHANCA) 19 trial at the European Cancer Congress, Daniel Zips, MD, University Hospital for Radiation Oncology, Tübingen, Germany, said that the DAHANCA trial program is impressive and conducted with stringent quality assurance. Unfortunately, he pointed out, the addition of zalutumumab was of no benefit for locoregional control or other outcomes at 3 years. Although Daniel Zips, MD p16 status is an important prognostic factor for locoregional control, p16 status did not affect locoregional control in patients treated with zalutumumab, Dr. Zips told listeners. “In patients with [head and neck squamous cell carcinoma], 3-year locoregional control has increased from 30% to 80% within the past 3 decades. This has been optimized by consecutive trial design, radiobiological knowledge, and translating that into clinical trials,” he continued. “This trial will not change clinical practice. DAHANCA 19 is the second trial to show that an [epidermal growth factor receptor] antibody added to chemoradiotherapy will not improve outcomes. CONCERT I and II showed that the addition of panitumumab [Vectibix] to radiotherapy did not improve outcome,” he said. “Chemoradiotherapy remains the standard of care for locally advanced squamous cell cancers of the head and neck,” Dr. Zips concluded. n Disclosure: Dr. Zips reported no potential conflicts of interest.

ryngeal carcinomas were positive), and concurrent cisplatin (70% of patients). Intensity-modulated radiotherapy was given to all patients, and those

with stage III/IV carcinomas were given concurrent weekly cisplatin at 40 mg/ m2. The radiosensitizer nimoracontinued on page 100

The ASCO Post | DECEMBER 1, 2013

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News

Zalutumumab continued from page 99

zole (not available in the United States) was given 90 minutes prior to radiation. Patients were randomly assigned to identical chemoradiation with or without zalutumumab. The median duration of observation was 36 months. Both treatment arms were well balanced for baseline demographic and disease characteristics; 97% of patients were treated with at least 66 Gy radiotherapy, and 97% were offered nimorazole.

The strongest prognostic factor in the overall trial was p16-positive status. Performance status as well as tumor and nodal stage were also prognostic. Patients randomly assigned to zalutumumab had more mucositis than controls, and a significant increase in folliculitis (94% any grade and grade 3/4,

29% in the zalutumumab arm). Overall, 11% of patients withdrew from zalutumumab therapy due to skin rash. n

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

Reference 1. Eriksen JG, Maare C, Johansen J, et

al: DAHANCA 19: First results of a randomized phase III study of the importance of the EGFR-inhibitor zalutumumab for the outcome of primary curative radiotherapy for squamous cell carcinoma of the head and neck. 2013 European Cancer Congress. Abstract 12. Presented September 30, 2013.

Key Findings At the time of data cutoff for the interim analysis, 126 locoregional events had occurred; 71 patients had died due to head and neck squamous cell carcinoma, and 45, from other causes. No difference was seen between arms in the rate of locoregional control: The 3-year locoregional control rate was 78% in the zalutumumab arm vs 79% in controls. When overall results were analyzed according to p16 status, locoregional control was improved in p16-positive patients (83% vs 73% in those who were p16-negative). However, p16 status had no effect on locoregional control in patients who received zalutumumab: 83% in p16-positive patients in both arms and 83% in p16-negative patients in both arms. Disease-specific survival and overall survival were comparable between the two arms.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology DRUG RESISTANCE Phospho-cMET Inhibition in Multiple Myeloma In a study reported in Clinical Cancer Research, Moschetta and colleagues

characterized the involvement of the cMet oncogene in drug resistance and the activity of a novel selective inhibitor of cMET/phospho-cMET (SU11274) in multiple myeloma cells sensitive (RPMI-8226 and MM.1S) and resistant (R5 and MM.1R) to multiple my-

eloma drugs, primary plasma cells, and multiple myeloma xenograft models. Resistant R5 and MM.1R cells exhibited higher cMET phosphorylation, leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited higher sus-

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ceptibility to the effects of SU11274 in inhibiting viability, proliferation, chemotaxis, and adhesion and in promoting apoptosis.

Role of SU11274 SU11274 was able to reverse drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMETdependent activation of the MAPK pathway. cMET and phospho-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or with drug resistance than on those from patients at diagnosis or in complete/partial remission or those from patients with monoclonal gammopathy of unknown significance. SU11274 markedly inhibited viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients. SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reversed bortezomib resistance. The investigators concluded: “Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/ refractory multiple myeloma.” n Moschetta M, et al: Clin Cancer Res 19:4371-4382, 2013. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Journal Spotlight Breast Cancer

Cost-Effectiveness of MRI Screening for Women With Familial Risk of Breast Cancer in the Netherlands By Matthew Stenger

nnual screening for breast cancer with magnetic resonance imaging (MRI) has been found to be cost-effective in women aged 30 to 60 years who are BRCA1 or BRCA2 carriers or who have a 50% chance of being a carrier, and such screening is recommended in these women by many authorities. It is unclear whether MRI screening is cost-effective in women with a family history of breast cancer without a proven mutation.

Sepideh Saadatmand, MD

In a study reported in the Journal of the National Cancer Institute, Sepideh Saadatmand, MD, of Erasmus Medical Center in Rotterdam, and colleagues analyzed data from a large Dutch prospective screening study (Dutch MRI Screening Study, or MRISC) in women with a familial risk for breast cancer to determine cost-effectiveness of annual MRI screening.1 They found that MRI screening may improve survival for women with familial risk but that it is expensive, particularly in the youngest age categories.

Study Details In MRISC, 1,597 women (8,370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and annual mammography and MRI between 1999 and 2007. Cumulative lifetime risk was calculated according to modified tables created by Claus et al.2,3 Cumulative lifetime risks of 30% to 50% and 15% to 30% were categorized as high-risk and moderate-risk, respectively. Costs per detected and treated breast cancer were calculated, and different screening strategies were modeled to estimate cost per life-year gained compared with the Dutch nationwide breast cancer screening program, which consists of biennial mammography from age 50 to 75 years. Costs were based on current costs in centers in the Netherlands and were calculated in euros and converted to U.S. dollars.

