TAP Vol 6 Issue 8

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

ASCO Releases 2015 Report on The State of Cancer Care in AmericaThe report highlights impressive gains in treatment but increasing challenges to a system under stress.By Jo Cavallo

In March, ASCO published its second annual re-port, The State of Cancer Care in America: 2015.1

Its findings show a mixed landscape, on the one hand, spotlighting advances in therapy and improving sur-vival rates, but on the other, describing a cancer care system under stress from increasing demand for ser-vices, disparities in access, skyrocketing health-care costs, and an aging oncology workforce.

The report’s assessment of the demographic, eco-nomic, and oncology practice trends that will im-pact cancer care in the United States over the coming years was delivered at a congressional news briefing in Washington, DC, by Richard L. Schilsky, MD, FACP, FASCO, Chief Medical Officer of ASCO; Philip Stella, MD, incoming Chair of ASCO’s Government Relations Committee and Medical Director of the On-cology Program at St. Joseph Mercy Hospital in Ann Ar-

bor, Michigan; and Robin Zon, MD, FACP, FASCO, Chair of ASCO’s Clinical Practice Committee and a medical oncologist at Michiana Hematology Oncol-ogy in South Bend, Indiana. They were joined by Rep. Andy Harris, MD (R-MD), who talked about the need to focus resources at the National Institutes of Health on biomedical innovation and treatment in cancer care.

Progress and ChallengesAccording to the report, 2014 saw significant prog-

ress in the improvement in the 5-year cancer survival rate for many cancer types, contributing to a record 14.5 million cancer survivors, and in the availability of new drugs, medical devices, and tests for the diagno-sis, treatment, or management of cancer. In addition to 10 new drugs and 4 new medical devices and tests

AACR Annual Meeting

The Centers for Medicare and Medicaid Services projects that U.S. health-care

spending will reach $4.3 trillion and account for 19.3% of the nation’s gross domestic prod-uct by 2019.1 Although cancer care represents a small fraction of overall health-care costs, the cost of cancer care is rapidly increasing, now estimated to reach $158 billion in 2020—an increase of 26% over just a decade.2

These expenditures are driven by the in-creasing prevalence of cancer due to the overall aging of the population and the introduction of costly, but hopefully more effective, new drugs as well as improved techniques in radiation ther-apy and surgery, resulting in more patients con-tinuing on treatment for longer periods of time. Also contributing to rising costs are physician

Creating a Collective Path Forward to

Optimize Value in Cancer Care

By Richard L. Schilsky, MD, FACP, FASCO

Oncology Meetings CoverageAACR Annual Meeting ��1, 5, 6, 8Miami Breast Cancer Conference �� 3 NCCN Annual Conference ��10–14Society of Gynecologic Oncology Annual Meeting ��15, 35National Cancer Policy Forum ��27–29

SGR Formula Repealed �� 4Post-Transplantation in Hodgkin Lymphoma��17ASCO State Affiliate: Maryland ��21Direct From ASCO ��22–26Richard R. Barakat, MD, FACS, on Gynecologic Oncology ��35Meeting Calendar ��44–45

MORE IN THIS ISSUE

continued on page 37

Issues in Oncology

Practice-Changing Study: Pembrolizumab Outperforms Ipilimumab in Advanced Melanoma By Alice Goodman

Pembrolizumab (Keytruda) proved superior to ipilimumab (Yervoy) for the treatment of unre-

sectable advanced melanoma in the global phase III KEYNOTE-006 trial. Pembrolizumab significantly improved overall survival, progression-free survival, and overall response rate compared with ipilimumab, which is the current standard of care for the treatment of advanced melanoma. In addition, pembrolizumab was associated with fewer toxicities, including high-grade adverse events.

New ParadigmKEYNOTE-006 was stopped early based on these

promising results at the second interim analysis. Re-sults were published in The New England Journal of Medicine1 to coincide with presentation of the data at the 2015 Annual Meeting of the American Associa-tion for Cancer Research (AACR).2

“The data from KEYNOTE-006 should change

the standard of care for ad-vanced melanoma regard-less of whether patients have received prior ipilim-umab therapy,” stated pre-senter and senior author of the study, Antoni Ribas, MD, PhD, Professor of Medicine and Hematolo-gy/Oncology and Director of Tumor Immunology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

“Not that long ago, we would be discussing treat-ments that helped 1 in 10 patients. With the develop-ment of agents that turn on the immune system, we now have therapies that help one in three patients. This is a new paradigm,” he stated.

Ipilimumab, an anti–cytotoxic T-lymphocyte-

Antoni Ribas, MD, PhD

Congress Repeals SGR 4 | Ovarian Cancer 14, 15 | High-Risk Hodgkin Lymphoma 18 VOLUME 6, ISSUE 8MAY 10, 2015

continued on page 5

Dr. Schilsky is Chief Medical Officer of the American Society of Clinical Oncology.

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PAGE 2 The ASCO Post | MAY 10, 2015

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 appropri-ate 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.

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJame Abraham, MD Cleveland Clinic

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Joseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Health System

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

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

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Wisconsin School of Medicine

Harold J. Burstein, MD Dana-Farber Cancer Institute

Robert W. Carlson, MD National Comprehensive Cancer Network

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

Jay S. Cooper, MD Maimonides Medical Center

John Cox, DO Texas Oncology

E. David Crawford, MD University of Colorado

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

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

Bishoy Morris Faltas, MD Weill Cornell Medical College

John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Moffitt Cancer Center

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

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

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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

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

Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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

William T. McGivney, PhD Philadelphia, Pennsylvania

James L. Mulshine, MD Rush University Medical Center

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

Steven T. Rosen, MD City of Hope National Medical Center

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

George W. Sledge, MD Indiana University

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

Jamie Von Roenn, MD American Society of Clinical Oncology

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

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

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

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Rakesh Chopra, MD Artemis Health Institute Gurgaon, India

Nagi El-Saghir, MD American University of Beirut, Lebanon

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

Jacek Jassem, MD Medical University of Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

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

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

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

John F. Smyth, MD University of Edinburgh Edinburgh, Scotland

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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

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Editorial Board

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ASCOPost.com | MAY 10, 2015 PAGE 3

Experts Debate: Can We Cure Metastatic Breast Cancer?By Caroline Helwick

Can metastatic breast cancer ever be cured? This issue was debated at

the 32nd Annual Miami Breast Cancer Conference by two experts in the field: George W. Sledge, Jr, MD, Professor of Medicine at Stanford University Medical Center, Palo Alto, California, and Clif-ford A. Hudis, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine, Weill Cornell Medical Col-lege, New York.

Not Much Has Changed in 30 Years

“This has been a disease for which I sit with the patient, and almost the first words out of my mouth are, ‘You have a disease that’s likely to claim your life,’” Dr. Sledge said. “This conversation has not changed in 30 years.” Despite this discouraging, repetitive dialogue, Dr. Sledge maintained that the field of on-cology is “journeying toward a cure and a more positive future.”

Dr. Hudis agreed that the future may be brighter but said the present is still fairly dire. “Don’t mistake my position for pessimism over the ability to prolong life and palliate symptoms. We are doing better,” he acknowledged. “We continue to make remarkable progress. Death rates are falling. But when we focus on metastatic breast cancer, and not all

breast cancer, the results are somewhat less impressive,” he indicated.

Steep declines in overall mortality owe more to early detection of nonmetastatic disease, as a result of massive screening programs, Dr. Hudis said. And although patients with de novo metastatic disease and those relapsing after treatment do have somewhat different long-term outcomes, both groups of patients have “a steady pro-gression toward death,” he added.

“Living with disease and the risk of re-lapse is the definition of not being cured,” Dr. Hudis countered. “I believe, at pres-ent, the reality is that we cannot cure metastatic breast cancer.”

What Does ‘Cure’ Really Mean?Drs. Sledge and Hudis agreed that

these two perspectives may relate to how one defines “cure.” With a “statis-tical cure,” no patient relapses and no patient dies. To the patient, a “personal cure” means death from something other than breast cancer, Dr. Sledge said, adding, “The latter definition is the fruitful one for the patient.”

According to Dr. Sledge, metastatic breast cancer is already being cured. “We cure it in the adjuvant setting when it’s micrometastatic. We cure some patients with oligometastatic breast cancer. We also do a good job with lo-coregional recurrence,” he indicated, citing data from the recent CALOR trial, which showed an advantage for adjuvant chemotherapy in patients with isolated locoregional recurrence.1

“There are already patients we are curing with metastatic breast cancer,” emphasized Dr. Sledge. “There are pa-tients who, despite my lecture that their disease will take their life, keep coming back and coming back without disease. We all see patients like these.” To Dr. Sledge, the question is not why meta-static breast cancer cannot be cured but why more patients cannot be cured.

Dr. Hudis, on the other hand, cited the “crowd-sourced” definition of cure as “the end of a medical condition” and

emphasized that when chronic diseases like diabetes and hypertension are well controlled, they are not believed to be “cured.” The same is true with metastat-ic cancer, he said.

“Unless we change our definition of cure, the successes described by Dr. Sledge—now and in the future—tech-nically do not fit the bill,” he main-tained. “Patients living well with breast cancer are still being treated for breast cancer. A remission is a temporary end to the medical signs and symptoms of an incurable disease.”

Dr. Hudis also offered an anecdote from 1992—a patient with a lesion on

the inner surface of the thoracic pleura that was consistent with primary breast cancer. After resection, she received an experimental regimen of interleukin-6, doxorubicin, and thiotepa. “That was her last medical intervention,” he noted.

“The personal cure George de-scribed might aptly describe her out-come. It was remarkable, so much so that we have gone back and rechecked her biopsy. But she continues to be in the hands of a medical oncologist, who monitors her for relapse potential,” he said. The patient with an incurable dis-

ease has an ever-present risk for relapse, no matter how long the duration of re-mission, he reiterated.

“If cure is the end of a medical con-dition, we are, unfortunately, far from this. If we want to label ‘remission’ as a cure and call living with disease and its threat a cure, then Dr. Sledge and I are closer to this issue,” he concluded.

How to ‘Cure’ More PatientsAside from the nuances of the defi-

nition, it is likely that more “cures” are possible. Dr. Sledge proposed three means through which this could hap-pen: finding and treating small metas-tases, giving the right drugs to the right patients, and using “new” biology to de-velop new drugs.

The CALOR trial suggested that small (localized) metastatic disease can be successfully treated, he noted, “but we gave up looking for low-volume metastatic disease in the 90s,” after sur-veillance screening proved incapable of finding small-enough tumors to made a difference in survival.

“Maybe it’s time to look at this ques-tion again,” Dr. Sledge suggested, as the definition of “metastasis” shifts down-ward. New and evolving technology al-lows for the identification of ever-small-er tumors, including advanced imaging, circulating tumor cells, and circulating tumor DNA. Hopefully, more easily de-tectable metastatic disease will translate

into more curable disease, he said. Treating the right patient with the

right drug “may matter in the metastatic setting,” continued Dr. Sledge. This im-perative will become easier, once better biomarkers are discovered.

Part of this challenge is embodied in the National Cancer Institute’s “Ex-ceptional Responder Initiative.” The initiative is collecting cases in which patients have dramatic and long-lasting responses to standard and experimen-tal treatments that were not seen in similar patients on the same treatment.

Insights regarding underlying molecu-lar mechanisms of response should be gained from this program, Dr. Sledge suggested.

Finally, it will be important to use “new” biology to develop more effec-tive drugs. A well-established example of this is the identification of HER2 and the development of trastuzumab (Her-ceptin), which improved median sur-vival from 16 months to 56.5 months. “We simply got better in treating these patients,” noted Dr. Sledge.

But a vexing problem is the emer-gence of compensatory mechanisms of resistance. “This heterogeneity has defeated much of what we have done in the metastatic setting,” he noted. In tackling this problem, emerging immu-notherapies hold promise.

Dr. Hudis agreed that emerging ap-proaches will yield more successes, as more is learned about the heterogeneity of breast cancer at the population and individual levels. Whether they will be “cures” is another matter, he added, not-ing that tumor biology was not predic-tive of response to everolimus (Afini-tor) in the BOLERO-2 trial.2

“We continue to struggle with the simple idea of targeted therapy and in whom it works,” he commented. “We don’t understand as much about the bi-ology and compensatory mechanisms as we would like.” In Dr. Hudis’ opin-

Miami Breast Cancer ConferenceBreast Cancer

We gave up looking for low-volume metastatic disease in the 90s. Maybe it’s time to look at this question again.

—George W. Sledge, Jr, MD

Living with HER2-positive metastatic disease and its consequential anxieties is not a cure. I believe it is theoretically possible to cure metastatic breast cancer. We just aren’t there yet.

—Clifford A. Hudis, MD

continued on page 4


News

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

Otis Brawley, MD, on Comorbidities and Psychosical Needs of Pediatric Cancer Survivors see page 27

Theodore M. Tarasow, PhD, on Immunosignatures in Ovarian Cancer Detection see page 14

Craig H. Moskowitz, MD, on Brentuximab Vedotin in Hodgkin Lymphoma Patients see page 17

Jeffrey Guss, MD, on Hallucinogenic Therapies for Cancer Anxiety see page 30

Kirsten McCaffery, PhD, on Informed Decision-Making in Breast Cancer Screening see page 19

Visit The ASCO Post online at ASCOPost.com

Richard R. Barakat, MD, on Health Care Changes in Gynecologic Oncology see page 35

After Decades of Uncertainty, the Sustainable Growth Rate Formula Is Repealed by CongressBy Ronald Piana

The U.S. Congress recently did something remarkable: both par-

ties reached across the aisle and over-whelmingly passed H.R. 2, a bill that will permanently repeal the sustainable growth rate (SGR), the problematic formula for Medicare reimbursement. It just needed the President’s signature, which it received on April 17, ending an era of uncertainty for the oncology community. In typical D.C. fashion, the Senate’s vote came just a few nail-biting hours before physicians faced a 21% Medicare pay cut, which would have been untenable for many of the nation’s community practices.

No More ‘Doc Fixes’Enacted by the Balanced Budget

Act of 1997, the SGR was designed to control Medicare spending on physi-cian services, to ensure that the yearly increase in the expense per Medi-care beneficiary does not exceed the growth in the gross domestic prod-uct. It is a complex and unwieldy tool, which has long been criticized by

health-care experts but never fixed. On January 1 of every year, the phy-

sician fee schedule has been updated to reflect its need to match a target num-ber, related to the sustainable growth rate. Congress has had the power to suspend implementation of the SGR, long known in the vernacular as a “doc fix,” which it has done routinely year after year, fueling frustration in the medical community.

ASCO and other major cancer or-ganizations have lobbied vigorously over the years to repeal the SGR and move to a more stable and equitable way to determine Medicare payment. With the passage of the bill, known as the Medicare Access and CHIP Re-authorization Act of 2015, lawmak-ers contend the repeal of the SGR is immensely meaningful not just for physicians who will avoid deep cuts in Medicare payment, but also for the long-awaited move toward value-based reimbursement as a whole.

ASCO and other leaders in the can-cer community support the idea of

value-based reimbursement, as long as the new payment models are imple-mented effectively, taking into consid-eration the multiple nuances of oncol-ogy practice that are more difficult to place dollar value on than procedure-based medical care.

Moving ForwardUnder the bill, the current reim-

bursement schedule will be replaced with a 0.5% increase in Medicare phy-sician reimbursement starting April 1, 2015 through December 2015 and then annual 0.5% increases lasting through 2019. After a period of stability, the bill will also merge various government-re-porting programs such as the “meaning-ful use” program for electronic health records and several quality-reporting initiatives into a new merit-based incen-tive payment system that would encour-age physicians to embrace alternative payment models, such as accountable care organizations.

A “technical advisory” committee will be charged to recommend and re-

view how to develop alternative pay-ment models. In short, several measures will be developed to judge the quality of care provided and how physicians will be rewarded or penalized based on their performance. There is a lot of heavy lift-ing ahead in order to transform words in a bill into actual payment models that will be seamlessly adopted by busy oncologists, many of whom are running very tight margins. We can expect in-tense lobbying from the oncology com-munity on every component of imple-mentation of the bill.