Cancer Incidence Overall, 47 breast cancers, including 9 ductal carcinomas in situ, were detected. Detection rates were 28 cases in 5,608 woman-years at risk in women in the high-risk group and 19 cases in 2,762 woman-years at risk in the medium-risk group. For the high-risk and mediumrisk groups, incidence rates per 1,000 woman-years were 0 and 0 in those aged < 30 years, 2.9 and 2.2 in those

Breast MRI to Screen Women With Familial Risk ■■ With the addition of annual MRI screening to annual mammography,

costs per breast cancer detected and treated decreased with increasing age cohort.

■■ The proportion of MRI-only detected breast cancers increased with increasing age cohort.

■■ Screening with clinical breast examination every 6 months and annual

mammography and MRI in women aged 35 to 50 years followed by biennial mammography until age 75 was estimated to result in a mortality reduction of 25% at $134,932 (€102,164) per life-year gained compared with a 17% mortality reduction at $54,665 (€41,390) per life-year gained with mammography only.

aged 30 to 39 years, 4.2 and 11.9 in those aged 40 to 49 years, 9.2 and 7.0 in those aged 50 to 59 years, and 12.1 and 13.7 in those aged ≥ 60 years.

Estimated Costs Screening with MRI was estimated to cost $123,672 (€93,639) per detected breast cancer and $133,760 (€101,277) per detected and treated

with mammography only. A strategy of annual screening with MRI followed by mammography and clinical breast examination 6 months later was more cost-effective, reducing mortality by 25% at $118,936 (€90,053) per lifeyear gained. The most cost-effective MRI screening strategy was alternate-year screening with mammography in year

Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories…. Still, it may be more cost-effective in select groups. —Sepideh Saadatmand, MD, and colleagues

breast cancer. Costs per detected and treated breast cancer decreased with increasing age cohort, likely reflecting the higher cancer incidence rate in older age cohorts: $333,930 (€252,836) in women aged < 30 years (no cancers detected), $270,677 (€204,944) in those aged 30 to 39 years, $116,403 (€88,135) in those aged 40 to 49 years, $91,491 (€69,273) in those aged 50 to 59 years, and $60,315 (€45,668) in those aged ≥ 60 years. Unexpectedly, however, the proportion of cancers detected by MRI only (and not mammography) also increased with increasing age cohort: 1 of 5 (20%) in women aged 30 to 39 years, 7 of 18 (39%) in those aged 40 to 49 years, 6 of 14 (43%) in those aged 50 to 59 years, and 0 of 2 in those aged ≥ 60 years (14 of 39, 36%, overall).

Cost-Effectiveness Analyses Screening with clinical breast examination every 6 months and annual mammography and MRI in women aged 35 to 50 years followed by biennial mammography until age 75, as in MRISC, was estimated to result in a mortality reduction of 25% at $134,932 (€102,164) per life-year gained (3.5% discounting), compared with a 17% mortality reduction at $54,665 (€41,390) per life-year gained

1 followed by MRI in year 2, which was associated with a mortality reduction of 21% at $79,654 (€60,310) per lifeyear gained. Postponing this alternating scheme until age 40 resulted in a mortality reduction of 18% at $60,267 (€45,631) per life-year gained. The investigators concluded, “Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories…. Still, it may be more cost-effective in select groups.” n

Disclosure: The Dutch MRISC study was supported by ZonMw. The study authors reported no potential conflicts of interest.

Reference 1. Saadatmand S, Tilanus-Linthorst MMA, Rutgers EJT, et al: Cost-effectiveness of screening women with familial risk for breast cancer with magnetic resonance imaging. J Natl Cancer Inst 105:13141321, 2013. 2. Claus EG, Risch N, Thompson WD: Autosomal dominant inheritance of earlyonset breast cancer. Implications for risk prediction. Cancer 73:643-651, 1994. 2. Kriege M, Brekelmans CT, Boetes C, et al: MRI screening for breast cancer in women with familial or genetic predisposition: Design of the Dutch National Study (MRISC). Fam Cancer 1:163-168, 2001. Commentary on page 103

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Journal Spotlight Continued from page 102

Evaluation of Breast Cancer MRI Screening Strategies By Rinaa S. Punglia, MD, MPH, and Natasha K. Stout, PhD

ecent years have witnessed much heated debate about the benefits of breast cancer screening and optimal screening strategies. Unlike with mammography, no randomized data are available to determine whether screening with magnetic resonance imaging (MRI) reduces mortality from breast cancer. Therefore, modeling analyses are especially useful in assessing the utility and costs of MRI in select populations, such as women with a family history of breast cancer. This issue of The ASCO Post presents an analysis by Saadatmand and colleagues, who incorporated data from a large prospective MRI screening study (MRISC) into a simulation model to evaluate alternative MRI screening strategies and assess cost per life-year gained relative to mammography alone among women with familial risk for breast cancer.

even greater. These figures are consistent with those reported by Teneja and colleagues, who found that for non–BRCA carriers, with an annual breast cancer prevalence of 2% or 1%, the incremental cost per additional QALY was $154,045 and $315,210, respectively.2 When compared to other lifesaving interventions, in terms of the cost per life-year saved, MRI screening for breast cancer is expensive. Indeed,

Ultimately, it is not the cumulative lifetime risk of breast cancer but criteria defining clinically meaningful risk of breast cancer that should be central to stratifying women for assessment of screening strategies.

Relative Costs Previous studies have shown that annual screening with MRI is costeffective for women between the ages of 30 and 60 years who either carry a BRCA mutation or have a 50% chance of carrying such a mutation. Plevritis and colleagues reported that the cost per quality-adjusted life-year (QALY) gained by screening with MRI for women between the ages of 35 and 54 years was $55,420 for those with a known BRCA1 mutation and $130,625 for those with a BRCA2 mutation.1 In the presented study, screening with MRI and mammography for women with at least a 15% cumulative lifetime risk of breast cancer cost $134,932 per additional life-year. The authors did not report the results by QALY, but had they done so, the ratios would have been Dr. Punglia is Assistant Professor of Radiation Oncology, Harvard Medical School, Department of Radiation Oncology and Center for Outcomes and Policy Research, Dana-Farber Cancer Institute, Boston. Dr. Stout is Assistant Professor, Department of Population Medicine, Harvard Medical School, and Harvard Pilgrim Health Care Institute, Boston.

ing patient age. The relative benefits of MRI have been classically thought to be greater in younger women, who have denser breasts, which renders mammography less sensitive. In the current study, however, only one of seven cancers found among women between the ages of 30 and 39 was detected by MRI only (14%), whereas for women between the ages of 40 and 49 and those between 50

—Rinaa S. Punglia, MD, MPH, and Natasha K. Stout, PhD

the incremental cost per life-year gained for the least expensive MRI strategy assessed by the present study (alternating MRI and mammogram every year compared to annual mammography) was $212,183. While no absolute numbers exist, typical thresholds for reasonable value in the United States range from $50,000 to $100,000 per QALY gained. Indeed, the United Kingdom’s National Institute for Health and Care Excellence (NICE) uses £20,000 to £30,000 per QALY (roughly $30,000–$45,000/ QALY) as its limit for approving coverage of new medical technologies.3

MRI Sensitivity Relative to Age Curiously, the authors found that the percentage of cancers detected by MRI-only increased with increas-

and 59, the percentages of cancers detected by MRI only were 33% and 40%, respectively. Whether this finding is spurious due to the relatively small numbers of cancers detected in this prospective screening study or actually a real feature of MRI sensitivity needs to be explored in other clinical settings.

Improved Risk Estimation in the Future The findings from the Saadatmand et al study also highlight the significant limitations of using cumulative lifetime risk as the primary mechanism for identifying which women should be considered eligible for MRI screening/surveillance. The observed number of breast cancer cases in the MRISC study on which the authors’ model is calibrated actually revealed a lower incidence of

breast cancer in the group of women calculated to be at higher risk of having breast cancer (5.0 cancers found per 1,000 patient-years for women with a cumulative lifetime risk between 30% and 50%) vs the group of women with a calculated cumulative lifetime risk between 15% and 30% (6.9 cancers found per 1,000 patient-years). There are inadequacies in our current methods of estimating cumulative lifetime risk. Furthermore, there is significant disparity in assessment of cumulative lifetime risk among risk models.4 Research should be focused on developing improved prediction models that incorporate family history, clinical risk factors, and results from testing of additional genes. Ultimately, however, it is not the cumulative lifetime risk of breast cancer but criteria defining clinically meaningful risk of breast cancer that should be central to stratifying women for assessment of screening strategies. The risk of developing breast cancers using such criteria will need to be weighed against the specificity of imaging techniques to determine the optimal screening strategy. n Disclosure: Drs. Punglia and Stout reported no potential conflicts of interest.

References 1. Plevritis SK, Kurian AW, Sigal BM, et al: Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA 295:2374-2384, 2006. 2. Taneja C, Edelsberg J, Weycker D, et al: Cost effectiveness of breast cancer screening with contrast-enhanced MRI in high-risk women. J Am Coll Radiol 6:171-179, 2009. 3. McCabe C, Claxton K, Culyer AJ: The NICE cost-effectiveness threshold: What it is and what that means. Pharmacoeconomics 26:733-744, 2008. 4. Ozanne EM, Drohan B, Bosinoff P, et al: Which risk model to use? Clinical implications of the ACS MRI screening guidelines. Cancer Epidemiol Biomarkers Prev 22:146-149, 2013.

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In the News Gynecologic Oncology

‘Reasonable but Not Required’ for Women With BRCA Mutations to Have Hysterectomy Concurrent With Salpingo-Oophorectomy By Charlotte Bath

or women with BRCA1 or BRCA2 mutations who choose to have salpingo-oophorectomy to reduce their risks of ovarian and breast cancer, also choosing to have a hysterectomy is “reasonable but not required,” noted Noah D. Kauff, MD, Director of the Ovarian Cancer Screening and Prevention Program and Associate Attending Physician on the Clinical Genetics and Gynecology Services, at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. The decision to have a concurrent hysterectomy should be individualized, Dr. Kauff stressed, and based on a careful appraisal of the risks and benefits of also removing the uterus. While not new, risk-reducing surgery has been in the news lately. “Particularly in the last 6 months, following Angelina Jolie’s revelation that she carries a BRCA1 mutation, the discussion of risk-reducing surgery, be it riskreducing mastectomy or risk-reducing salpingo-oophorectomy, has been brought again to the forefront. People are reexamining the pros and cons of these procedures,” Dr. Kauff said. A recent article in The New York Times1 begins with the case of a woman who tested positive for a BRCA mutation and chose to have her ovaries and fallopian tubes removed, but not her uterus. Five years later, she was diagnosed with stage III cancer of the uterus. “If I had known, I would have absolutely taken it out,” she told the Times. To put the risk in context, Dr. Kauff pointed out in an interview with The ASCO Post that “1 out of 40 women in the United States will get uterine cancer in their lifetime. So if you leave behind 100 uteruses at risk-reducing surgery, you would expect 2 to 3 of those women to get uterine cancer,” he explained. “What the article in The New York Times did not say, and what is not clear from the literature, is whether there is an increased risk of uterine cancer in women with BRCA1 or BRCA2 mutations. The data on this has been controversial,” Dr. Kauff noted.

Changed Standard of Care “Surgery to reduce breast and ovarian cancer risk should only be recommended for women with a docu-

mented BRCA1 or BRCA2 mutation,” Dr. Kauff stressed. Two studies2,3 published simultaneously in the The New England Journal of Medicine in 2002, looking at the impact of risk-reducing salpingo-oophorectomy, “very rapidly changed the standard of care for women with BRCA1 or BRCA2 mutations,” according to Dr. Kauff, who was the lead author of one of those studies. “Our study showed a reduction in the combined risk of breast and gynecologic cancer by 75% in women who had risk-reducing surgery,” he said. “Since then, multiple additional studies have shown that BRCA1 and BRCA2 mutation carriers get anywhere from a 70% to 96% reduction in

According to the ACOG practice bulletin: The decision to perform a concurrent hysterectomy should be individualized. Salpingo-oophorectomy alone confers a significant cancer risk reduction with less surgical risk and shorter postoperative recovery. Arguments in favor of hysterectomy include a more simplified hormone therapy strategy (with estrogen only) and a theoretical increased risk of cancer in the cornual fallopian tube. In addition, hysterectomy may be considered where there are other medical indications for removal of the uterus and cervix. For women taking tamoxifen, hysterectomy may be considered to reduce their endometrial cancer risk.