The SGR was an inconsistent and flawed tool, creating tension and un-certainty among doctors who care for the nation’s vulnerable cancer patients. Its repeal is evidence that beneficial change is possible, even in today’s contentious political climate. ASCO and other cancer organizations have been ahead of the curve in the move from quantity to quality care. H.R. 2 is a work in progress, but all interested parties are glad that the SGR is now a thing of the past. n

Health-Care Policy

ion, extending remissions through bet-ter science and drugs is more likely to be “delaying the inevitable.”

He noted that even in the HER2 setting, with the unprecedented over-all survival improvement gained by combining pertuzumab (Perjeta) with trastuzumab in CLEOPATRA,3 “those patients are on ongoing and, parentheti-

cally, expensive therapy and live with a constant ongoing risk, if not certainty, of eventual progression and continued medical care until their death, poten-tially from their disease.”

“Living with HER2-positive meta-static disease and its consequential anx-ieties is not a cure. Waiting for the next shoe to drop is not a cure,” offered Dr. Hudis. “I believe it is theoretically pos-sible to cure metastatic breast cancer.

We just aren’t there yet.” nDisclosure: Drs. Sledge and Hudis reported

no potential conflicts of interest.

References1. Aebi S, Gelber S, Anderson SJ, et al:

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): A randomised trial. Lancet Oncol 15:156-163, 2014.

2. Hortobagyi GN, Piccart-Gebhart

MJ, Rugo HS, et al: Correlation of mo-lecular alterations with efficacy of evero-limus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Pre-sented June 3, 2013.

3. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.

Metastatic Breast Cancercontinued from page 3


AACR Annual Meeting

associated protein 4 (CTLA-4) thera-py, was the first drug of any kind to im-prove overall survival in patients with advanced melanoma, and it became the standard of care. Pembrolizumab is an anti–programmed cell death protein 1 (PD-1) antibody. Both are immune checkpoint inhibitors.

These immunotherapies have distinct mechanisms of action: blocking CTLA-4 enables T-cell activation, whereas block-

ing PD-1 modulates T-cell activity via the protein’s interaction with its ligands, PD-L1 and PD-L2, during the effector phase of the immune response. Two anti–PD-1 inhibitors, pembrolizumab and nivolum-ab (Opdivo), are approved by the U.S. Food and Drug Administration (FDA) for use in patients with disease progression during or after ipilimumab therapy, and if disease is BRAF V600 mutation–positive, after treatment with a BRAF inhibitor.

Study DetailsKEYNOTE-006 included 834 pa-

tients from 83 sites in 16 different coun-tries with unresectable stage III or IV advanced melanoma and no more than one prior systemic therapy. Patients were excluded if they received previous therapy with CTLA-4, PD-1, or PD-L1 inhibi-tors. Study participants were randomly assigned 1:1:1 to pembrolizumab at 10 mg/kg every 2 weeks (n = 279), pem-

brolizumab at 10 mg/kg every 3 weeks (n = 277), or four cycles of ipilimumab at 3 mg/kg every 3 weeks (n = 278).

Dr. Ribas explained that at the time KEYNOTE-006 was designed, the best dosing regimen of pembrolizumab was not known. The currently approved dos-ing regimen for pembrolizumab is 2 mg/kg every 3 weeks.

“There seems to be little difference between these dosing regimens [ie, all three pembrolizumab regimens],” he noted, “and there is no evidence

that one of the two dosing regimens in KEYNOTE-006 is better.”

At a median follow-up of 7.9 months, median progression-free survival was 5.5 months for the every-2-week pembro-lizumab group and 4.1 months for the every-3-week group, vs 2.8 months for ipilimumab, reflecting a 42% reduction in risk of disease progression with pembroli-zumab (P < .00001).

Estimated 6-month progression-free survival rates were 47.3%, 46.4%, and 26.5%, respectively. “Progression-free survival is close to double with pembro-lizumab,” Dr. Ribas noted.

At a median follow-up of 13.8 months, 1-year overall survival rates were 74.1% and 68.4% for the 2-week and 3-week pembrolizumab groups, respectively, vs 58.2% for ipilimumab, reflecting a 37% improvement in survival that was statis-tically significant (P = .00052 and P = .00358, respectively).

“This study exceeded our expecta-tions, even for the control arm,” he said.

Objective response rates according to RECIST criteria for tumor shrinkage were about 33% in the pembrolizumab arms vs 11.9% in the ipilimumab arm. Complete response rates were 5%, 6.1%, and 1.4%, respectively. Responses were ongoing in 89.4% of the 2-week pem-brolizumab group, 96.7% of the 3-week pembrolizumab group, and 87.9% of the ipilimumab group.

Improved Tolerability“The toxicity profile favored pem-

brolizumab, with fewer side effects even though there was greater continuous ex-posure to the drug than with ipilimumab,” Dr. Ribas commented. Grade 3/4 tox-icities were reported in 19% of the ipilim-umab-treated patients and in 10% to 13% of those receiving pembrolizumab.

Treatment-related autoimmune- or immune-related adverse events with pembrolizumab were hypothyroidism (10.1% for the 2-week group and 8.7% for the 3-week group) and hyperthyroid-ism (6.5% and 2.5%, respectively). Colitis was reported in 8.2% of those assigned to ipilimumab.

“I’ve been treating melanoma for 15 years. This is the first time I have seen patients with durable responses, and the majority with no side effects. We saw no nausea, no vomiting, while the immune

system is attacking the cancer. There is no better personalized therapy than this,” Dr. Ribas commented during the question-and-answer session following presentation of these data at an AACR press conference.

Dr. Ribas also said that pembrolizu-mab is approved for upfront use by Medi-care and included as a first-line option in the recently released National Compre-hensive Cancer Network Guidelines.

“The field is going faster than FDA approval. I anticipate that the FDA la-bel [for pembrolizumab] will change to include first-line treatment. I won’t stop using ipilimumab, because this drug can achieve durable responses. It is part of our armamentarium. We highly anticipate that combining ipilimumab with an anti–PD-1 antibody will improve responses, but we need to know in which patients.” n

Disclosure: Dr. Ribas has consulted for Merck, with the honoraria paid to his institution.

References1. Robert C, Schachter J, Long GV, et al:

Pembrolizumab versus ipilimumab in ad-vanced melanoma. N Engl J Med. April 19, 2015 (early release online).

2. Ribas A, Schachter J, Long GV, et al: Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipi-limumab-naive advanced melanoma. AACR Annual Meeting 2015. Abstract CT101. Pre-sented April 19, 2015.

Dermatologic Oncology

Pembrolizumabcontinued from page 1 EXPERT POINT OF VIEW

Press conference moderator Suzanne L. Topalian, MD, Director of the Melanoma

Program at Sidney Kimmel Comprehensive Can-cer Center, Johns Hopkins University, Baltimore, said, “The approval of ipilimumab [Yervoy] as first-line therapy for advanced melanoma in 2011 was a landmark moment. This was the first drug ever to show a survival advantage in melanoma. It was also a landmark moment for immunotherapy and checkpoint blockade. Ipilimumab became the gold

standard for treatment of advanced melanoma.” She continued, “KEYNOTE-006 is the first demonstration that pem-

brolizumab [Keytruda] is superior to ipilimumab. We expect this study to change the treatment landscape for melanoma.”

Important areas of future research include combinations of immune ther-apies and optimal sequencing, she noted. n

Disclosure: Dr. Topalian receives research grants from Bristol-Myers Squibb, and her spouse is a consultant for Merck.

Suzanne L. Topalian, MD

The data from KEYNOTE-006 should change the standard of care for advanced melanoma regardless of whether

patients have received prior ipilimumab therapy. —Antoni Ribas, MD, PhD

Pembrolizumab vs Ipilimumab in Melanoma

■ Pembrolizumab was superior to ipilimumab as upfront immunotherapy in advanced melanoma in a pivotal phase III trial.

■ Pembrolizumab significantly increased overall survival, progression-free survival, and objective response rates.

■ Pembrolizumab had an improved toxicity profile compared with ipilimumab.

■ These results were reported after the second interim analysis, and the trial was subsequently stopped.

■ This study should change practice, making pembrolizumab a good option for first-line treatment of advanced melanoma.

More on Melanoma in This Issue

Christine V. Kinnier, MD, on Sentinel node positivity, see page 10

F. Stephen Hodi, MD, on Combination immunotherapy, see page 8

May Is Melanoma Cancer Awareness Month


AACR Annual Meeting

José Baselga, MD, PhD, Inaugurated as AACR President

The American Association for Cancer Research (AACR) inau-

gurated José Baselga, MD, PhD, as President for 2015–2016 at the AACR Annual Meeting 2015.

Dr. Baselga, an internationally recog-nized physician-scientist whose research focuses on the clinical development of novel molecularly targeted agents (particularly for the treatment of breast cancer), is Physician-in-Chief and Chief Medical Officer at Memorial Sloan Ket-tering Cancer Center, New York.

“It is an honor to serve as president of the AACR,” Dr. Baselga said. “We are currently in the midst of a revolution in cancer research, where new technolo-gies and therapies are being developed at a record pace. The AACR is uniquely positioned to advance the promise of precision medicine initiatives. As presi-dent, I am eager to work with the AACR community as a whole to integrate basic and clinical research, improve access to clinical trials, coordinate our regulatory policies, and increase our ability to col-laborate on the many breakthroughs oc-curring in cancer prevention, detection, and treatment.”

Treatment BreakthroughsDr. Baselga is a pioneer in the de-

velopment of treatments for women with HER2-positive breast cancer. He conducted the initial clinical trial dem-onstrating that patients with advanced HER2-positive breast cancer benefited

from treatment with the anti-HER2 monoclonal antibody trastuzumab (Herceptin). He also led the clinical development of the second anti-HER2 monoclonal antibody to receive U.S. Food and Drug Administration approv-al, pertuzumab (Perjeta).

In addition to Dr. Baselga’s appoint-ment, Nancy E. Davidson, MD, Di-rector of the University of Pittsburgh Cancer Institute and UPMC Cancer Center, was inducted as AACR Pres-ident-Elect. Carlos L. Arteaga, MD, Professor of Medicine and Cancer Biol-

ogy at Vanderbilt University School of Medicine, Associate Director for Clini-cal Research, Director of the Center for Cancer Targeted Therapies, and Direc-tor of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, now serves as AACR Past-President. n

I am eager to … integrate basic and clinical research, improve access to clinical

trials, coordinate our regulatory policies, and

increase our ability to collaborate on breakthroughs

in cancer prevention, detection, and treatment.

—José Baselga, MD, PhD


FDA Update

Crizotinib Receives Breakthrough Therapy Designation for ROS1-Positive NSCLC

The U.S. Food and Drug Admin-istration (FDA) has granted

Breakthrough Therapy designation to crizotinib (Xalkori) for the po-tential treatment of patients with ROS1-positive non–small cell lung cancer (NSCLC). Crizotinib currently

is FDA-approved for the treatment of patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive.

The Breakthrough Therapy des-ignation was based on data from an expansion cohort of a global

phase I study that evaluated crizo-tinib in 50 patients with ROS1-pos-itive advanced NSCLC. These data, published last year in The New England Journal of Medicine,1 demon-strated that crizotinib exhibited marked antitumor activity in patients with

ROS1-positive advanced NSCLC. n

Reference1. Shaw AT, Ou S-HI, Bang Y-J, et al:

Crizotinib in ROS1-rearranged non-small cell lung cancer. N Engl J Med 371:1963-1971, 2015.

http://www.neulastahcp.com/characteristics/neulasta-delivery-kit/


AACR Annual MeetingDermatologic Oncology

Combination Immunotherapy Better Than Monotherapy in Advanced MelanomaBy Alice Goodman

A s clinical research struggles to keep up with the pace of new im-

munotherapies, one of the burning

questions is how best to combine the new drugs. A new study found that the combination of nivolumab (Opdivo)

and ipilimumab (Yervoy) is superior to ipilimumab alone as front-line therapy for untreated metastatic melanoma.1

“The combination of ipilimumab and nivolumab achieved durable responses and a substantially higher response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy in patients with both wild-type BRAF and BRAF mutation–positive tumors,” said lead author F. Stephen Hodi, MD, Direc-tor of the Melanoma Center at Dana-Farber Cancer Institute in Boston. “It’s very encouraging to see this pattern in previously untreated patients.”

Dr. Hodi presented these study find-ings at the 2015 Annual Meeting of the American Association for Cancer Re-search, and the study was published on-line in The New England Journal of Medi-cine to coincide with his presentation.1,2

Ipilimumab, an anti–CTLA-4 (cy-totoxic T-lymphocyte–associated an-tigen) antibody, has been approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of ad-vanced melanoma. Nivolumab, an anti–PD-1 (programmed cell death protein 1) monoclonal antibody, has been ap-proved by the FDA for patients with metastatic melanoma whose disease has progressed after treatment with ipi-limumab or a BRAF inhibitor.

After a phase I study showed high overall response rates for the combina-tion, a randomized phase II study was mounted to compare the combination

Combination Immunotherapy for

Advanced Melanoma

■ Upfront combination therapy with ipilimumab plus nivolumab achieved superior outcomes compared with ipilimumab monotherapy in untreated advanced melanoma, according to the results of a phase II randomized trial.

■ Further confirmation is needed before combination therapy is adopted as standard practice.

■ Trials of other immunotherapy agents and other combinations are ongoing.

■ More data are needed to determine the best combinations for specific patient groups. Biomarkers are also needed to select the best therapy.


AACR Annual Meeting

of ipilimumab plus nivolumab vs ipilim-umab alone in 142 previously untreated patients with advanced melanoma. Patients were stratified according to BRAF-mutation status (wild-type or mutation-positive).

Patients were randomized 2:1 to receive ipilimumab every 3 weeks for 4 cycles followed by nivolumab alone every 2 weeks vs ipilimumab mono-therapy followed by placebo. Patients were treated until disease progression or unacceptable toxicity.

Response RatesThe investigator-assessed, confirmed

overall response rate was 61% for the combination vs 11% for ipilimumab in patients with BRAF wild-type tumors (P < .001). The complete response rate was 22% for the combination therapy vs 0% for ipilimumab for both wild-type and BRAF-mutated patients.

Among the patients with BRAF wild-type tumors, the median duration of re-sponse was not reached in either treat-ment arm, with an ongoing response in 82% in the combination group and 75% in the ipilimumab-monotherapy group.

Among BRAF mutation-positive patients, the overall response rate was 52% for the combination group, with a similar 22% complete response rate compared with the BRAF wild-type tu-mor group.

Median progression-free survival was not reached in the BRAF wild-type group for the combination and was 4.4 months for ipilimumab monotherapy (P < .001). Among BRAF mutation–positive tumors, median progression-free survival was 8.5 months for the combination group and 2.7 months for ipilimumab monotherapy.

Among patients who discontinued treatment due to toxicity, the overall response rate was 68% in the combi-nation arm vs 10% in the ipilimumab-alone arm.

Safety and TolerabilityThe rate of investigator-assessed

treatment-related adverse events was 91% for combination therapy compared with 93% for ipilimumab monotherapy. Treatment-related events leading to dis-continuation of therapy were reported

in 47% of the combination arm and 17% of the ipilimumab-alone arm.

Grade 3 or 4 adverse events were re-ported in 54% of the combination arm vs 24% of the ipilimumab-alone arm. The most common grade 3 or 4 drug-related events in the combination arm were coli-tis (17%), diarrhea (11%), and an elevat-ed alanine aminotransferase level (11%). For ipilimumab, the most frequently re-

ported grade 3 or 4 adverse events were diarrhea (11%) and colitis (7%). Treat-ment with steroids resolved most of the adverse events, Dr. Hodi said.

Interestingly, 69% of those in the combination arm who discontinued therapy continued to experience com-plete response or partial response, Dr. Hodi noted.

Other studies have shown that pa-

tients whose tumors express the PD-1 ligand, PD-L1, are more likely to re-spond to single-agent nivolumab. In this study, response in the combination arm was not related to PD-L1 status. “These data suggest that PD-L1 should not be used as a biomarker for selecting patients for combination treatment,” Dr. Hodi stated. n

Disclosure: Dr. Hodi has been an unpaid consultant for Bristol-Myers Squib and his institution has received grant and clinical research support.

References1. Hodi FS, Postow MA, Chesney J, et al:

Improved clinical response in patients with advanced melanoma treated with nivolum-ab combined with ipilimumab compared to ipilimumab alone. 2015 AACR Annual Meeting. Abstract 2860. Presented April 20, 2015.

2. Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipi-limumab in untreated melanoma. N Engl J Med. April 20, 2015 (early release online).

EXPERT POINT OF VIEW

“In the past 10 years, we have begun to unlock the keys to

the puzzle of the body’s immune sys-tem. The study presented here drives home the important point that we can

elicit immune responses with unusual durability,” said Louis Weiner, MD, Director of the Georgetown Lombar-di Cancer Center in Washington, DC, and moderator of a press conference where these data were discussed.

“When I finished my training and started as a junior faculty member, melanoma was a cancer that gave can-cer a bad name. Now we have treat-

ments for melanoma that yield du-rable responses. This [treatment with immunotherapy] is truly revolution-ary,” he continued.

Remaining questions to be ad-

dressed include the optimal duration of combination therapy, the optimal number of treatments, and the op-timal dose and duration of mainte-nance therapy. “These are important questions, especially with this combi-nation,” Dr. Weiner added.

Other combinations of immuno-therapies are being studied in mela-noma, including ipilimumab and

pembrolizumab, another anti–PD-1 antibody.

“The combination is not approved yet. We need more data and longer follow-up. Since biomarkers have not yet panned out [for patient selection], this necessitates a discussion with pa-tients about benefits and toxicities. The best we can do today is to have these discussions. We await more data and phase III studies on the combina-tions,” Dr. Weiner stated.

“We are in the middle of a revolu-tion, with the incredible advances we are seeing in melanoma. It’s not just this one disease; we are seeing broad utility of immunotherapy approaches that promise to change the way we treat melanoma and other cancers, including kidney, bladder, Hodgkin lymphoma, and non–small cell lung cancers. Immunotherapy won’t cure everyone with cancer, but we can cure some patients. This is a powerful inflection point,” Dr. Weiner said. n

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

We are in the middle of a revolution, with the incredible advances we are seeing in melanoma. Immunotherapy won’t cure everyone with cancer, but we can cure some patients.

—Louis Weiner, MD

The combination of ipilimumab and nivolumab achieved durable responses and a substantially higher response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy in patients with both wild-type BRAF and BRAF mutation–positive tumors.

—F. Stephen Hodi, MD

Cancer Has Left an Indelible Mark on Me

Barb Young is cancer-free today, but she explains how coming to terms with her cancer experience remains a struggle, see page 41


National Comprehensive Cancer Network Annual Conference

NCCN Posters of Interest Included Studies in Kidney, Breast, and Endometrial Cancers, Melanoma, and Cost IssuesBy Caroline Helwick

The quality and quantity of original research presented at the Nation-

al Comprehensive Cancer Network (NCCN) Annual Conference continue to grow since poster sessions debuted a few years ago. The ASCO Post offers summaries for just a few that caught our eye, out of more than 65 presented this year.

Active Surveillance for Small Renal Masses

For the management of renal cell carcinoma, active surveillance with delayed intervention appears to be a noninferior management strategy with regard to oncologic outcomes for well-selected patients with small renal masses. This finding came from a pro-spective multicenter trial led by Phillip M. Pierorazio, MD, of the James Bu-chanan Brady Urological Institute and Department of Urology at Johns Hop-kins Medical Center, Baltimore.1

Most studies evaluating active sur-veillance for these tumors have been retrospective and “limited by selection and reporting bias,” according to the investigators.

In the current prospective multi-center study, the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry was used to evalu-ate 497 patients with tumors ≤ 4 cm who chose intervention or active surveillance. Patients underwent imaging (computed tomography, magnetic resonance imag-ing, or ultrasound) at enrollment and ev-ery 4 to 6 months for 2 years, then every 6 to 12 months thereafter.

Patients with a tumor growth rate > 0.5 cm/year or tumor diameter > 4.0 cm (indicative of disease progression) were recommended for intervention, al-though a patient could choose delayed intervention at any time. Percutaneous renal biopsy was offered at enrollment and recommended when the growth rate exceeded 0.5 cm/yr.

The study enrolled 274 patients (55%) who elected primary interven-tion and 223 (45%) who selected ac-tive surveillance. Twenty-one patients (9.4%) crossed over to delayed inter-vention.

For the active surveillance patients, the growth rates and progression were as follows:• Median growth rate was 0.11 cm/yr.• A total of 125 patients (79%) had a

tumor growth rate < 0.5 cm/yr. • Tumors in 16 patients (10%) dem-

onstrated zero tumor growth.• Overall, 34 patients showed dis-

ease progression by growth rate, and 2 showed progression by tumor diameter. At a median follow-up of 2.1 years, 23

patients had died. Of 10 patients in the intervention group, 2 died of renal cell carcinoma; of 13 in the active surveil-lance group, none died of the disease.

The cancer-specific survival rate exceeded 99% in both arms. Five-year overall survival was 92% with pri-mary intervention and 75% for active surveillance.

Two Paclitaxel Regimens Compared

In the treatment of breast cancer, dose-dense paclitaxel is often assumed to be more toxic than weekly paclitaxel, but investigators from Edwards Com-prehensive Cancer Center in Hunting-ton, West Virginia, reported that the regimens have a comparable tolerability profile.2

Mohamed Alsharedi, MD, suggest-ed that some clinicians favor weekly pa-clitaxel because they deem the toxicities to be more than with dose-dense pacli-taxel, based on the profile observed with weekly paclitaxel in the SWOG S0221 trial.3 To make treatment dura-tion equal, however, SWOG S0221 tested six cycles of dose-dense pacli-taxel, not four, which is the standard, he pointed out.

At the NCCN Conference, Dr. Alsharedi reported the results of a retrospective analysis of 121 patients treated with the two main paclitaxel regimens from 2008 to 2014 at his institution. “To our knowledge, there are no other data in the literature comparing the toxicities and toler-ability between two commonly used standard-of-care paclitaxel-based reg-imens,” he said.

The comparison of these common paclitaxel schedules showed that 4 cy-cles of standard dose-dense paclitaxel was comparable to 12 weekly pacli-taxel cycles in terms of toxicities and tolerability.

“Toxicity was comparable, even for the most concerning side effect, neu-ropathy,” Dr. Alsharedi said.

Grade 3/4 neuropathy occurred in 17% with dose-dense dosing and 18% with weekly dosing. Dose-dense dos-ing was associated with a significantly lower incidence of neutropenia grades 1/2 (10% vs 23%; P = .02) and a trend toward less grade 3/4 neutropenia (12% vs 24%; P = .07). Musculoskel-etal adverse events, however, were higher with dose-dense dosing (71% vs 33%; P < .001).

The authors suggested that pegfil-grastim (Neulasta) is the most likely factor contributing to the lower inci-dence of neutropenia seen with dose-dense paclitaxel and could have con-tributed to the higher incidence of musculoskeletal toxicity. There was no significant difference in the need for dose reductions, treatment interrup-tion, or drug discontinuation between the arms.

Dr. Alsharedi said the data can be used to inform patients that the two regimens are tolerable, with compa-rable toxicities. “We don’t want the on-cologist to be biased in choosing weekly paclitaxel over dose-dense, based on toxicity,” he noted. “Patients can choose between these regimens, based on fac-tors other than toxicity.”

Sentinel Node Positivity Rates by Hospital

In melanoma patients, positive rates for sentinel lymph node biopsy vary across hospitals. In low-volume hospi-tals, a lower-than-expected positivity rate is associated with decreased stage I survival, according to an analysis of

33,639 melanoma patients from 646 hospitals led by Christine V. Kinnier, MD, and Karl Y. Bilimoria, MD, MS,

of the Northwestern Institute for Com-parative Effectiveness Research in On-cology, Chicago.4

The researchers looked for the ob-served-to-expected ratios, dividing hos-pitals into terciles. The middle tercile of sentinel lymph node biopsy positivity is the desired range, thought to most ac-curately reflect optimal care.

Of the 33,639 patients, 2,918 (8.7%) had positive sentinel lymph nodes. Hospitals with the lowest vol-ume of sentinel lymph node biopsies were the most likely to fall into “the ex-treme group,” ie, with more than 30% in the lowest positivity tercile, 30% in the highest, and only 17% in the ideal middle tercile range.

In contrast, in hospitals with the highest procedural volume, 30% fell into the middle positivity range. Hospi-tals falling mostly in the middle tercile also had the best overall survival rates at 5 years (90%).

“We found that the more [senti-nel lymph node biopsies] you did for melanoma, the more likely you were to fall into the middle tercile for the observed-to-expected ratio of positive sentinel lymph node biopsies,” said Dr. Kinnier. If the hospital’s ratio is too low, the hospital may be missing true positive sentinel lymph node biopsies. If the hospital’s ratio is too high, the hospital may have a high number of false-positive sentinel lymph node bi-opsies, she indicated.

Dr. Kinnier suggested that, regard-less of the number of lymph node bi-opsies performed annually, hospitals where few lymph node biopsies are performed annually might be expected to fall outside the middle tercile. How-ever, high-volume hospitals with un-favorable rates might want to look for underlying reasons.

Phillip M. Pierorazio, MD

Mohamed Alsharedi, MD

Christine V. Kinnier, MD

Research Roundup



“We have suggested to the NCCN that this could be a process measure to use for quality reporting,” she said.

Endometrial Cancer Risk and Lynch Screening

Since endometrial cancer is part of the constellation of malignancies in Lynch syndrome, the current NCCN guidelines recommend that persons diagnosed with endometrial cancer before age 50 be screened for Lynch syndrome. The authors of a study reported at the NCCN Conference are suggesting that merely screen-ing for Lynch syndrome does not go far enough in determining possible underlying genetic susceptibilities.5 Nearly 40% of the gene variants they

found in their study were not tradi-tionally associated with endometrial cancer, and the presence of pathogen-ic variants was similar in women over and under age 50.

The genetic risk of endometrial can-cer has not been actively researched. Persons with Lynch syndrome have a 40% to 60% increased risk, while persons with mutations in PTEN and CHEK2 are at modestly increased risk. Genetic testing for women with en-dometrial cancer has focused primar-ily on mismatch repair genes, as 9% of cases diagnosed under age 50 will car-ry these mutations, but the role played by other cancer susceptibility genes is unknown.

“We looked at the yield of patho-genic mutations identified in women

diagnosed with endometrial cancer, and we found a few surprises,” said Dana Farengo-Clark, MS, a certified genetics counselor at GeneDx in Gaith-ersburg, Maryland. “There are genes not traditionally associated with endo-metrial cancer that we found by doing broad panels.”

Researchers found that of 489 women with endometrial cancer, 56 (11.5%) harbored at least one patho-genic or likely pathogenic variant, and the frequency was similar for women ≤ 50 and > 50. Pathogenic/likely patho-genic mismatch repair gene variants ac-counted for most of the variants (92%) in the younger cohort, but they also were identified in 51% of those diag-nosed over age 50. The analysis further

showed:• 61% of the pathogenic/likely patho-

genic variants were identified in a mismatch repair gene.

• 61% of women with a mismatch re-pair variant reported a family history of colon cancer, and 32% met Am-sterdam II criteria.

• 12.5% of pathogenic/likely patho-genic variants were identified in CHEK2, and of individuals with these variants, 85% reported a fam-ily history of breast cancer.

• All women carrying a pathogenic/likely pathogenic variant in either BRCA1 or BRCA2 also reported a family history of breast cancer.

• 14% of women were diagnosed with breast cancer in addition to endome-trial cancer.

The authors suggested that genetic testing via a multigene panel be con-sidered for all women with a personal history of endometrial cancer who also report a family history of colon and/or breast cancer, regardless of their age at diagnosis, to increase the likelihood of clarifying an underlying hereditary predisposition. “We think we need a broader brush here,” Ms. Farengo-Clark commented.

Impact of Generic ImatinibImatinib (Gleevec) is expected to

lose patent exclusivity in the near fu-ture. The entry into the marketplace of generic imatinib could significantly reduce health plan expenditures on ty-rosine kinase inhibitor therapy and fa-cilitate changes in class management by payers. Xcenda LLC and Bristol-Myers Squibb estimated the economic impact of the brand-name product’s loss of ex-clusivity and potential formulary man-agement of requiring generic imatinib before use of a branded tyrosine kinase inhibitor.6

Xcenda’s Lisa Bloudek, PharmD, and colleagues used Truven Health MarketScan Commercial and Medicare Supplemental Data from patients with at least one claim for a tyrosine kinase inhibitor, stratifying patients by health plan type and patient age. The major-ity of patients received imatinib (69%), followed by dasatinib (Sprycel, 18%) and nilotinib (Tasigna, 12%).

They determined that the introduc-tion of generic imatinib would result in

a 29% reduction in tyrosine kinase in-hibitor pharmacy spend, independent of additional formulary management,

for both commercial and Medicare payers. The cumulative cost savings for a million-member plan over 2 years was estimated to be $6,840,427 and $22,952,646 for commercial and Medi-care, respectively. The impact of formu-lary management, on the other hand, would be miniscule, with a cost savings of only 1% to 2%. n

Disclosure: Dr. Pierorazio’s study was funded by an NCCN Young Investigators Award. Dr. Alsharedi reported no potential conflict of interest. Ms. Farengo-Clark and Dr. Kinnier reported no potential conflicts of interest. Dr. Bloudek reported that Bristol-Myers Squibb sponsored this work.

References1. Pierorazio P, Trock BJ, Chang P, et

al: Five-year analysis of multi-institutional prospective clinical trial of delayed inter-vention and surveillance for small renal masses: The DISSRM Registry. NCCN Annual Conference. Presented March 13, 2015.

2. Alsharedi M, Dotson J, Tirona M: Standard of care four doses of dose dense paclitaxel in the adjuvant treatment of breast cancer has equal toxicity profile to weekly paclitaxel. NCCN Annual Confer-ence. Presented March 12, 2015.

3. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial com-paring chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.

4. Kinnier C, Paruch JL, Dahlke AR, et al: Does hospital proficiency vary for mel-anoma sentinel lymph node biopsies? An evaluation of hospital level adjusted node positivity rates and outcomes. NCCN Annual Conference. Presented March 13, 2015.

5. Farengo-Clark D, Klein R, Mar-shall M, et al: Testing for inherited cancer pathogenic variants in women with endo-metrial cancer: Who to treat and for which genes to test? NCCN Annual Conference. Presented March 12, 2015.

6. Bloudek LM, Makenbaeva D, Eaddy M: Anticipated impact of generic imatinib market entry on tyrosine kinase inhibitor-related pharmacy costs. NCCN Annual Conference. Presented March 13, 2015.

We looked at the yield of pathogenic mutations identified in women diagnosed with endometrial cancer, and we found a few surprises. There are genes not traditionally associated with endometrial cancer that we found by doing broad panels.

—Dana Farengo-Clark, MS

Lisa Bloudek, PharmD

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NCCN Foundation Awards Grants to Six Young Investigators

The National Comprehensive Can-cer Network (NCCN) Founda-

tion has awarded grants to six young investigators from NCCN Member In-stitutions.

These awardees, dedicated to ad-vancing and discovering new treat-ments for cancer, enhancing quality, and improving patient education, repre-sent the fifth series of the NCCN Foun-dation Young Investigator Awards—a program initiated in 2011. The grants will provide $150,000 in funding over a 2-year period, beginning in July 2015.

“The NCCN Foundation is proud to foster the development of six promising oncology investigators,” said Gary J. Weyhmuller, Executive Vice President and Chief Operating Officer, NCCN. “The support of the NCCN Founda-tion Young Investigator Awards will indeed provide the opportunity for these young researchers to further high-quality research and improve the lives of people with cancer.”