The reason risk-reducing salpingooophorectomy is so commonly used [in women with a BRCA mutation] is that there is no good screening alternative for ovarian cancer. —Noah D. Kauff, MD

ovarian cancer risk and anywhere from a 40% to 70% reduction in breast cancer risk if the procedure is performed premenopausally,” Dr. Kauff stated. “It is very unusual for a woman at Memorial who is otherwise healthy and has a BRCA1 or BRCA2 mutation not to ultimately undergo risk-reducing salpingo-oophorectomy, either after childbearing is complete or after menopause. The vast majority of patients do have risk-reducing salpingooophorectomy,” Dr. Kauff said. “The reason risk-reducing salpingo-oophorectomy is so commonly used is that there is no good screening alternative for ovarian cancer.”

Guidance for Women and Physicians Dr. Kauff has contributed to several documents4-6 that can provide guidance on risk-reducing salpingooophorectomy. “Probably the most important is a practice bulletin4 that the American College of Obstetricians and Gynecologists (ACOG) put out in April 2009 on hereditary breast and ovarian cancer syndrome,” he said.

Residual Fallopian Tube Risk? Concern has been raised about cancer developing in the small amount of fallopian tube that is in the body of the uterus and is left behind when the fallopian tubes, but not the uterus, are removed. “That has been a theoretical risk that has become less of a concern over the past 4 to 5 years for several reasons,” Dr. Kauff said. “Although we think the fallopian tube is likely very important at least for a fraction of BRCA-associated ovarian and fallopian tube cancers, the areas that are most important are the fimbrial ends, which are the farthest away from the uterus and the nearest to the ovary. And the fimbriae are always removed in their entirety when you do a risk-reducing salpingo-oophorectomy,” Dr. Kauff remarked. “What is not as clear is if the residual tube, which has a very different biology, is particularly important from an ovarian cancer standpoint. Additionally, there is not a single welldocumented case in the literature of a fallopian tube cancer arising in a stump of a fallopian tube following a risk-re-

ducing surgery in a BRCA mutation carrier,” he continued. “It’s a theoretical risk only.” Another area that has been “somewhat controversial,” Dr. Kauff said, concerns whether BRCA mutations are associated with “an increased risk of a more aggressive type of uterine cancer—serous uterine cancer—which in many ways behaves more similarly to ovarian cancer than it does to more common uterine cancers.” Some studies have suggested that serous cancers are more common among women with a BRCA1 or BRCA2 mutation, but this has not been confirmed, Dr. Kauff noted. Even if there is an increased risk of serous cancer, “the lifetime risk of this cancer is still likely less than 1%,” Dr. Kauff noted. “So from a biologic standpoint, it may have an impact, but it is not as clear how much of an impact it has from a clinical standpoint.”

Hysterectomy Rate Is ‘Center-Dependent’ The New York Times article reported that about half of women who have BRCA mutations and have their ovaries and fallopian tubes removed to reduce the risk of ovarian cancer, also opt for removal of the uterus. But that percentage “is actually very center-dependent,” Dr. Kauff said. “For example, at Memorial, it is a much lower number than 50%.” On average over the past 15 years, “about 16% of our patients who undergo risk-reducing salpingooophorectomy elect concomitant hysterectomy,” Dr. Kauff said. “If you go out to the West Coast, that number is probably closer to 70% to 80%. At a national level, it would not surprise me if it was 50%, but those data are not currently available.” He added that those numbers have been changing and that for 2013, the percentage of women treated at MSKCC who elect concomitant hysterectomy with salpingo-oophorectomy “is probably in the low 20% range. Our rate is probably going up, and the West Coast rate is coming down. Everyone is being more conscious of this issue and having better discussions with patients,” Dr. Kauff said. “At Memorial, we believe that if you need to remove an organ surgically, we absolutely do it. But I think we are very cognizant of the need to ask ourselves

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In the News

why we are removing a particular body part and whether it is necessary. I don’t think there is convincing evidence that we have to remove the uterus in the case of a woman with BRCA mutation, and this is why we have a very detailed discussion. When we have this discussion, the vast majority of our patients with BRCA mutations elect not to have a hysterectomy, unless there is another gynecologic reason,” he noted. “We have already put together a team to look at our data again and reassess whether there is an increased risk of subsequent uterine cancer in our prospective follow-up. So it is something that we are going to readdress. At this point, I don’t know whether we are going to come to any new conclusions, but I think it does make sense to reconsider it, and we are uniquely positioned to be able to do that.” Dr. Kauff ’s team is uniquely positioned because “Memorial has the United States’ largest single-institution

prospective cohort of BRCA mutation carriers,” he explained. “Currently we are following over 1,400 individuals who have documented BRCA1 or BRCA2 mutation with annual prospective follow-up, looking at cancer risk-reduction strategies and the occurrence of subsequent cancers.” The women are offered enrollment in the studywhen they come in for genetic testing, “but before we know the results,” Dr. Kauff said. “Almost 83% of the women who have undergone BRCA1 and BRCA2 mutation testing at MSKCC in the past decade have enrolled on this prospective follow-up study.”

Potential Markers for Uterine Cancer Asked if there were any markers or other indications to gauge who might be likely to develop uterine cancer, Dr. Kauff noted that there is a genetic marker for Lynch syndrome, “which is associated with a very high risk of

both colon and uterine cancer, and it is actually the most important inherited cause of uterine cancer. For Lynch syndrome, the lifetime risks of uterine cancer can be as high as 40% to 60% vs 2.5% in the general population. So for that group, as opposed to the group with BRCA1 or BRCA2 mutations, if you are going to do risk-reducing surgery, hysterectomy is a required procedure,” Dr. Kauff stated. “But by far the most important marker of risk of uterine cancer is obesity. That is the single biggest risk factor for uterine cancer, and that is modifiable,” he added. “Patients who are severely obese may have a 10-fold increased risk of uterine cancer compared to the general population.” n

Disclosure: Dr. Kauff has consulted and provided expert testimony for Pfizer relating to hormone replacement therapy.