Following are the 2015 NCCN Foundation Young Investigator Awards recipients, as well as the focus of their studies:• James Blachly, MD, The Ohio State

University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Genomic Stratification and Prognostication of Adult Acute Myeloid Leukemia by Combination Mutation Status

• Roisin Connolly, MB, BCh, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Harnessing the Immune System to Treat Breast Cancer: Novel Mecha-nisms of Resistance and Treatment Strategies

• Areej El-Jawahri, MD, Dana-Far-ber/Brigham and Women’s Cancer Center, Massachussetts General Hospital Cancer Center A Multi-modal Intervention to Address Sexual Dysfunction in Hematopoietic Stem Cell Transplant Survivors

• Douglas B. Johnson, MD, Vander-bilt-Ingram Cancer Center, Survi-vorship in Patients Receiving Immune Checkpoint Inhibitors

• Todd Morgan, MD, University of Michigan Comprehensive Cancer Center, Tissue-Based Genomics for

James Blachly, MD

Roisin Connolly, MB, BCh

Areej El-Jawahri, MD

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Risk Stratification in Localized Renal Cell Carcinoma

• Alpa Nick, MD, The University of Texas MD Anderson Cancer Center, Matched Pair Pharmacodynamics and Feasibility Study of Pembrolizumab in Combination With Chemotherapy in Frontline Ovarian CancerAwardees were selected based on

several key components, including scientific merit and study design. The studies will be managed and overseen by the NCCN Oncology Research Pro-gram (ORP).

Since their inception in 2011, NCCN Foundation Young Investiga-tor Awards have been received by 23 individuals. In March 2015, NCCN featured abstracts highlighting the work of the third series of Young Investigator Awards at the NCCN General Poster Sessions during the NCCN 20th Annu-al Conference: Advancing the Standard of Cancer Care.

The 2015 NCCN Foundation Young Investigator Awards were made possi-ble through support from AbbVie, Am-gen, Genentech, Gilead, Merck, Millen-nium, Pfizer, and Sigma-Tau.

For more information about the NCCN Foundation Young Investigator Awards, visit NCCN.org. n

Douglas B. Johnson, MD Todd Morgan, MDAlpa Nick, MD

Editorial CorrespondenceJames O. Armitage, MD

Editor-in-Chief e-mail: [email protected]

Cara H. Glynn Director of Editorial

e-mail: [email protected]: 631.935.7654

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Immunosignature Technology May Detect Ovarian Cancer With a Drop of BloodBy Caroline Helwick

“Immunosignatures” may be well suit-ed to enable the detection of ovar-

ian cancer, researchers reported at the Na-tional Comprehensive Cancer Network (NCCN) 20th Annual Conference.1

“We developed a new concept for disease detection based on immunosig-natures. From a drop of blood, Health-Tell’s immunosignature technology is capable of profiling the immune re-sponse to disease—in this case ovarian cancer. We are getting very high AUC [area under the receiver operating char-acteristic curve], with sensitivity, speci-ficity, and overall accuracy all in the 90% range,” said Theodore M. Tarasow, PhD, Vice President of Product De-velopment at HealthTell, the company developing the assay in San Ramon, California. The ASCO Post interviewed Dr. Tarasow at his poster presentation.

Natural Signal AmplificationThe immunosignature technology

measures the body’s immune response to disease, taking advantage of the im-mune system’s natural signal amplifica-tion: more than 1,000 antibodies can be produced per B cell per second.

“The immune system amplifies the disease signal through B cells, which are creating thousands of antibodies per second that are specific to a given dis-ease. This has advantages over looking for a protein or DNA biomarker that gets diluted once it goes out into the blood,” he explained.

The technology uses arrays of hun-dreds of thousands of unique peptides

designed to broadly survey an individ-ual’s antibody-binding repertoire from a drop of blood, serum, or plasma; it zeroes in on the signal generated by the disease response antibodies.

“The technology holds promise for detecting the presence of virtually any disease that generates a significant B-cell response,” Dr. Tarasow suggested. “For cancer, the technology has been dem-onstrated to distinguish patient samples representing several different cancers from each other, as well as from noncan-cer controls, with high accuracy.”

Highly Accurate in Ovarian Cancer Detection

To determine the feasibility of us-ing the immunosignature technology to detect ovarian cancer, the research-ers tested samples from 39 patients with biopsy-confirmed ovarian cancer (stages IA to IV) and 49 age-matched controls with benign breast disease. They chose this control group because

it may demonstrate inflammation, and the researchers wanted to be sure the immunosignature did not simply reflect an inflammatory process.

They identified peptides with statis-tically significant differences in bind-ing signal between cases and controls and trained a support vector machine model as the classification algorithm using the 500 most significant features. Classification performance character-istics were evaluated using cross-vali-dation techniques.

For all stages, the AUC was deter-mined to be 0.96, sensitivity for detect-ing ovarian cancer was 91%, specificity was 93%, and overall accuracy was 93%. The cross-validated ovarian cancer classification performance, by stage, is shown in Table 1.

The next step is to evaluate the im-munosignatures in larger, more diverse cohorts and to validate the findings in blinded studies, which are underway.

Dr. Tarasow said the test will prob-ably be most useful in a high-risk population, not for general popula-tion screening, where incidence rates are very low. He noted that in future studies, they can power the cohorts enough to separate among stages and cell histologies. n

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

Reference1. Tarasow T, Haddad M, Legutki JB, et

al: Detection of stage I-IV ovarian cancer from a drop of serum. NCCN Annual Con-ference. Presented March 12, 2015.

Biomarkers

For cancer, the technology has demonstrated the capability to distinguish patient samples representing several different cancers from each other, as well as from noncancer controls, with high accuracy.

—Theodore M. Tarasow, PhD

Table 1: Cross-Validated Ovarian Cancer Classification Performance

Ovarian Cancer Stages

AUC (CI)

Accuracy (CI)

Sensitivity (CI)

Specificity (CI)

All Stages 0.96 (0.94–0.99)

93% (88%–7%)

91% (84%–98%)

93% (89%–98%)

Stage IIIC and Stage IV

0.96 (0.93–0.98)

94% (83%–99%)

82% (70%–96%)

98% (88%–00%)

Stage I 0.88 (0.80–0.92)

87% (77%–93%)

59% (46%–77%)

95% (85%–97%)

Ovarian cancer immunosignature performance within the entire cohort, as well as within subsets of early and late stages only. n = 49 controls, stage I = 13, stage IIIC = 5, stage IV = 18. AUC = area under the receiver operating characteristic curve, CI = confidence interval.

Announcements

Groups Join Together to Form Ovarian Cancer Research Team

S tand Up To Cancer , Ovarian Can-cer Research Fund, Ovarian Can-

cer National Alliance, and National Ovarian Cancer Coalition, along with the American Association for Cancer Research (AACR), announced the for-mation of a “Dream Team” devoted to ovarian cancer research at the AACR Annual Meeting 2015.

Alan D’Andrea, MD, Codirector of the Gene Therapy Center at Dana-Farber Cancer Institute, and the Fuller-American Cancer Society Professor of Medicine at Harvard Medical School, will lead the Dream Team. Elizabeth M. Swisher, MD, Professor in the De-

partment of Obstetrics and Gynecolo-gy at the University of Washington, will be Coleader.

The collaborating organizations will devote $6 million over 3 years to a proj-ect entitled “DNA Repair Therapies for Ovarian Cancer.”

Targeting Genetic MutationsThe U.S. Food and Drug Administra-

tion (FDA) last year approved the drug olaparib to treat women with advanced ovarian cancer associated with defective BRCA genes, which are among a number of DNA repair genes identified as mu-tated in ovarian cancer. By targeting DNA

repair pathways, the Dream Team hopes to build and expand on the recent clini-cal advances seen with olaparib and other PARP inhibitors in current clinical trials.

The team will also focus on preven-tion and early detection of ovarian can-cer, which tends to be diagnosed at a late stage of the disease.

“We plan to develop a new web-based approach to genetic testing and counseling that will increase access to ovarian cancer risk assessment, so women can take action if they are at high risk,” Dr. Swisher said. A key fea-ture of the prevention approach pro-posed by the Dream Team is to offer

women identified as genetically high risk a choice of surgical options, includ-ing one that removes the fallopian tubes but spares the ovaries.

The Dream Team also includes three advocates: Kathleen Gavin, Execu-tive Director of the Minnesota Ovarian Cancer Alliance; Sue Friedman, Ex-ecutive Director of FORCE (Facing Our Risk of Cancer Empowered); and Jamie Crase, an ovarian cancer survivor.

The project marks the first time that all three of the major ovarian cancer groups in the United States have come together to support a single research initiative. n


Combining Antiangiogenic and Vascular-Disrupting Agents Improves Progression-Free Survival in Persistent Ovarian CancerBy Charlotte Bath

“B evacizumab [Avastin] prevents new blood vessels from grow-

ing, but what about the blood vessels that are already in the tumor?” Present-ing that challenge to participants at the Society of Gynecologic Oncology An-nual Meeting on Women’s Cancer in Chicago, Bradley J. Monk, MD, of the University of Arizona Cancer Center in Phoenix, then suggested combining bevacizumab with an agent from “the complementary class of antivascular agents that target existing blood ves-sels” to “capitalize” on results produced by bevacizumab in patients with persis-tent or recurrent ovarian cancer. This complementary class of agents, called vascular-disrupting agents, Dr. Monk explained, can cause vascular collapse,

reduce tumor blood flow, and are un-likely to lead to resistance, based on their mechanism of action.

A phase I study1 showed that com-bining the antiangiogenic agent beva-cizumab with the vascular-disrupting agent fosbretabulin produced a “39% persistent reduction in vasculariza-tion,” Dr. Monk said. “This led to a ran-domized phase II trial, trying to assess whether the addition of fosbretabulin to bevacizumab could do better than what we had done with bevacizumab as a single agent,” Dr. Monk stated.

‘Intriguing, Positive Study’The phase II study compared beva-

cizumab and fosbretabulin with beva-cizumab alone among patients with persistent or recurrent ovarian, fallo-pian tube, or primary peritoneal carci-noma. Fosbretabulin is a water-soluble prodrug of cis-combretastatin A4 (cis-CA4), a natural product isolated from the African bush willow (Combretum

caffrum). The study was conducted by NRG Oncology and the Gynecologic Oncology Group.

“This was a very intriguing, positive study,” Dr. Monk reported. “Patients were randomized in an open-label fash-ion to bevacizumab vs bevacizumab/fosbretabulin given every 3 weeks,” Dr. Monk explained. The intent-to-treat population of 107 patients included 54 patients who received the combina-tion of bevacizumab and fosbretabulin and 53 patients who received bevaci-zumab alone. A total of 103 patients were evaluable, 52 treated with the combination and 51 treated with beva-cizumab alone.

“Patients “were well balanced in re-gard to age, ethnicity, performance sta-

tus, cell type, and number of prior regi-mens,” Dr. Monk said. Most patients in both treatment groups were between 50 and 80 years old, and 85% in both groups had serous cell tumors. Most patients, 77.8% in the combination group and 73.6% in the bevacizumab-alone group, had measurable disease.

Patients were allowed to have one to three prior chemotherapy regimens with no more than one nonplatinum, nontaxane regimen. Prior front-line bevacizumab was also allowed. “Inter-estingly, there were only 5 patients in each arm, a total of 10, who had had prior bevacizumab,” Dr. Monk noted.

Statistically Significant Improvement

“When fosbretabulin was added to bevacizumab, there was a statistically significant improvement in progres-sion-free survival,” Dr. Monk reported. The median progression-free survival was 7.3 months in the combination

arm, compared with 4.8 months in the bevacizumab-alone arm, with a haz-ard ratio of 0.685. Among platinum-resistant patients, the median progres-sion-free survival was 6.7 months with combination treatment vs 3.4 months with bevacizumab alone. “We wanted to look at the resistant patients,” Dr. Monk noted, “because they are the highest unmet medical need.”

The difference in median progres-sion-free survival among platinum-sensitive patients with a platinum-free interval of more than 6 months was 7.6 months for the combination treatment vs 6.1 months for bevacizumab alone, but “the hazard ratio was still 0.67.”

Noting that the study was “a small phase II trial,” and the results were “hypotheses-generating,” Dr. Monk said, “I think this proves that vascular disruption is important and that we can add vascular-disrupting agents and antiangiogenic medications together.” Based on these results, he added, “the combination regimen warrants further evaluation in ovarian cancer.”

Dr. Monk pointed out that the me-dian progression-free survival for plat-inum-resistant patients in this study was “exactly the same” as in the AU-RELIA study of single-agent chemo-therapy with or without bevacizum-ab—6.7 months with the combination therapy and 3.4 months with single-agent chemotherapy alone.2 The AU-RELIA study formed the basis of the U.S. Food and Drug Administration’s (FDA) approval in November 2014 of bevacizumab in combination with pa-clitaxel, pegylated liposomal doxoru-bicin, or topetecan for the treatment of patients with platinum-resistant recur-rent ovarian, fallopian tube, or primary peritoneal cancer.3

Response Rates IncreasedIn the phase II trial reported by Dr.

Monk, the objective response rates among the intent-to-treat population were 27.8% for bevacizumab plus fos-bretabulin vs 20.8% for bevacizumab alone. For patients with measurable disease, objective response rates rose to 35.7% in the combination group and 28.2% in the bevacizumab-alone

group. The odds ratio for responding to the combination vs single-agent treatment was 1.41.

“There was long-term control and an increase in response rate,” Dr. Monk stated. “Overall survival data are imma-ture, with only 33 patients having died.”

‘Relatively High’ HypertensionTreatment was tolerable for pa-

tients in both groups. “There were patients in both arms who had more than 9 cycles,” Dr. Monk said. Previ-ous experience, he said, has shown that “bevacizumab as a single agent is active and well tolerated, and patients can stay on treatment for a long time. I am here to tell you that when you add fosbretabulin, they can stay on treat-ment even longer.”

Hypertension “is relatively high,” Dr. Monk noted. Grade 3 hypertension oc-curred in 37.2% of patients in the com-bination arm compared with 19.6% in the bevacizumab-alone arm. There were no grade 5 adverse events in either arm, but there was one grade 4 event on each treatment arm, related to hypertension in the combination arm and metabo-lism/nutrition in the bevacizumab-alone arm. There was also one bowel perforation in the bevacizumab-alone arm. “All adverse events were manage-able,” Dr. Monk reported. n

Disclosure: Dr. Monk’s institution has received funding from the Gynecologic Oncology Group, NRG Oncology, and Genentech. Dr. Monk has received honoraria from and is a consultant and speaker for Genentech.

References1. Nathan P, Zweifel M, Padhani AR, et

al: Phase I trial of combretastatin A4 phos-phate (CA4P) in combination with beva-cizumab in patients with advanced cancer. Clin Cancer Res 18:3428-3439, 2012.

2. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with che-motherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32:1302-1308, 2014.

3. National Cancer Institute: FDA ap-proval for bevacizumab. Available at http:// www.cancer.gov/cancertopics/treatment/drugs/fda-bevacizumab. Accessed April 21, 2015.

Gynecologic Oncology

Society of Gynecologic Oncology Annual Meeting

Bevacizumab as a single agent is active and well tolerated, and patients can stay on treatment for a long time. When you add fosbretabulin, they can stay on treatment even longer.

—Bradley J. Monk, MD

For more from the SGO Annual Meeting, see page 35.


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Journal Spotlight

Improved Progression-Free Survival With Brentuximab Vedotin After Transplantation in Hodgkin Lymphoma Patients By Matthew Stenger

In the phase III AETHERA trial reported in The Lancet, Craig H.

Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, and col-leagues found that brentuximab vedo-tin (Adcetris) consolidation therapy af-ter autologous stem cell transplantation prolonged progression-free survival by 18 months vs placebo in patients with Hodgkin lymphoma at risk for relapse or disease progression.1

Study DetailsIn this double-blind trial, 329 pa-

tients from 78 sites in North America and Europe with unfavorable-risk re-lapsed or primary refractory classic Hodgkin lymphoma were randomized between April 2010 and September 2012 to receive 16 cycles of 1.8 mg/kg of brentuximab vedotin (n = 165) or placebo (n = 164) given IV every 3 weeks, starting 30 to 45 days after au-tologous stem cell transplantation. Ran-domization was stratified by best clini-cal response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and according to primary refractory Hodg-kin lymphoma vs relapsed disease < 12 months and vs ≥ 12 months after completion of front-line therapy. The primary endpoint was progression-free survival on independent review in the intention-to-treat population.

The brentuximab vedotin group had more female than male patients (54% vs 41% female; 46% vs 59% male) and a greater proportion of black patients (6% vs 1%; 93% vs 95% white, 1% vs 2% Asian). Otherwise, the two groups were generally balanced with regard to age (median 33 and 32 years, range 18–71 and 18–76 years), Eastern Cooperative Oncology Group performance status (0 for 53% and 59%, 1 for 47% and 41%), number of prior systemic salvage thera-pies, receipt of at least one autologous stem cell transplantation, time from

autologous stem cell transplantation to first study dose, front-line therapy, con-ditioning regimen, lymphoma status after front-line therapy, best response to salvage therapy after stem cell trans-plantation, pre-stem cell transplanta-tion positron emission tomography status, extranodal involvement at pre-stem cell transplantation relapse, and B symptoms after front-line therapy.

Improved Progression-Free Survival

After a median follow-up of 30 months, median progression-free sur-vival on independent review was 42.9 months (95% confidence interval [CI] = 30.4–42.9 months) in the brentuximab vedotin group vs 24.1 months (95% CI = 11.5 to not estimable) in the pla-cebo group (hazard ratio [HR] = 0.57, P = .0013). Two-year progression-free survival was 63% vs 51%. Hazard ratios favored brentuximab vedotin in all sub-groups analyzed and were significant among patients with partial response to salvage therapy, those with relapse < 12 months, those aged < 45 years, female patients, those with a performance status of 1, those who received at least two pri-or systemic treatments, those with pre-stem cell transplantation extranodal in-volvement, and those with B symptoms after front-line therapy.

At the time of the progression-free survival analysis, interim analysis of overall survival showed no difference between the two groups, with death oc-curring in 17% vs 16% of patients (HR = 1.15, P = .6204). However, 72 of 85 pa-

tients (85%) in the placebo group who received treatment after disease pro-gression received brentuximab vedotin, compared with 18% of patients in the

brentuximab vedotin group. As noted by the authors, recent data have shown that retreatment with brentuximab ve-dotin can be beneficial in patients with relapsed/refractory disease. In addition, allogeneic stem cell transplantation was less common in the brentuximab vedo-tin group (12 vs 23 patients).

Adverse EventsThe most frequent adverse events of

any grade in the brentuximab vedotin group were peripheral sensory neuropa-thy (56% vs 16% in the placebo group), neutropenia (35% vs 12%), and upper re-spiratory infection (26% vs 23%). Grade ≥ 3 adverse events occurred in 56% vs 32% of patients, with the most common in the brentuximab vedotin group be-ing neutropenia (29% vs 10%), periph-eral sensory neuropathy (10% vs 1%),

and peripheral motor neuropathy (6% vs 1%). Only one case of febrile neutro-penia was observed in the brentuximab vedotin group. Growth factor support

was required in 25% vs 11% of patients. Severe infection was observed in 7% vs 6%. Treatment discontinuation due to adverse events occurred in 33% vs 6% of patients, with the most common causes in the brentuximab vedotin group being pe-ripheral sensory and motor neuropathies.

The investigators concluded: “Early consolidation with brentuximab vedotin after autologous stem cell transplanta-tion improved progression-free survival in patients with Hodgkin lymphoma with risk factors for relapse or progres-sion after transplantation. This treatment provides an important therapeutic op-tion for patients undergoing autologous stem cell transplantation.” n

Disclosure: The study was funded by Seattle Genetics and Takeda Pharmaceuticals International. For full disclosures of the study authors, visit www.thelancet.com.

Reference1. Moskowitz CH, Nademanee A, Masszi

T, et al: Brentuximab vedotin as consoli-dation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. March 18, 2015 (early release online).

Hematology

Early consolidation with brentuximab vedotin after autologous stem cell transplantation improved progression-free survival in patients with Hodgkin lymphoma with risk factors for relapse or progression after transplantation.

—Craig H. Moskowitz, MD, and colleagues

Brentuximab Vedotin in Hodgkin Lymphoma

■ Brentuximab vedotin consolidation reduced the risk of disease progression or death by 43%.

■ Three-year overall survival was more than 80% in both the brentuximab vedotin and placebo groups, with brentuximab vedotin being use in the majority of patients in the latter group who received subsequent treatment.

High-Risk Hodgkin Lymphoma: Implications of the AETHERA Trial

Stephen M. Ansell, MD, PhD, of the Mayo Clinic, Rochester, Minnesota, offers his perspective on brentuximab vedotin after autologous stem cell transplantation in high-risk lymphoma as discussed above. See page 18.


Perspective

Brentuximab Vedotin After Autologous Stem Cell Transplantation in High-Risk Hodgkin Lymphoma: Implications of the AETHERA Trial By Stephen M. Ansell, MD, PhD

Hodgkin lymphoma is gener-ally thought to be a malignancy

with a favorable prognosis. Overall, approximately 80% of patients will have durable, long-term remissions with initial chemotherapy. Some pa-tients, however, demonstrate evidence of disease progression, and these pa-tients usually receive salvage chemo-therapy followed by autologous stem cell transplantation. Although pa-tients can be cured with this approach, at least 50% of patients subsequently progress, and many of these patients are not cured despite the use of novel treatment approaches and allogeneic stem cell transplantation. Therefore, a strategy to prevent progression of disease in patients undergoing an au-tologous stem cell transplant could significantly impact the outcome of this population of patients.

Review of Study FindingsAs recently reported in The Lan-

cet and reviewed in this issue of The ASCO Post, Dr. Moskowitz and col-leagues tested whether such a strat-egy would be successful by perform-ing a randomized, double blind, placebo-controlled, phase III trial in patients at high risk for disease pro-gression after an autologous stem cell transplant.1 Patients were defined as having high-risk disease if they had failed to achieve a complete remis-sion with initial chemotherapy, had evidence of disease progression with-in the first year after initial treatment, or had extranodal involvement at the time of disease progression (even if the period was longer than 1 year). To test whether brentuximab vedo-tin (Adcetrix) could prolong pro-gression-free survival in unfavorable-risk, relapsed or primary refractory classic Hodgkin lymphoma, patients

were randomized to receive 16 cycles of brentuximab vedotin at a dose of 1.8 mg/kg or a placebo. The therapy was infused every 3 weeks, starting 4 to 6 weeks after the autologous stem cell transplant.

A total of 329 patients were en-rolled in this clinical trial, and after a median follow-up of 30 months, the median progression-free survival on independent review was 42.9 months in the brentuximab vedotin group compared with 24.1 months in the placebo group. This was a statisti-cally significant difference, and the 2-year progression-free survival was also significantly different, with 63% of patients progression-free in the brentuximab vedotin group vs 51%

in the placebo group. In all the sub-groups analyzed, the hazard ratios favored brentuximab vedotin use in comparison to placebo. At the time of the report, however, the overall sur-vival analysis showed no difference between the two groups.

Adverse events were obviously greater in the brentuximab vedo-tin–treated group, with neuropathy and neutropenia significantly more frequent in the brentuximab vedotin patients. One-third of patients dis-continued brentuximab vedotin due to adverse events compared with 6% who discontinued therapy in the pla-cebo group. The overall conclusion of the study was that early consolida-tion with brentuximab vedotin after

stem cell transplantation improved progression-free survival in patients with high-risk Hodgkin lymphoma.

Challenging the Standard of Care

The findings of this study are signifi-cant in that, for the first time, a random-ized controlled trial has shown that the use of a single agent reduced the rate of relapse or disease progression after au-tologous stem cell transplant for Hodg-kin lymphoma. The findings challenge the assumption that the standard of care in patients with Hodgkin lympho-ma after transplantation is observation with best supportive care until the dis-ease progresses or relapses.

The fact, however, that overall sur-

vival is not impacted as yet by the use of brentuximab vedotin does bring to question whether it is required to ad-minister brentuximab vedotin in the post-transplant setting or whether a similar outcome could be achieved if patients are treated with brentuximab vedotin at the time of disease pro-gression. In this trial, it is likely that patients in the placebo arm will subse-quently receive brentuximab vedotin at the time of disease progression, and therefore demonstrating a survival ad-vantage between the two arms will be extremely difficult.

Furthermore, multiple new agents that have significant activity in Hodg-kin lymphoma, including immune checkpoint inhibitors, histone deacet-

ylase inhibitors, and immune modu-latory drugs, are now available. The use of these agents in patients who have undergone a previous autolo-gous stem cell transplant for Hodgkin lymphoma will further complicate the analysis to determine whether pa-tients do better overall with the use of a maintenance approach after trans-plant.

For many Hodgkin lymphoma pa-tients, however, remaining in remis-sion without evidence of progression of their high-risk disease is an impor-tant factor in treatment decisions. The data from this trial confirm that the use of brentuximab vedotin decreases the rate of disease progression and relapse, and therefore the addition of brentuximab vedotin after transplant will be an attractive option for many patients at risk for disease progres-sion. The increased rate of side effects will need to be balanced against the concern for disease relapse in making a decision to use maintenance therapy after transplant.

In closing, the results of this trial are extremely encouraging, confirm-ing that we continue to make progress in maintaining remissions for patients with Hodgkin lymphoma and may be decreasing the number of patients who subsequently progress. The hope for the future is that the use of novel agents in patients with Hodgkin lym-phoma will further improve the num-ber of patients who are cured of this disease and do not require additional therapy for disease relapse. n

Disclosure: Dr. Ansell received research funding from Seattle Genetics, Bristol-Myers Squibb, and Celldex Therapeutics.

Reference1. Moskowitz CH, Nademanee A,

Masszi T, et al: Brentuximab vedotin as con-solidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse Lancet. March 18, 2015 (early release online).

Dr. Ansell is Professor of Medicine at the Mayo Clinic, Rochester, Minnesota.

For the first time, a randomized controlled trial has shown that the use of a single agent reduced the rate of relapse or disease progression after autologous stem cell transplant for Hodgkin lymphoma.

—Stephen M. Ansell, MD, PhD

Visit The ASCO Post website at ASCOPost.com


Journal Spotlight

Impact of Informed Decision-Making on Breast Cancer Screening By Matthew Stenger

In a study reported in Lancet, Jolyn Hersch, MApplSc, of the Univer-

sity of Sydney, and colleagues found that use of a decision aid containing information on overdetection in breast cancer screening was associated with an increased rate of informed choice regarding screening, a reduced rate of positive attitudes toward screening, and reduced intention to be screened compared with use of a decision aid not including such information.1 Kirsten McCaffery, PhD, of the University of Sydney, is the corresponding author of the Lancet article.

Study DetailsIn the community-based trial con-

ducted in New South Wales, Australia, 879 women aged 48 to 50 years who had not had mammography in the past 2 years and did not have a personal or strong family history of breast can-cer were randomized between Janu-ary 2014 and July 2014 to receive an intervention decision aid including evidence-based explanatory and quan-titative information on overdetection, breast cancer mortality reduction, and false-positive results (n = 440) or a con-trol decision aid including information on breast cancer mortality reduction and false-positive results (n = 439).

The intervention decision aid con-tained evidence-based information about outcomes of breast screening vs no screening over a period of 20 years, including information on breast cancer mortality reduction, overdetection, and false-positive results. The control ver-sion was identical except for exclusion of all content about overdetection.

The quantitative evidence included in the decision aids was from a model of mammography screening outcomes for women in Australia; estimates of over-detection and reduction in breast can-cer mortality associated with screen-ing were derived from a meta-analysis of randomized trial data and adjusted to account for the effect of regular screening rather than ‘invitation to be screened.’ The estimates were applied

to current Australian data for incidence and mortality to provide quantitative cumulative outcomes with biennial screening vs no screening from ages 50 to 69 years. The 20-year cumulative likelihood of a false-positive result (in-cluding the number of women screened with a false-positive result and the num-ber having a biopsy) was modeled from current Australian data.

The primary outcome was informed choice about breast screening, defined

as adequate knowledge and consistency between attitudes and screening inten-tions. Participants answered questions regarding knowledge, attitudes, and in-tentions about screening and were con-sidered to have made an informed choice if they had adequate knowledge, based on predefined subscale scores, and if atti-tudes and intentions were consistent (ie, positive attitudes and intentions or nega-tive attitudes and intentions).

Knowledge was assessed by ques-tions on benefit, false-positive results, and overdetection, with questions on both conceptual knowledge and numeri-cal knowledge. Participants were inter-viewed via telephone at 3 weeks after randomization. The primary outcome was analyzed in all women who com-pleted all follow-up interview questions.

Informed Choice Among the two cohorts, 21 women

in the intervention group and 20 in the control group were lost to follow-up, and 10 and 11 did not answer all in-terview questions. Among 409 women in the intervention group and 408 in the control group, 99 vs 63 (24% vs 15%, difference = 9%, P = .0017) were considered to have made an informed choice regarding screening. In an analysis including conceptual knowl-

edge but not numerical knowledge, informed choice was made by 50% vs 19% (P < .0001).

Overall KnowledgeCompared with the control group,

significantly more women in the in-tervention group met the predefined threshold for adequate overall knowl-edge on conceptual and numerical items combined for the benefit, false-positive results, and overdetection subscales (29% vs 17%, P < .0001).

The difference was attributable to better performance of the intervention group on the overdetection subscale. There was no difference between the in-tervention group and the control group with regard to knowledge about breast cancer mortality benefit (65% vs 61%), better knowledge in the control group regarding false-positive results (58% vs 66%, P = .0154), and better knowledge in the intervention group regarding overdetection (55% vs 27%, P < .0001).

Among 11 individual conceptual items, there were no differences be-tween groups with regard to knowledge

reflected in response to “Screening is for women without symptoms” (89% vs 88%), “Screening reduces breast cancer deaths” (93% vs 95%), “Screening will not find every breast cancer” (95% vs 95%), or “Screening may lead to false-positive results” (99% vs 100%). How-ever, more women in the intervention group (all P < .05) had correct responses to the overdetection items of “Screening increases breast cancer diagnoses” (79% vs 73%), overdetection vs false-positive distinction (43% vs 12%), “Not all breast cancers cause illness or death” (68% vs 33%), “Cannot predict whether a cancer will cause harm” (78% vs 61%), “Cancer that might not cause problems is treated” (87% vs 76%), “Some women get treat-ment they do not need” (75% vs 26%), and “Overdetect more than prevent death” (77% vs 66%).

Attitudes and IntentionsSignificantly fewer women in

the intervention group expressed positive attitudes toward screening (69% vs 83%, P < .0001), with 24% vs 38% having highly positive attitudes.

Significantly fewer women in the intervention group indicated that they would definitely be screened or were likely to be screened (74% vs 87%, P < .0001); 47% vs 64% indicated they would definitely be screened, 26% vs 23% indicated they were likely to be screened, 16% vs 7% were unsure, and 10% vs 6% indicated they were unlikely to be screened or definitely would not be screened.

The investigators concluded: “Informa-tion on overdetection of breast cancer pro-vided within a decision aid increased the number of women making an informed choice about breast screening. Becoming better informed might mean women are less likely to choose screening.” n

Disclosure: The study was funded by the Australian National Health and Medical Research Council. For full disclosures of the study authors, visit www.thelancet.org.

Reference1. Hersch J, Barratt A, Jansen J, et al: Use

of a decision aid including information on overdetection to support informed choice about breast cancer screening: A ran-domised controlled trial. Lancet. February 18, 2015 (early release online).

Information on overdetection of breast cancer provided within a decision aid increased the number of women making an informed choice about breast screening. Becoming better informed might mean women are less likely to choose screening.

—Jolyn Hersch, MApplSc, Kirsten McCaffery, PhD, and colleagues

Informed Decision-Making About Breast Cancer Screening

■ Inclusion of information on overdetection in a decision aid resulted in higher rates of informed choice regarding breast screening.