References 1. Harris JW: Weighing surgeries in light of a breast cancer gene. New York

Times, October 7, 2013. 2. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002. 3. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002. 4. American College of Obstetricians and Gynecologists: Hereditary breast and ovarian cancer syndrome: Clinical management guidelines for obstetriciansgynecologists. ACOG Practice Bulletin 103:957-966, 2009. 5. Society of Gynecologic Oncologists Clinical Practice Committee: Statement on prophylactic salpingo-oophorectomy. Gynecol Oncol 98:179-181, 2005. 6. Kauff ND, Barakat RR: Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2: J Clin Oncol 25:2921-2927, 2007.

Expect Questions From Your Patients

isk-reducing salpingo-oophorectomy “is an important strategy for reducing both breast and gynecologic cancer risk for women with BRCA1 or BRCA2 mutations and is proven to improve life expectancy,” Noah D. Kauff, MD, told The ASCO Post. Questions persist, however, about whether women undergoing salpingo-oophorectomy should also have a hysterectomy to prevent later development of uterine cancer. Dr. Kauff, who is Director of the Ovarian Cancer Screening and Prevention Program and Associate Attending Physician on the Clinical Genetics and Gynecology Services at Memorial Sloan-Kettering Cancer Center in New York, advises women with a family history of breast and ovarian cancer that they need to undergo genetic counseling to see whether genetic testing can help clarify that risk. Then, if they do elect risk-reducing surgery because of an inherited risk, “it is reasonable but not required to remove the uterus.” The decision should be based on a careful discussion of the pros and cons of including a hysterectomy with salpingooophorectomy.

Potential Benefits As to the potential benefits of including hysterectomy, Dr. Kauff listed: (1) It addresses the baseline risk of

uterine cancer that all women have. (2) There is a theoretical risk of cancer developing in the fallopian tube stump if the fallopian tubes and ovaries but not the uterus are removed. He stressed that the risk is only theorectical at this point and

ment. We have to be very careful about extrapolating data from the Women’s Health Initiative, which was conducted in asymptomatic women in their early 60s without an inherited predisposition, to women who are frequently in their mid to late 30s with an inherited predis-

If you have been exposed to tamoxifen, there is an increased risk of uterine cancer even in the absence of a BRCA mutation, and that may be even greater in the presence of a BRCA mutation. That may ‘tip the scales’ toward having a hysterectomy —Noah D. Kauff, MD

may not be a “real concern.” (3) If the woman is at increased risk of high-grade uterine cancers, it also reduces that risk. (4) It may simplify hormone replacement therapy, because if you remove the uterus, you can give estrogen alone as hormone replacement therapy, as opposed to giving the combination of estrogen and progesterone if a woman has a uterus in situ. Dr. Kauff cautioned that it is not entirely clear that removing the uterus and then giving estrogen-alone hormone replacement therapy “is safer from a breast cancer standpoint than estrogen and progesterone hormone replace-

position. For this group, I don’t think it is clear that one approach to hormone replacement is safer than another. I just don’t think we have data on that at this point,” he said. “There are reasons why you might lean toward removing the uterus,” he added. “For example, if you have been exposed to tamoxifen, there is an increased risk of uterine cancer even in the absence of a BRCA mutation, and that may be even greater in the presence of a BRCA mutation. That may ‘tip the scales’ toward having a hysterectomy.” Another reason, he noted, is “if there is other gynecologic pathology—for example, fibroids that are symptomatic,

or if there is pelvic prolapse or urinary incontinence that requires a concomitant procedure. Sometimes that is easier to do with a hysterectomy at the same time.”

Potential Downsides As to the potential downsides of including a hysterectomy with a salpingooophorectomy, Dr. Kauff pointed out: (1) It is a bigger procedure. (2) It is associated with a higher risk of complications. These complications are rarely life-threatening, but because we are operating near the nerves and tissues that affect not only the uterus, but also the bladder, the rectum, and the sexual organs, there can be immediate or long-term impact on bladder function, rectal function, or sexual function. (3) Life-threatening complications are still rare, but they are a little bit more common with hysterectomy than without. (4) Doing surgery on some of the pelvic support tissues may change the risk of pelvic prolapse and perhaps urinary incontinence in the future, but again, “the data on that are quite controversial,” Dr. Kauff said. When all these factors are looked at together, “in the absence of other gynecologic indications, we think it is reasonable but not required to remove the uterus,” he concluded. n

The ASCO Post | DECEMBER 1, 2013

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Issues in Oncology

ASH as Part of ‘NDD United’ Releases Report on Effects of Sequestration

new report recently released and supported by the American Society of Hematology (ASH) details the crippling effects of sequestration on programs that rely on discretionary federal funding, including the National Institutes of Health (NIH).

In “Faces of Austerity: How Budget Cuts Have Made Us Sicker, Poorer, and Less Safe,” NDD United, an alliance of more than 3,200 national, state, and local organizations working to stop needless cuts to core government functions, goes sector by sector

detailing the stories of those who have been affected by sequestration. ASH is a member of the NDD United alliance and represents more than 14,000 hematologists worldwide, many of whom heavily rely on NIH funding to conduct cutting-edge re-

search that results in cures and better treatments for millions of patients with blood diseases and cancer. In FY 2013, NIH awarded 640 fewer competitive research grants than in FY2012, some of which are in hematology.