■ Inclusion of information regarding overdetection reduced positive attitudes toward screening and intention to be screened.

Breast Cancer

See commentary by Ruth Etzioni, PhD, on page 20.


Perspective

Informing Decision-Making About Mammography ScreeningBy Ruth Etzioni, PhD

Overdiagnosis associated with breast cancer screening has been

the subject of much attention in recent years. The notion that cancer screen-ing—largely believed to be beneficial—could actually be harmful is simultane-ously fascinating and difficult to believe.

With the publication of multiple studies suggesting alarmingly high frequencies of overdiagnosis, calls for shared and informed decision-making have intensified. By being aware of both the benefits and the harms of screening, women should ideally be able to make decisions about screen-ing that are in accordance with their preferences and values.

As knowledgeable consumers of health care, we should absolutely be aware of both the upside and the downside of any intervention that we are offered. However, the notion of informed decision-making presumes that the information is actually there to be packaged up and provided to the patient.

Unfortunately, this is not true in the case of overdiagnosis due to mammog-raphy screening. What is true is that the plethora of studies on the topic and the repeated citation of a few high-profile estimates have given us a false sense of security about the estimated frequency of overdiagnosis. In fact, most pub-lished estimates are either biased, mis-interpreted, or both.

Dubious EstimatesRecently, an article in the journal

Health Affairs was published with the title, “National Expenditure for False-Positive Mammograms and Breast Cancer Overdiagnoses Estimated at $4 Billion a Year.”1 Anybody would be forgiven for presuming that the num-ber of overdiagnoses must be known in order to derive national cost figures. However, a closer look at the article re-veals that this is not the case. Not only does the article consider a wide range of overdiagnosis frequencies but the valid-ity of the two studies2,3 specifically cited —yielding estimates of 31% and 22% of cases diagnosed—is controversial.

The estimate of 31% comes from

comparing the observed incidence of invasive and in situ breast cancer in the United States in 2008 with an extrap-olation of what the incidence would have been in 2008 in the absence of screening.2 However, there are no con-crete data on how breast cancer rates would have changed in the relevant age group from the late 1970s, when mammography began, to almost 3 decades later. Indeed, the duration of the extrapolation—30 years—means that the results are highly sensitive to

any assumption made about what the trend in incidence would have been in the absence of screening.

The estimate of 22% comes from a clinical trial that included a control group.3 Thus, one does not have to guess at what the incidence would have been without screening. Even so, there are issues with this figure. The trial was a stop-screen trial of clinical breast exam vs mammography plus clinical breast exam. This means that women were offered screening only for the first 5 years and simply fol-lowed for mortality thereafter.

The 22% represents the excess invasive cases in the screened arm after 15 years divided by the cases detected on the same arm in the first 5 years. In this setting, the correct denominator for the overdiagnosis estimate is debatable: should it be cases detected after 5 years or cases detected after 15 years? It seems that the jury is still out on this one.

Perhaps equally important, the screening behavior on the two arms was not monitored after the initial screening period. If, after this time, women who had been assigned to the screening arm sought mammog-raphy more frequently than women

who had been assigned to the control arm, the estimated number of overdi-agnosed cases would be too high.

Meta-analysis CitedA recently reported study by

Hersch et al,4 reviewed in this issue of The ASCO Post, found that use of a de-cision aid with information on over-detection was associated with a re-duced rate of positive attitudes toward screening and a reduced intention to be screened compared with use of a

decision aid not including such infor-mation. The investigators used neither of the above estimates of overdiag-nosis in their decision aid, citing in-stead a number from a meta-analysis conducted by the Independent UK Panel on Breast Cancer Screening,5 to whom they attribute this state-ment: “Although diverse estimates of overdetection are available, derived from various data and methods, ran-domised trials provide the best evi-dence for the extent of overdetection.”

This too bears closer scrutiny, be-cause overdiagnosis estimates based on cumulative excess incidence in a trial are highly inflated under typical follow-up durations, which tend to be modest. Even with longer follow-up, conditions for validity are often not satisfied. Thus, relying on clinical trials to automatical-ly provide unbiased estimates of over-diagnosis is problematic.

Further Challenges to ValidityUnfortunately, most published es-

timates of overdiagnosis suffer from such limitations. Consequently, at this point, we still don’t really know how frequently breast cancer cases detected by mammography are over-diagnosed. Even the Independent UK

Panel, in their report, noted that their estimates were “the best estimates from a paucity of reliable data.”

Many methodologic investigations have pointed out the challenges to va-lidity of available estimates, and some have even provided more mathemati-cally based alternatives, which tend to produce lower values. But, clearly, methods and media don’t mix, and simpler studies that use excess inci-dence as a proxy for diagnosis have dominated the popular press.

Hersch et al deserve to be com-mended for their trial, which not only provided information about the dismal state of public knowl-edge about overdiagnosis, but also indicated that improving the state of knowledge could influence women’s screening behavior. However, it is unclear whether the women who got the enhanced decision aid were influ-enced more by the information that overdiagnosis exists or by the little dots in the accompanying graphic showing how many screen-detected cases it affects. Hopefully, the former was the principal factor; at least the information that overdiagnosis does exist is watertight. n

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

References1. Ong M-S, Mandl KD: National ex-

penditure for false-positive mammograms and breast cancer overdiagnoses estimated at $4 billion a year. Health Aff 34:4576-4583, 2015.

2. Bleyer A, Welch HG: Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 367:1998-2005, 2012.

3. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian Na-tional Breast Screening Study: Randomised screening trial. BMJ 348:g366, 2014.

4. Hersch J, Barratt A, Jansen J, et al: Use of a decision aid including informa-tion on overdetection to support informed choice about breast cancer screening: A randomised controlled trial. Lancet. Feb-ruary 18, 2015 (early release online).

5. Independent UK Panel on Breast Cancer Screening: The benefits and harms of breast cancer screening: An independent review. Lancet 380:1778-1786, 2012.

Dr. Etzioni is a biostatistician and mem-ber of the Public Health Sciences Divi-sion, Fred Hutchinson Cancer Research Center, Seattle.

Hersch et al deserve to be commended for their trial, which not only provided information about the dismal state of public knowledge about overdiagnosis, but also indicated that improving the state of knowledge could influence women’s screening behavior.

—Ruth Etzioni, PhD


ASCO State Affiliates

Maryland Oncologists Faced With Navigating the Maze of Chemotherapy Safety RegulationsBy Randi Londer Gould

In March 2013, 60 Minutes aired a devastating piece about a Massachu-

setts compounding center that shipped an injectable steroid contaminated with fungus. One of the many ripple effects from this story of horrendous patient suffering was felt in Maryland, where it sparked legislative action in the An-napolis State House.

“Maryland passed a compounding bill, which at first we didn’t think had anything to do with oncology,” recalled Paul Celano, MD, FACP, Chief of the Division of Medical Oncology at the Greater Baltimore Medical Center. “But as the law was being implemented, it was clear that it applied to any medication that was being ordered, mixed, and given to patients anywhere.” Dr. Celano is Pres-ident of the Maryland/DC Society of Clinical Oncology and a member of both ASCO’s State Affiliate Council Executive Subcommittee and ASCO’s Task Force on Safe Handling of Chemotherapy.

At the time, said Dr. Celano, there were no oncology-based standards or recommendations to help guide phy-sicians. “Everything defaulted back to USP [U.S. Pharmacopeial Convention] standards, which are very broad-based and apply to anything and everything. No one would argue with the principle of safety for patients and employees, but it has been the application of these stan-dards that is the point of contention.”

Major ImplicationsIf oncology practices were com-

pelled to follow the proposed Chapter <797> or Chapter <800> recommen-dations (designed to protect patients and health-care workers, respectively), it would have major implications, par-ticularly for those in rural areas or free-standing practices, Dr. Celano asserted.

USP is a scientific nonprofit or-

ganization that sets standards for the quality and purity of medicines, food ingredients, and dietary supplements worldwide. The organization works with experts in a number of countries to develop and revise standards that help protect public health. Enforced by the U.S. Food and Drug Administration, USP standards help secure the quality of the American drug supply.

That’s the view from 30,000 feet. At ground level, the picture looks quite different.

“There’s a patient access issue,” said Dr. Celano. “With these rules in place, [many] patients could not even receive therapy. And there are issues around physical changes: The regula-tions would require external venting of

chemotherapy hoods in all situations. In some places—for instance, where practices lease office space—that isn’t practical. They could not make those kinds of alterations.”

Challenges to StatesWhat has been happening in Mary-

land in part inspired ASCO to form the Task Force on Safe Handling of Chemotherapy, said Dr. Celano. Robin Zon, MD, FACP, FASCO, head of the Task Force on Safe Handling of Chemotherapy and Chair of ASCO’s Clinical Practice Committee, credits Dr. Celano with shining a bright light on the safety compliance struggles of practices in states such as Maryland. “He has brought to our attention first-hand knowledge of the challenges states are facing when it comes to the maze of regulations,” Dr. Zon said. “He has helped guide us as we continue to de-velop safe handling recommendations.” Dr. Zon is Vice President and one of the Senior Partners at Michiana Hematolo-gy Oncology, PC, in Northern Indiana.

“It was ASCO’s State Affiliate Coun-cil that served as a sounding board for Dr. Celano’s concerns,” said James N. Frame, MD, FACP, Chair of the Coun-cil and Medical Director of the David Lee Cancer Center in Charleston, West

Virginia. During a February 2014 Coun-cil meeting, Dr. Celano expressed his concerns, and “it galvanized ASCO’s re-view and action on the potential loss of cancer treatment access in Maryland’s community oncology practices,” said Dr. Frame. That rapid response, he notes, also “engendered a broader discussion on core chemotherapy safety standards that are practicable and implementable.”

Working with the Maryland Depart-ment of Health and Mental Hygiene, Dr. Celano and his colleagues were able to, at least partially, put the brakes on a compounding bill in 2013 and 2014. “We were able to exempt oncology,” he said. “In return, we said we would help develop safety regulations in the state. The standards we developed are for the

proper administration of chemothera-py and infectious issues—which USP doesn’t address directly—and hazard-ous drug administration. In the absence of any national regulations, we needed to do something.”

However, he said ruefully, when deal-ing with bureaucracies, the path is rarely smooth. “There is never just one agency we had to deal with. MOSH [Maryland Occupational Safety and Health] had its own set of regulations. That is still the loose end in Maryland. There was a

change of administration. We went from having a Democratic governor to a Re-publican governor and a change in the Secretary of Health. They put everything on hold. The Republicans want to get rid of the regulations, but that’s not going to happen. It’s not realistic.”

Unified Standard NeededWhat is happening in Maryland is

a warning sign of what is happening throughout the country, Dr. Celano said. “The USP <800> regulations have added another level to this. If we could have one unified standard that we can all live with that is proper, safe, and do-able, we can use that as our reference so we don’t have to fight 50 individual battles in 50 states.”

Aside from Quality Oncology Practice Initiative (QOPI®) standards, ASCO, working with the Oncology Nursing Society, has also adopted rec-ommendations from the Centers for Disease Control and Prevention for proper infection control procedures and hazardous drug handling issues.

“We’re all wrestling with the same issues,” said Dr. Celano. “What are the proper precautions on taking the drugs in, unpacking them, preparing them, and handling the drugs? What happens if the drug spills on the floor? If someone is exposed, is it necessary to have medical surveillance? We have outlined the is-sues. Now we need to make decisions on how to address these issues. I do feel that the solution will evolve over time.” n

Disclosure: Drs. Celano, Zon, and Frame reported no potential conflicts of interest.

USP Urged to Work With ASCO on Hazardous Drug Regulations

In July 2014, ASCO President Peter Paul Yu, MD, FACP, FASCO, wrote a lengthy letter to the CEO of the U.S. Pharmacopeial Convention (USP),

commenting on the proposal for Chapter <800> regulations, saying “it is not evidence-based and is fundamentally flawed” and urging USP to “engage with ASCO in a more collaborative process before finalizing recommenda-tions in this area.”

In response, USP revised its recommendations and offered them for pub-lic comment until May 31. For more information, go to http://www.usp.org/ usp-nf/notices/general-chapter-hazardous-drugs-handling-healthcare-settings.

To download the proposed Chapter <800> revisions, go to www.usp.org/sites/default/files/usp_pdf/EN/m7808.pdf.

To read Dr. Yu’s letter, go to www.asco.org/sites/www.asco.org/files/asco_usp_800_comments_final-c-c.pdf. n

Drug Safety

Paul Celano, MD, FACP

We’re all wrestling with the same issues…. Now we need to make decisions on how to address these issues.

I do feel that the solution will evolve over time. —Paul Celano, MD, FACP


Direct From ASCO

Enhance Your Annual Meeting Experience With Attendee Resources

At the end of May, more than 25,000 oncology professionals from around

the world will meet in Chicago for the 2015 ASCO Annual Meeting. This year’s theme, “Illumination & Innovation: Transforming Data into Learning,” re-flects the current state of oncology.

The accelerating volume and variety of cancer data challenges our capacity to assimilate and transform them into usable knowledge that impacts cancer care. Innovation—the imaginative and creative use of knowledge to transform how we improve the lives of patients in a sustainable and scalable manner—is the necessary companion to illumina-tion. ASCO’s goal is not the accumula-tion of knowledge for its own sake, but rather the application of knowledge to patient care. With data as a shared re-source, we can accelerate learning from one another and from our patients, sharing new insights and making faster strides against cancer.

Are you planning to join this global community? As you consider what to pack for your trip, keep in mind that you have a host of electronic resources at your fingertips that will help you plan and enhance your onsite experience.

The mobile-friendly Attendee Re-

source Center (am.asco.org/arc) serves as a one-stop shop for ASCO’s entire suite of Annual Meeting apps, publications, and products. You can view, print, or down-load a variety of resources to help you get the most out of the Annual Meeting.

Know Before You Go The Attendee Resource Center

houses several tools to help you prepare.• Build your Meeting itinerary with

the iPlanner, a scheduling tool that allows you to search by session, speaker, or abstract to narrow down sessions of interest. The iPlanner is available via desktop site and as a mobile app (available for Apple and Android devices). Conveniently, both versions automatically sync, so the itinerary you build on your com-puter will be available to you at the Meeting on your mobile device.

• Browse and download abstracts from the Annual Meeting Proceedings Part I, available in several digital for-mats. This publication will be avail-able for download after the May 13 abstract launch at 5:00 PM (EDT) as a PDF (with a by-track or full- download option) or as an ePub file (for iPads and Nooks).

• Review articles written by Annual Meeting faculty in the ASCO Edu-cational Book. This peer-reviewed publication highlights standards of care and offers insight into future therapeutic possibilities in oncolo-gy. Download the ASCO Educational Book as a PDF (with a by-track or full-download option), as an ePub file (for iPads and Nooks), or as a mobi file (for Kindles).

Stay In-the-Know During the Annual Meeting

The Attendee Resource Center also offers a host of resources that will streamline and enhance your An-nual Meeting experience once you arrive in Chicago. Find shuttle sched-ules, easily locate exhibitors, complete evaluations, and request Continuing Medical Education (CME) credits and Certificates of Attendance on the go. The ASCO Daily News is the official news source of the Annual Meeting, with issues produced Friday through Tuesday containing Expert Editorials and columns on topics of interest to the oncology community, helpful in-formation for navigating the Meeting, program listings, and live coverage up-

dates. You can pick up your daily copy of the ASCO Daily News throughout McCormick Place, and you can find additional content at am.asco.org/dn.

Continue Learning After You Leave

Onsite or online, you can rewatch fa-vorite sessions or catch up on the ones you missed with the Virtual Meeting. The Virtual Meeting provides access to posters and presentations from your computer, smartphone, or tablet, and the companion iPad app, ASCO iMeet-ing, even allows you to save videos for offline viewing.

Access to these resources and more are available through the Attendee Re-source Center at am.asco.org/arc. n

© 2015. American Society of Clinical Oncology. All rights reserved.