Devastating Impact of Budget Cuts The “Faces of Austerity” report released recently features a quote from ASH member Giuseppina Nucifora, PhD, of the University of Illinois College of Medicine, about the devastating impacts the budget cuts have had on hematology research. In a testimonial originally published in The Huffington Post and reprinted in the report, Dr. Nucifora writes that her lab “has unfortunately lost the 20-year continuous NIH support for research on a disease that affects the blood cells of mostly older patients.” Dr. Nucifora is one of 29 recipients to date of a special ASH Bridge Grant Award created to help sustain critical blood disease research amid severe NIH budget cuts and to support researchers who recently applied for NIH funds but, despite high scores, did not make the pay line. As an ASH Bridge Grant recipient, Dr. Nucifora has received $100,000 from the Society to help her bolster her application and bridge her to receipt of her next

Janis Abkowitz, MD

NIH grant. While programs like this may provide temporary relief, they will not solve the problem of inadequate NIH funding plaguing the U.S. biomedical research enterprise. “Continued, devastating cuts to NIH due to sequestration and years of flat funding pose a significant threat to medical research in the United States, forcing researchers to slow or stop their critical work and even persuading talented investigators to abandon biomedical research as a career path,” said ASH President Janis Abkowitz, MD, of the University of Washington. “Faces of Austerity” is available online at www.nddunited.org. n

ASCOPost.com | DECEMBER 1, 2013

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Patient’s Corner

It Sounds Crazy, but Cancer Has Made Me a Better Chef

A diagnosis of stage IV squamous cell carcinoma of the tongue threatened to take away not only my livelihood but my life as well. By Grant Achatz, as told to Jo Cavallo

was diagnosed with stage IVB squamous cell carcinoma of the tongue in 2007, when I was just 33 years old, but the cancer had started to show itself long before then. I first noticed a white dot on the left side of my tongue in 2002, and as time went on, the sore became annoying and hurt when it rubbed against my teeth. Visits to the dentist eased any concerns I had. “You are working 18 hours a day, raising two young children, and are stressed. Chances are you are biting your tongue at night when you sleep,” said my dentist. I had no reason to doubt him. I was young, I never smoked, and rarely drank. The possibility that I could have a life-threatening disease was the last thing on my mind. My restaurant Alinea, which I had opened 2 years earlier, had just been named the Best Restaurant in America by Gourmet magazine, and all my attention was focused on creating the next menu. Still, I wasn’t ignoring my symptoms. As the sore on my tongue got bigger and more painful, I saw another dentist who essentially confirmed what the first dentist said and fitted me for a mouth guard. She later sent me to an orthodontist to correct an overbite she thought was the cause of the sore. As soon as the orthodontist looked into my mouth, she told me I would need to see an oral surgeon for a biopsy. It was then that I found out that I had advanced-stage tongue cancer that had metastasized to the lymph nodes in my neck.

Seeking Better Options The news was stunning—and would get worse. I had been complaining about the pain in my tongue and the golf ball–sized swollen lymph node on the left side of my neck for years, and no one, not my dentists or primary care physician, ever expressed any

concern that I could have cancer. In hindsight, perhaps I should have been more assertive in asking questions and challenging their diagnosis. I wouldn’t make that same mistake again. When I met with an oncologist in Chicago, he told me that my stage IVB disease and neck metastases would require radical treatment, including neck dissection and removal of 75% of my tongue. The protocol was a sure careerender for a chef who needs his taste buds to create the unusual mixture of flavors and scents that are the hallmark

way, then I would decide against the treatment.

Thinking Outside the Box My close friend and business partner Nick Kokonas said, “We need to find someone who thinks about medicine the way you think about food: outside the box.” Nick made an appointment with Everett Vokes, MD [John E. Ultmann Professor of Medicine and Radiation Oncology and Physician-in-Chief, University of Chicago Medicine and Biological Sciences], and that was the game changer.

Having cancer has given me a greater appreciation for the importance of cancer research, and each year we hold fundraisers at our three restaurants. —Grant Achatz

of the progressive American cuisine served at Alinea. The treatment would also include chemotherapy and radiation, and after it was completed, said the oncologist, not only would I lose my ability to taste food, my ability to speak and swallow would be severely compromised. He also said my chances of surviving longer than 2 years were slim. I went to two other cancer centers in Chicago and one in New York for additional opinions, and the oncologists all agreed with the proposed treatment protocol and prognosis. Being a chef isn’t just my vocation; it’s my passion. I considered my options. If I could no longer do what I love, and the quality of my life was going to be so diminished, with a good possibility I wouldn’t survive long any-

Dr. Vokes suggested that instead of doing surgery first, then chemotherapy and radiation, the plan could be reversed. He and his team put me into a clinical trial that included a combination of four chemotherapy drugs, two of which were cetuximab (Erbitux) and cisplatin, followed by targeted radiation therapy. Dr. Vokes told me that even if the chemotherapy and radiation didn’t completely eliminate the tumor, they would reduce it enough so that surgery would be less invasive. Within 2 weeks of beginning my chemotherapy regimen, the tumor started shrinking. Five months later, after I had completed 12 rounds of chemotherapy and 65 radiation treatments, my cancer was in remission. My tongue and neck were spared, and I’ve been in remission for 6 years.

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Life Changer Although I continued to work throughout my treatment, it was tough. The radiation burned my tongue, destroying my taste buds, and shed the lining of my esophagus. I had to rely on my staff to taste the food for me. Even after the treatment ended, it took about a year before my sense of taste was completely restored. I know it sounds crazy, but I really believe that having cancer has made me a much better chef and entrepreneur and improved my life. The experience taught me it was okay to let go of some of my control in the kitchen and trust the talent of my staff so they could grow in their careers. It also gave me a greater willingness to take chances, which led to the opening of two more restaurants.

Discovering New Ways to Treat Cancer Having cancer has also given me a greater appreciation for the importance of cancer research, and each year we hold fundraisers at our three restaurants. Thus far, we’ve raised approximately $1 million for head and neck cancer research at the University of Chicago. We want to encourage the pursuit of cutting-edge research so physician/scientists can discover new approaches to treating cancer, and more patients like me can not only live but thrive after their diagnosis. n Grant Achatz lives in Chicago and is the executive chef and co-owner of Alinea, Next, and Aviary. He is the coauthor of Life, on the Line: A Chef’s Story of Chasing Greatness, Facing Death, and Redefining the Way We Eat (Gotham Books, 2011). In 2008, a year after his cancer diagnosis, Mr. Achatz was named Best Chef in America by the James Beard Foundation.

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The ASCO Post | DECEMBER 1, 2013

PAGE 112

In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER One in Three American Adults Do Not Comply With Screening Guidelines for Colorectal Cancer

The percentage of American adults aged 50 to 75 who are upto-date with recommended screening for colorectal cancer “increased from 54% in 2002 to 65% in 2010, primarily driven by increased use

of colonoscopy,” according to data from the 2012 Behavioral Risk Factor Surveillance System survey. However, 1 in 3 adults aged 50 to 75 have not complied with national screening guidelines. Developed by

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the U.S. Preventive Services Task Force, the guidelines recommend either a high-sensitivity fecal occult blood test annually, colonoscopy every 10 years, or sigmoidoscopy every 5 years with fecal occult blood test every 3 years. As reported in Morbidity and Mortality Weekly Report, published by the Centers for Disease Control and Prevention (CDC), “The proportion of respondents who had never been screened was greater among those without insurance (55.0%) and without a regular care provider (61.0%) than among those with health insurance (24.0%) and a regular care provider (23.5%).” Men and those who do not live in metropolitan areas were also more likely to never have been screened. “As education level and annual household income increased, the proportion of respondents who had never been screened decreased,” according to the report.

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Among survey respondents who were up-to-date with colorectal cancer screening, “colonoscopy was the most commonly used test (61.7%), followed by [fecal occult blood test] (10.4%), and sigmoidoscopy in combination with [fecal occult blood test] (0.7%).” While fecal occult blood test was infrequently used, the authors noted, “Newer tests, such as the high-sensitivity guaiac [fecal occult blood test] and high-sensitivity fecal immunochemical test are recommended for colorectal cancer screening in current guidelines.” Variations in the use of tests might be attributed to patient and provider preferences or reimbursement policies and availability. “The potential to increase screening rates exists if health-care providers identify the test that their patient is most likely to complete and consistently offer all recommended screening tests,” the authors noted. Achieving the CDC’s Colorectal Cancer Control Program goal of increasing colorectal cancer screening to 80% by 2014 will also require “development of organized, population-based strategies that extend colorectal cancer screening efforts to settings beyond the medical provider’s office.” Klabunde CN, et al: MMWR 62:881-888, 2013.

ASCOPost.com | DECEMBER 1, 2013

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In the Literature

BREAST CANCER Nodal Status and Tumor Size Predicted Late Recurrences of ER-Positive Breast Cancer in Postmenopausal Women Only nodal status and tumor size provided statistically significant prognostic information for predicting recurrences 5 to 10 years after diagnosis for postmenopausal women with early estrogen receptor–positive breast cancer enrolled in the monotherapy arms of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial. “Nodal status and tumor size were at least as strong in years 5 to 10 as in years 0 to 5,” Ivana Sestak, PhD, Queen Mary University, London, and coauthors reported in the Journal of the National Cancer Institute. None of the other immunohistochemical (IHC4) markers provided significant prognostic information in years 5 to 10. “These results may help select patients who could benefit most from hormonal therapy beyond 5 years of treatment,” the authors concluded.

Key Results The investigators analyzed data from 940 postmenopausal women for whom values for IHC4, and two gene-expression tests—the recurrence score and the PAM50 risk of recurrence—were available. These women received either tamoxifen or anastrozole alone and did not receive chemotherapy. “There were 154 distant recurrences; 71 occurred in years 0 to 5 and 83 occurred in years 5 to 10 (for all recurrence: 83 in years 0 to 5, 107 in years 5 to 10),” the investigators summarized. “Nodal status and tumor size were the only individual factors that added prognostic information in years 5 to 10 in the multivariable model (nodal status: χ2 = 21.72, P <.001; tumor size: χ2=10.52, P = .001; ),” the investigators reported. “None of the individual immunohistochemical markers added prognostic information in this time period.” The risk of recurrence score “was the strongest molecular prognostic factor in the late follow-up period (χ2 = 16.29; P < .001).” Results were similar for all subgroups and all recurrences.

Major Clinical Problem “The prediction and treatment of late breast cancer recurrence is an important and largely unmet need

and remains a major clinical problem,” the authors concluded. “Although nodal status and tumor size added prognostic value 5 years after diagnosis, conventional immunohistochemical markers did not add information for late recurrence of those evaluated. The [risk of recurrence] score was the only molecular factor that showed promise in predicting late recurrence and to discriminate patients into low and high risk for late distant recurrence,” they said. “These results help to identify women who are at high risk of late recurrence and who may benefit from either more intensive treatment (ie, chemotherapy) or extended endocrine treatment beyond 5 years. Validation of these results in other cohorts is needed,” the authors added. Sestak I, et al: J Natl Cancer Inst 105:1504-1511, 2013.

ENDOMETRIAL CANCER Impact of Pelvic Radiotherapy and Lymphadenectomy on Endometrial Cancer Mortality Analysis of data from 58,172 patients identified from Surveillance, Epidemiology, and End Results (SEER) registries as having stage I or II endometrial adenocarcinoma found that pelvic radiotherapy and lymphadenectomy were associated with statistically significantly reduced noncancer mortality, particularly among those with intermediate-and high-risk disease. Among low-risk stage I patients, however, both treatments were associated with statistically significant increased endometrial cancer–specific mortality. Pelvic radiotherapy was also associated with increased cancer-specific mortality in stage II patients, whereas lymphadenectomy was associated with decreased endometrial cancer mortality in stage II patients.

radiotherapy] and lymphadenectomy and improved overall survival reported in other SEER studies [are] largely due to the selection of healthier patients with higherrisk disease for these interventions, rather than effects of the treatments per se,” Loren K. Mell, MD, and colleagues from the University of California San Diego in La Jolla wrote in the Journal of the National Cancer Institute. The number of deaths totaled 2,589 from endometrial cancer, 3,019 from secondary malignancies, and 8,015 from other causes. The median times to death were 31 months for endometrial cancer, 57 months for secondary malignancy, and 78 months for noncancer causes. “Pelvic radiotherapy was associated with statistically significantly increased endometrial cancer mortality (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.52 to 1.82) in all stage I and II patients and decreased noncancer mortality in intermediate and high-risk stage I and II patients (HR = 0.82; 95% CI = 0.77 to 0.89),” the researchers reported. “Lymphadenectomy was associated with increased endometrial cancer mortality in stage I patients (HR = 1.27; 95% CI = 1.16 to 1.39), decreased endometrial cancer mortality in stage II patients (HR = 0.61; 95% CI = 0.52 to 0.72), and decreased noncancer mortality in both stage I and II patients (HR = 0.84; 95% CI = 0.80 to 0.88),” they added.