A New Way to Connect: Access the Message and Network-ing Center to search for registered attendees, send personal mes-sages, and learn about network-ing opportunities available at the Meeting. Visit am.asco.org/arc

ASCO Submits Comments to FDA on Next-Generation Sequencing TestsA SCO submitted comments to the

U.S. Food and Drug Administra-tion (FDA) on its white paper, “Op-timizing FDA’s Regulatory Oversight of Next-Generation Sequencing Diag-nostic Tests.” The Society expressed its support of the exploration of new regu-latory strategies for next-generation sequencing diagnostic tests (given the tests’ potential to identify individuals at high risk for developing cancer), and to support clinical decisions for those already diagnosed.

In the comments letter, ASCO stat-ed its support for a standards-based approach to regulatory review of next-generation sequencing tests that would not only ensure continued quality, but would also validate the tests for ana-lytic performance. Although ASCO strongly recommended that regulation be implemented in such a manner as to ensure ongoing innovation in the field

of molecular diagnostics development, as well as timely patient access to the new generation of molecular and ge-nomic tests that can improve care, the Society recognized the harm failed tests can cause patients by recom-mending them for inappropriate, and potentially harmful, treatment.

Similarly, ASCO warned against misinterpretation or overinterpre-tation of test results, both of which could potentially mislead physicians and expose patients to undue risk. Consequently, ASCO urged the FDA to establish guidelines regarding how next-generation sequencing test re-

sults are reported, to ensure that re-sults are clear and easily interpretable.

Read the full letter at www.asco.org/ sites/www.asco.org/files/asco_ngs_comments_03.20.2015.pdf. n


Save the Date: Community Research Forum 2015 Annual Meeting

The Community Research Forum (CRF) will hold its Annual Meet-

ing this fall, September 20 to 21, 2015. This meeting will provide an exclusive opportunity for community-based re-searchers and research staff to network and collaborate with colleagues from all types of research sites and programs. It will also provide a unique forum to

discuss barriers and propose solutions to common challenges in conducting research and to provide input on ASCO programs and policy issues impacting clinical research.

The CRF received a grant from ASCO’s Conquer Cancer Foundation Mission Endowment Fund to award a stipend to up to 20 research staff from

community-based research sites. For details about the meeting, in-

cluding registration and the stipend ap-plication process, visit www.asco.org/ practice-research/community-research -forum. n


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Direct From ASCO

Five Reasons to Use Social Media at the ASCO Annual Meeting• Join the discussion: Use #ASCO15

on Twitter to follow and participate in the conversation around the Annual Meeting in real time! During last year’s Annual Meeting, over 43,000 Tweets were sent by more than 8,500 individ-

uals, reaching an estimated 145 mil-lion Twitter users. Tweets about the Meeting were sent and shared in 93 countries by health-care professionals, researchers, news outlets, patients, ad-vocates, and many others.

• Connect with colleagues virtually: With social networking, it’s easier than ever to reach out to colleagues to initi-ate conversations. Twitter handles will be printed on attendee badges at the Annual Meeting, are included in the

Membership Directory, and can be found in the speaker information sec-tion of the iPlanner.

• Connecting in person: Don’t miss the #ASCO15 “Tweetup,” a chance



Direct From ASCO

Maintenance of Certification Activities: Earn Points at the ASCO Annual Meeting

The 2015 ASCO Annual Meeting will feature three activities to help at-

tendees earn American Board of Internal Medicine (ABIM) Maintenance of Certi-fication (MOC) points while onsite.

Annual Meeting Practice-Centered Session MOC Self-Assessment Activity

This activity is designed for attendees who want to refresh their knowledge, update their skills, or prepare for their

board certification or MOC examina-tion. Participants will take a 30-question online pretest to identify their knowl-edge gaps, attend appropriate Practice-Centered Sessions to assist with areas of weakness, and complete an online post-test. Data and scores can be sent directly to ABIM, and participants are eligible for 10 MOC points in Self-Assessment of Medical Knowledge upon successful completion of the post-test.

To take advantage of this opportunity,

add the Maintenance of Certification Practice-Centered Session Self-Assess-ment Activity to your Meeting registration at am.asco.org. Participants will receive the online pretest beginning the week of May 13.

MOC and Lifelong Learning Workshops

In 2015, ASCO is offering two 3.5-hour interactive sessions that will use audience response technology to

review an ABIM medical oncology module. Each of the module’s 30 mul-tiple choice questions will be reviewed through detailed group discussion led by expert faculty. At the completion of each session, diplomates will be able to submit their answers to ABIM and receive 10 MOC points.

MOC and Lifelong Learning Work-shop: ABIM Module 2014Module Utilized: ABIM 2014 Update in Medical OncologyFriday, May 29: 1:00 PM–4:15 PM

MOC and Lifelong Learning Work-shop: ABIM Module 2013Module Utilized: ABIM 2013 Update in Medical OncologySaturday, May 30: 1:00 PM–4:15 PM

Visit am.asco.org/maintenance-certi-fication to learn more about these oppor-tunities. n


Providing Survivorship Care Bundle: Oncology Provider Guides and Patient Guides

ASCO’s new product bundle com-bines provider and patient infor-

mation about cancer survivorship. Providing High Quality Survivorship

Care in Practice: An ASCO Guide aims to assist oncologists and other clini-cians with implementing high-quality survivorship care programs within their practice. The topics covered include

identifying the components of survi-vorship care, building a survivorship care program, outlining the different models of care delivery, and measuring the quality of the care.

To complement the provider guide, this bundle also includes ASCO An-swers: Cancer Survivorship for patients. This guide helps patients better un-derstand survivorship, including its psychological, physical, sexual, repro-ductive, financial, and work-related challenges.

With these guides, both patients and oncology providers will have the prac-tical tools they need to work together to help the transition into survivorship.

Each bundle contains 10 provider booklets and 40 patient guides. Visit www.cancer.net/estore to order copies for your practice. Enjoy free shipping on all patient education products—and ASCO mem-bers save 20% with member ID. n


Conquer Cancer Foundation

Be on the lookout for a big an-nouncement from the Conquer

Cancer Foundation at the 2015 An-nual Meeting. How will you be able to

take part? By making a gift in support of vital cancer research, education, and tools to improve the quality of cancer care. Donations can be made online at ccf.asco.org, and onsite at the Donor Lounge (Room S401, open May 29–June 1) or the Founda-tion Desk in the Hall D1 Lobby, right next to the video wall. Conquer Can-cer Foundation donors are invited to

visit the Donor Lounge to relax, re-charge, and enjoy light refreshments. Attendees can also stop by the Foun-dation Desk to learn more about the Foundation, make a donation, and even snag a snack or souvenir during selected hours. n


Best of ASCO® BostonJuly 31-August 1, 2015

Renaissance Boston Waterfront Hotel

Boston, Massachusetts

Save the Date

Best of ASCO® San FranciscoAugust 7-8, 2015

Marriott Marquis

San Francisco, California

Best of ASCO® ChicagoAugust 28-29, 2015

Swissotel Chicago

Chicago, Illinois


Direct From ASCO

for attendees interested in oncol-ogy’s intersection with social media to meet, talk, and, of course, tweet. The Tweetup will take place on Saturday, May 30 at 5:45 PM. For more details and to RSVP, visit tweetvite.com/event/ASCO15.

• Stay up-to-date: Following ASCO on social media during the Annual Meeting will ensure you’re seeing the latest information from the Society. ASCO shares useful information such as live updates on new research, tips to help you navigate McCormick Place, and alerts when last-minute logistical changes occur.

• Enhance your learning: Several ASCO members have been selected as “Featured Voices” for the ASCO An-nual Meeting. These volunteers will share their expertise and impressions on Twitter throughout the Meeting. Watch for their tweets as they lead this social media conversation!The Conquer Cancer Foundation of

ASCO and Cancer.Net, ASCO’s patient information website, can also be found on the platforms listed in the sidebar, as well as on Google+. Visit asco.org/social-me-dia to learn more about how to get started using social media. n


Social Mediacontinued from page 24

YouTube: ASCOCancer

Twitter: @ASCO

Facebook: ASCOCancer

LinkedIn: American Society of Clinical Oncology

Can’t make it to Chicago? No problem! Social media makes it easy to follow along and join the conversation.

Connect with ASCO on the following platforms:

ASCO Annual MeetingMay 29-June 2, 2015

McCormick Place

Chicago, Illinois

Save the Date

www.bostonbiomedical.com

Malignancies, like normal adult tissue, have been shown to contain a subset

of cells that have the capacity to both self-renew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6

Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence.

Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10

Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

Understanding Cancer Stem CellsCancer Stem Cells Signal Pathways Regrowth Metastasis

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Childhood Cancers: Significant Medical Success but Many Psychosocial Needs Still Unmet By Margot J. Fromer

T reatment of childhood cancer is remarkably successful, but still,

2,000 children die of it each year, and for some forms of the disease, no prog-

ress has been made at all, said Otis Brawley, MD, Chief Medical Officer, American Cancer Society (ACS). “At least half of all pediatric cancer survi-

vors have five comorbid conditions di-rectly related to the cancer—or more likely, its treatment—and some prove fatal,” he added. He made these obser-

vations in his introduction to a National Cancer Policy Forum, cosponsored by ACS, held at the Institute of Medicine.

Joanne Wolfe, MD, Director of Pediatric Palliative Care, Boston Chil-dren’s Hospital and Division Chief, De-partment of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer In-

stitute, added that the general public is becoming aware of quality of life in can-cer, especially for children. “Advances in treatment are costly in ways other than economic. Many young survivors suffer mental impairment, poor motor func-tioning, and highly compromised social well-being that last for decades.”

“In addition, the disease necessitates difficult decisions about treatment, al-most all of which carries significant tox-icity. They are forced to balance survival and quality of life—with limited sup-port to guide them.”

Progress and ChallengesGregory Reaman, MD, Associate

Director for Oncology Sciences, U.S. Food and Drug Administration Center

National Cancer Policy ForumSupportive Care


Otis Brawley, MD

Parents typically hope for a cure, longer life—a miracle; and at the same

time, they hope for comfort and meaning, no matter

what the illness course. —Joanne Wolfe, MD

www.bostonbiomedical.com

Malignancies, like normal adult tissue, have been shown to contain a subset

of cells that have the capacity to both self-renew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6

Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence.

Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10

Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

Understanding Cancer Stem CellsCancer Stem Cells Signal Pathways Regrowth Metastasis

EDU-NPS-0009 12/2014 ©2014 Boston Biomedical

ADVERTORIAL

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National Cancer Policy Forum

for Drug Evaluation and Research, said there has been considerable progress in treatment. Multicenter, multidisci-plinary research, a highly effective clini-cal trials infrastructure, and a practice

model that integrates clinical care and clinical research explain the improved outcome for the nearly 15,000 patients diagnosed annually. There is a highly ef-fective national clinical trials infrastruc-ture, and clinical practice models lead to integrated clinical care and research.

Nevertheless, challenges remain. “Childhood cancers are only 1% of the United States total. Pharmacology is complex, because normal growth and development, changing organ function, and metabolic enzymes must be taken into consideration. Current industry re-search and development models do not favor pediatric drug development, and there are insufficient preclinical models and testing programs. Goals are dis-similar for pediatric drug development, where cure is the primary objective. For instance, what do we mean by “clini-cal benefit”: cure or prolongation of life? And should survivable childhood cancers be viewed as ordinary chronic diseases because they follow into adult-hood and not strictly pediatric ones?”

There has been progress in child-hood cancer genomics as well. “The vast majority of recurring genomic al-terations have been identified, and we know that pediatric tumors have fewer gene mutations than adult ones. Many are driven by mutations that are rare in adult cancers, such as high-grade glio-mas, neuroblastoma, rhabdomyosarco-ma and Ewing sarcoma, and some brain tumors, and are thus not relevant to molecularly targeted agents approved or in development for adults.”

Moreover, the relatively small num-ber of patients with any specific cancer makes clinical trials difficult. This is further complicated by subdivisions of diagnoses based on genomic char-acteristics; for example, there are four subtypes of meduloblastoma, each with its own therapeutic strategy.

Promising approaches are in devel-

opment, however, including mono-clonal antibodies, immunoconjugates, enhancement of host-effector T-cell function, and engineered cell therapy.

But even if every drug worked ev-ery time in every patient, short- and long-term toxicity may still be a prob-lem, even with targeted agents, said Dr. Reaman. The list of acute and chronic complications is long, often severe, and sometimes life-threatening: diarrhea; fever; chills; asthenia; cardiotoxicity; hy-pertension; and cerebrovascular, pulmo-nary, eye, musculoskeletal, neurologic, and endocrine-reproductive diseases, as well as immunodeficiency and autoim-munity. And there are second cancers.

Dr. Reaman is optimistic, but “we need to expand opportunities in preci-sion medicine, shift paradigms in study design, and develop science-based strat-egies to decide which new products to test—when and in what diseases—and how to integrate them with currently ef-fective standard therapy.”

Survival Comes With ProblemsSmita Bhatia, MD, MPH, Direc-

tor, Institute of Cancer Outcomes and Survivorship, University of Alabama at Birmingham, echoed the significant in-crease in survival since the 1970s. Then, only 63% survived; now close to 90% do. “There are now 379,000 survivors in this country [there will be half a million by 2020], all of whom are aging. Many

have significant morbidity, and as time away from diagnosis increases, so does the likelihood of early death. The impli-cations of cure are not trivial.” Ways to look at them include the following:• Describing known relationships be-

tween treatment and morbidity and premature mortality: for example, understanding various therapeutic exposures that can result in adverse events: anthracyclines and chest ra-diation and heart failure; radiation, alkylating agents, and topoisomer-ase II inhibitors and second cancers; steroids, radiation, and osteonecro-sis; and radiation and stroke.

• Understanding the pathogenesis of morbidity.

• Comparing survivors who suffer ad-

verse events with those who escape them.

• Developing targeted interventions to reduce morbidity: for example, banking DNA and RNA from sur-vivors with and without adverse events and exploring the role of ge-netic susceptibility.

• Optimizing long-term health by cre-ating partnerships with parents and patients. Only in the past 2 decades or so have

clinicians and researchers realized the enormous impact of survival, said Dr. Bhatia. “We need to extend and stan-dardize follow-up, which means that all providers—general pediatricians, inter-nists, and family practitioners, as well as pediatric oncologists—must be aware of the risks, so survivors receive long-term follow-up care.”

Mary Jo Kupst, PhD, Professor Emerita, Medical College of Wiscon-sin, talked about how children and their families cope with the disease. “Al-though end-of-life issues are important, we are placing increasing emphasis on living with childhood cancer.”

However, survival has more than medical problems—ending treatment, for example. Although patients and their families are relieved to be done with drugs, blood tests, and clinical vis-its, the loss of the “safety net” of treat-ment and supportive care is scary, and transition to follow-up carries its own stress. So does being a survivor. Most survivors require health monitoring of one kind or another for many years, usually forever, and life is significantly altered for all. Their personal outlook, academic and/or vocational plans, and social and spiritual lives change, again often forever.

Each age group has unique prob-lems, said Dr. Kupst. Very young chil-dren can regress developmentally and become fearful of things and situations they had mastered. School-aged chil-dren may be academically and socially left behind their peers and not able to participate in previous activities. Often because of the experience, they develop a different, more mature, emotional path than their peers and can no longer

relate well to friends.Adolescents, who are emotionally

labile in the best circumstances, suffer emotionally when their school and so-cial lives are disrupted. They may have problems with identity and need emo-tional support and/or psychological counseling. And it’s not uncommon for them to engage in risky behavior—as if they can survive anything because they have survived cancer.

Young adults have all these same problems and others unique to their age group: graduating from school later than their peers or not at all; limited types of work open to them; trouble with relationships and marriage; and long-term problems such as infertility.

“We have learned that character-istics from early in life (dealing with stress, coping mechanisms, family func-tion) tend to predict later outcomes and have strong influences on quality of life. Not all are helpful, but despite the dev-astating effect of cancer, most children and their families are able to cope with them. Although 25% to 33% of children and families have long-term significant distress and need continuing care—and cancer is not something one just gets over—survival of the disease itself is usually accompanied by survival of the psyche as well,” said Dr. Kupst.