Study Background The authors noted that while radiotherapy and lymphadenectomy have been associated with improved survival in population-based studies of endometrial cancer, randomized trials and meta-analysis of controlled trials have not found evidence that these interventions improve survival. “It is important to reconcile findings from both population-based studies and randomized trials because the latter cannot always be relied on to resolve every controversy. Patients represented on randomized trials are not drawn randomly from the population, so the degree to which the findings from clinical trials strictly represent the population to which their findings are applied may be questionable,” the investigators stated. “Moreover, because of the costs of conducting clinical trials, their power to estimate primary, secondary, and subgroup effects is nearly always constrained. It is often assumed that benefits of more aggressive treatment may be underestimated in observational studies because of selective application of these treatments in patients with higher-risk disease. However, our findings indicate that, conversely, their benefits can be overestimated as well because of selective application in patients at low risk of competing mortality.” n Mell LK, et al: J Natl Cancer Inst 105:1656–1666, 2013. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Interpretation of Data There was no evidence that whole-pelvic radiotherapy was associated with statistically improved endometrial cancer–specific mortality in any risk category. “On the whole, we interpret these findings as evidence that the associations between [whole-pelvic

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PAGE 115

Perspective

Sagar Lonial, MD, on the Meaning of Myeloma continued from page 1

confusing—when viewed in the context of the recent paper by Mateos et al in The New England Journal of Medicine, where early treatment of “smoldering myeloma” demonstrated an improvement in overall survival.1 Does this mean that “smoldering myeloma” and “symptomatic myeloma” are now the same entity? Have we changed what it means to say “myeloma”?

Need for Treatment Unlike many other diseases, the diagnosis of a plasma cell disorder or myeloma is only in part dependent on the pathologic identification of a malignant clone. The current or potential future impact of that clone is a clinical determination, and one that allots patients into either solitary plasmacytoma, monoclonal gammopathy of unknown significance (MGUS), asymptomatic (smoldering) myeloma, or symptomatic myeloma. The assignment of a patient into the symptomatic category requires the presence of the CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, or Bone disease), and the detection of even one of these symptoms indicates the need for treatment. Does this mean that patients in the other categories do not have a malignancy and therefore do not warrant treatment? No, but currently there is not sufficient evidence demonstrating that early treatment improves outcomes. Until symptoms are present, the natural history of MGUS or smoldering multiple myeloma is heterogeneous, and the challenge remains in identifying—among an older population—which patients will develop symptoms related to the plasma cell clone vs which will never be bothered by the presence of this indolent clonal disorder.

The basic issue at hand is this: Can we predict whose clone has or will have clinical impact in a relatively short time and intervene early to prevent this, while avoiding overtreatment of patients who may not harbor the risk of progression required to justify the risk of early treatment?

validated tool we can employ to define these patients. The ongoing E3A06 trial is seeking to prospectively test criteria developed by the Eastern Cooperative Oncology Group and Mayo Clinic. Utilizing flow cytometry, criteria from the PETHEMA Working Group seemed to identify a group of high-risk patients,

Before we can recommend the routine use of therapy for high-risk patients with smoldering myeloma, we need solid data that will enable routine identification of risk. —Sagar Lonial, MD

Identifying High-Risk Patients The key to success is to identify which patients have a high chance (70%–80%) of developing end organ damage with 2 years. For these patients, early treatment will likely prevent complications, while for others, the risk-benefit ratio likely does not favor early treatment. In the Spanish trial, using highly specialized flow cytometry, Mateos and colleagues clearly identify a group of patients who not only have a high risk of progression to myeloma in a short time, but whose mortality, when observed without intervention, is very high. By the “letter of the law,” none of the patients enrolled in the trial had any evidence of CRAB criteria. But is there a difference between the clear, symptomatic presence of CRAB vs nearly CRAB, vs smoldering? I think the answer is yes. This illustrates the real clinical decision-making at work every time we see a patient with a plasma cell disorder. However, there is no easy and prospectively

but even in their control group, > 50% had not converted to myeloma within 2 years. Thus, in a small PETHEMA study, there were patients with rapid disease progression, yet using the group’s definition of high risk, a significant fraction of patients did not show rapid progression.1 Can such an approach be used to categorize high risk?

Work in Progress How can we piece all this together as practicing clinicians with the goals of alleviating potential symptoms without increasing the risk of unnecessarily doing harm? First, we need to take care of those we know need treatment—those with evidence of end organ damage. This has not changed. Second, if a patient has what appears to be smoldering myeloma, we should either enroll him on a clinical trial, or closely watch him. The most important point from a clinician’s perspective, and one that is not addressed by current risk models,

is that a single data point is not the answer. We need longitudinal followup to see the tempo of disease progression, and with follow-up, many of those whom we may consider to be at high risk will declare themselves rapidly. Close monitoring will likely reveal any major changes before the development of end organ damage. The book is not yet closed on whether we can treat smoldering myeloma patients sooner. But before we as a community embark on treating all patients with the diagnosis of smoldering myeloma, we first need to identify which patients are at risk, and determine if these risk factors can be prospectively validated. The upsides of identifying and treating early are clear, as demonstrated by the Spanish study, but we must remain mindful of the downsides. Early treatment results in exposure to risks and side effects of treatment for a group of patients who may not need treatment at all, or for a long time. Before we can recommend the routine use of therapy for high-risk patients with smoldering myeloma, we need solid data that will enable routine identification of risk. In this way, we can exclude patients who won’t benefit from early treatment (or may be harmed)—patients in whom intervening early changes the natural history of their disease. The Spanish trial is an important first step, but it is not yet the final answer. n

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

Reference 1. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.

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