Patient-Reported OutcomesMalcolm A. Smith, MD, PhD, As-

sociate Branch Chief for Pediatric On-cology, National Cancer Institute, pref-aced a panel discussion with remarks about the need for collaboration, which he said is essential to pediatric oncol-ogy. “It answers important questions about therapy for clinically and genom-ically defined populations and is critical to the quality of survivorship.”

Childhood Cancerscontinued from page 27

Smita Bhatia, MD, MPH

Although 25% to 33% of children and families have long-term significant distress, survival of the disease itself is usually accompanied by survival of the psyche as well.

—Mary Jo Kupst, PhD

Gregory Reaman, MD

Malcolm A. Smith, MD, PhD


National Cancer Policy Forum

He also stressed the distinction be-tween prioritizing potential clinical tri-als based on the most important ques-tion of therapy for a specific anticancer drug vs prioritizing based on the most important question of therapy for a spe-cific childhood cancer. He urged priori-tization based on the latter, with clini-cal trials for specific childhood cancers focusing on the key factors that result in treatment failure and on the issues that diminish short- and long-term quality of life. With this focus, research teams can determine what are the best clinical research opportunities to address these problems.

Lillian Sung, MD, Staff Physician, Haematology/Oncology, The Hospital for Sick Children, Toronto, highlighted the important contributions that pa-tient-reported outcomes can make to clinical trials.

“A patient-reported outcome is a measurement based on a report that comes directly from the patient about the status of a health condition without amendment or interpretation by any-one else.” A proxy-reported outcome (common with children) is not a pa-tient-reported outcome, she added.

Patient-reported outcomes cover many aspects of what happens to chil-dren with cancer: symptoms; physi-

cal function; psychosocial health; and other issues, including satisfaction with care and adherence to treatment.

Dr. Sung said that collecting patient-reported outcomes in research as well as clinical practice is critical, because they can be used to counsel children and their families about what to expect, they can predict physical risk and determine which groups are at the highest risk for poor quality of life; and they can help

make decisions about treatment. “Few research studies include pa-

tient-reported outcomes,” said Dr. Sung, and there is no core set of in-struments or symptoms. Researchers should identify phase II and III trials in which patient-reported outcomes could be incorporated and integrated, espe-cially when the prognosis is poor.

The role of proxy reporting (par-ent or guardian) vs patient-reported outcomes also should be clarified. We need to understand what the smallest, clinically important difference is for physician-reported outcomes, to better understand the magnitude of change as-sociated with treatments. We also need instruments that can be used for adoles-cents and young adults, since generally, validated instruments are available for children < 18 years of age or adults, but not both.

Furthermore, researchers should fo-cus on data quality and dissemination of the knowledge gained about patient-re-ported outcomes. Endpoints should be analyzed and published along with oth-er trial results. Finally, patient-reported outcomes data should be brought to the bedside to enhance provider-patient communication, alert providers to key symptoms, improve patient satisfac-tion, make good use of time during clin-ical encounters, and improve symptom control and supportive care.

Pediatric Palliative CareJennifer Mack, MD, Co-Director,

Pediatric Hematology/Oncology Fel-lowship Program, Dana-Farber Cancer Institute, said that communication is critical. “It allows providers and patients to share knowledge, can relieve stress and uncertainty, may build a therapeutic relationship, and can create an opportu-nity for thoughtful decision-making.”

For instance, in conversations about prognosis, she and colleagues found that 61% of parents hold overly opti-mistic beliefs during the course of treat-ment, and Dr. Wolfe and colleagues found that parents of children who died of their disease realized that the child had no realistic chance of cure 3.4 months after physicians did. However,

those who grasped the reality sooner rather than later established earlier do-not-resuscitate orders and used less cure-directed therapy at the end of life.

She described key steps to advance communication in palliative care. First, physicians should be willing to talk about difficult topics. Tough conversa-tions occur throughout care: at diag-nosis, when complications occur, at relapse, during advance care planning, and even during survivorship. Many

physicians believe that bad news has negative consequences for patients and families, including unnecessary distress or lost hope, so they avoid the conver-sation and wait for patients and parents to ask direct questions. Or they talk in euphemisms and offer overly optimistic information. Although it seems para-doxical, the more information parents receive, even when the news is bad, the more hope they have—and the more they trust the physician.

Another step is to use communica-tion as an opportunity to build a rela-tionship. Even bad news can help with this. Parents need information about prognosis and find it helpful for deci-sion-making, even as they also find it upsetting. And, said Dr. Mack, parents who have too little information are most likely to be upset.

Finally, goal-oriented decision-mak-ing throughout care should be promot-ed. The less accurate the information, the more parents worry, and the more likely it is they will make poor choices for their children.

The most important thing that care-givers can do when developing relation-ships with cancer patients and their

parents is to listen, especially when chil-dren are present in the conversation. “By listening,” said Dr. Mack, “clinicians teach children and parents that their words have meaning, and when patients and families can express themselves, cli-nicians gain helpful information to pro-vide the best care.”

Dr. Wolfe described some of what happens in childhood cancer. “First, there is hope for a cure, longer life—a miracle. Then when that can’t happen,

parents hope for comfort and meaning.” Through it all, there should be pal-

liative care. All clinicians who care for children with cancer ought to have basic knowledge, skills, behaviors, and attitudes, but this often is not the case. “Most physicians learn primar-ily through trial and error, and 71% of training programs lack a palliative care curriculum. Nurses in particular need training,” said Dr. Wolfe. More-over, only 58% of Children’s Oncology Group member institutions have a pal-liative care program, and many are un-derstaffed.

Families may not realize that pallia-tive care improves outcomes, but data suggest that it does, said Dr. Wolfe. Children who receive palliative care are more likely to have fun than those who do not (70% vs 45%) and to experience things that add meaning to life (89% vs 63%). Families who received palliative care reported improved communica-tion. And children receiving palliative care had shorter hospitalizations and fewer emergency room visits. n

Disclosure: Drs. Wolfe, Reaman, Bhatia, Smith, Sung, and Mack reported no potential conflicts of interest.

Lillian Sung, MD

By listening, clinicians teach children and parents that their words have meaning, and when patients and families can express themselves, clinicians gain helpful information to provide the best care .

—Jennifer Mack, MD

George W. Sledge, Jr, MD, and Clifford A. Hudis, MD, debate the question “Can metastatic breast cancer ever be cured?”See page 3 in this issue of The ASCO Post.

Debate: Can We Cure Metastatic Breast Cancer?


Researchers Discuss Pilot Study on Hallucinogenic Therapies for Cancer AnxietyBy Ronald Piana

Although varying levels of existen-tial distress are near-ubiquitous

among patients with cancer, evidence-based interventions in this clinical area remain somewhat elusive. Seeking to explore novel approaches in the pal-liative care environment, New York University (NYU) School of Medicine principal investigator, Stephen Ross, MD, and researchers evaluated hal-lucinogenic therapies in their recently completed NYU Psilocybin Cancer Anxiety Study.1

According to co–principal investi-gator and director of palliative care re-search Anthony P. Bossis, PhD, results from the pilot study may indicate some promise for assuaging cancer-associated psychosocial distress. However, before psilocybin—known in street vernacu-lar as “magic mushrooms”—is ready for clinical use, the oncology community will need solid evidence from well-de-signed phase III trials—and then some.

Breaking the Perception Barrier

Deep-seated cultural perceptions about drugs are difficult to shake, and such is the case with psilocybin; it un-leashes images of 1960s hallucinogenic escapism. Moreover, the The Con-trolled Substances Act (CSA) as part of the Comprehensive Drug Abuse Prevention and Control Act of 1970 registered hallucinogens as schedule I drugs, meaning they had high potential for abuse and little to no medical value. However, Dr. Bossis noted that psilo-

cybin, which is an active compound found in many species of mushrooms, had been studied from the 1950s until the 1970s, when cultural, political, and regulatory forces closed the scientific door on hallucinogens.

During that 2-decade period, Dr. Bossis noted that more than 1,000 clini-cal and research papers were published on hallucinogens that were tested in various settings on approximately 40,000 patients. One population that demonstrated a positive response to hallucinogenic therapy was advanced cancer patients. Now, after decades of dormancy, regulatory strictures have eased, making it possible to fund and launch studies that assess the clinical value of psilocybin therapy in the can-cer setting.

The Mystical ExperienceOver the past few decades, methods

to assess and address the spiritual and psychosocial needs of cancer patients have been incorporated into the on-cologic palliative care model. Despite progress, numerous studies have found that a majority of late-stage cancer pa-tients still report unmet spiritual and existential needs.

Dr. Bossis commented that his per-sonal interest in the emotional anguish of cancer patients stemmed from his work at Bellevue Hospital Center, where he cofounded the hospital’s palliative care service. “I’ve always been intrigued by the psychospiritual existential com-ponent of the suffering associated with cancer. We’ve gotten better in palliative care, but we’re still struggling with treat-ing the deep emotional distress our pa-tients suffer,” said Dr. Bossis. “There has been some successful psychotherapy in palliative care, such as meaning-cen-tered group psychotherapy, which has been extensively studied by William S. Breitbart, MD, at Memorial Sloan Ket-tering Cancer Center.” (See sidebar for comments from Dr. Breitbart.)

Dr. Bossis and his fellow researchers hypothesized that properly controlled psilocybin therapy could fill a much-needed void in palliative care by initiat-ing a cathartic state of enhanced spiri-tual awareness.

“Psilocybin and other psychoactive organic compounds have been used for millennia and have reliably been shown to activate what is known as the mys-

tical experience in humans,” said Dr. Bossis. He explained that the mystical experience is a transcendent state, dur-ing which cancer patients may be able to separate themselves from the dis-ease—ie, “I am not my cancer.” In the NYU study, they found that this kind of mental recalibration engenders a vital sense of self-identity, which many can-cer patients struggle to maintain as their disease pushes them into the isolated world of the sick.

Dr. Bossis said, “The mystical ex-perience has been shown to improve a patient’s existential well-being and [his] ability to reframe the impact cancer has on [his] life by giving [the patient] an increased appreciation of time living. The patient recognizes that [he is] not dying per se; [he is] living, until the moment of death. Ultimately, the pa-tient fears death less and embraces life more, becoming an active participant in life and enriching [his] interpersonal relationships, which is one of the first casualties in advanced cancer.”

The TrialThe NYU Psilocybin Cancer Anxi-

ety Study is a double-blind, placebo-controlled pilot study to assess the safe-ty and efficacy of psilocybin-assisted therapy on psychosocial distress, with a specific primary outcome variable be-ing anxiety associated with advanced

cancer. Secondary outcomes will ex-amine the effect of psilocybin on symp-toms of pain perception, depression, at-titudes toward disease progression, and quality of life. Psilocybin was dosed at 0.3 mg/kg; enrollment began in April 2009, with 29 volunteers.

The inclusion criteria were age 18 to 76, historical diagnosis of cancer, and anxiety associated with cancer. Exclu-sion criteria were a personal or family history of a severe psychiatric disorder, epilepsy, diabetes, abnormal liver func-tion, or severe cardiovascular disease. The researchers hope to publish their results in the coming year.

The venue for the study was not the usual clinical setting. First, each patient underwent a screening process with the project manager and was then assigned to one of three therapists. “There are three 2-hour therapy sessions during which a sense of rapport is built be-tween the patient and therapist. With-out that rapport and trust, we wouldn’t go to the dosing session. Also, during the preparatory sessions, we get a full personal history, including [the pa-tient’s] childhood, social background, and how the cancer has affected [the patient],” said Dr. Bossis.

The therapy session is conducted in a comfortable living room–like set-ting, decorated with paintings and el-egant rugs and soothing lighting. “We

A Cautionary Note on Psilocybin TherapyBy William S. Breitbart, MD

The controversial nature of [psilocybin] is garnering attention before [the NYU inves-

tigators’] work has been peer-reviewed, which is concerning. Could psilocybin therapy be a help-ful anxiolytic in any patient? Yes, I suppose, but I’d like to see the data.

Is psilocybin an anxiolytic in cancer patients? One would have to compare cancer patients to another population to answer that question. The mechanism of anxiolytic effect would be difficult to tease out without a research methodology specifically designed to exam-ine the mechanism of action and the mediating factors that lead to a specific outcome. This would typically require large experimental and comparison groups—hundreds of patients. n

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

Dr. Breitbart is Chair, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York.

Psychosocial Oncology

Novel Therapies

Stephen Ross, MD

Anthony P. Bossis, PhD

William S. Breitbart, MD


Psychosocial Oncology

talk for a bit, and at 9 AM, the patient takes the capsule. It’s double-blinded so no one knows if it’s psilocybin or placebo. About 30 minutes later, the patient is encouraged to lie on a couch with eye mask to block external visual distraction and to wear headphones through which melodic classical music is played,” said Dr. Bossis. “We tell peo-ple to check their ego at the door, just go with where their mind takes them. If something frightening comes up, we’re here to help them through it.”

The first 2 hours of the approximately 6-hour psilocybin episode can be emo-tionally turbulent, but according to Dr. Bossis, it “evens out” and the patient “peaks,” experiencing visual images and memories that often elicit strong, emer-gent emotions. “We check in with a soft touch on the shoulder every hour or so, just to make sure everything’s smooth. When the drug wears off, the patient re-laxes and shares the experience if he or she chooses,” said Dr. Bossis. The patient’s vitals are monitored all day, and food and drink are available all day as needed.

The researchers conduct three follow-up psychotherapy integration sessions after the psilocybin episode, during which the patient discusses the experience and shares any insights. Then there’s a 7-week period before the next dosing of either placebo or psilo-cybin, followed by three sessions of psy-chotherapy integration. “For about 6 months after the last session, the patient is busy filling out paperwork detailing the measures that we’re aggregating for our results,” said Dr. Bossis.

Shrinking the Fear of CancerCo–principal investigator Jeffrey

Guss, MD, explained that psilocybin is 4-phosphoryloxy-N, N-dimethyl-trypt-amine and possesses a chemical structure

similar to the neurotransmitter serotonin (5-hydroxytryptamine). “The drug has a complex effect on many parts of the brain. It works at the cognitive level in the frontal cortex and affects the way that information is processed in the limbic system. There’s a certain amount of in-hibition release and a reduction in some of the top-down controls; thoughts flow more freely, which unseals a greater sense of sensation and imagination. It can also produce emotionally heightened states and internal visionary experiences. Ex-

actly how this process unfolds is still part-ly a mystery,” said Dr. Guss.

Asked about how the drug is formu-lated for consistent dosing, Dr. Guss replied, “The substance that we use has never had anything to do with the 180 or so different types of hallucinogenic mushrooms that exist. It is synthesized in an organic chemistry lab. It is quite pure, coming in a powder form. It is organically compounded psilocybin. With actual mushrooms, it is impossi-ble to titrate the dose of psilocybin pre-cisely. Naturally, in a research program, you need to be exact with your dosing.”

Phase III Study EssentialDr. Guss noted that all of the patient

volunteers tolerated the treatment ses-

sions well, with no significant adverse effects, and most of the patients dem-onstrated an improvement in their distress and anxiety. “I like to think of the psilocybin-assisted therapy as che-motherapy for the fear of cancer. Just as chemotherapy shrinks the tumor, psi-locybin helps shrink the preoccupation with cancer in a way that allows the per-son underneath the disease to emerge,” said Dr. Guss.

He continued, “We try to help our patients enter a mystical experience

during which they move away from a biographical narrative, opening up to a different level of consciousness where they can reconnect with unseen and unknown resources. And hope does seem to emerge when the tight nar-rative of being a cancer patient is re-leased. It’s wonderful to watch some of the amazing ways patients respond to the therapy.”

The NYU researchers have com-pleted their phase II study, in which they’ve established feasibility and safe-ty. However, psilocybin remains an il-legal schedule I drug, creating multiple challenges for widespread investiga-tion. Dr. Guss said, “The current study is designed to show safety and efficacy in terms of significant improvement in

cancer-related anxiety, but it is under-powered for petitioning the DEA to re-schedule psilocybin. The Heffter Re-search Institute is planning to launch a multicenter phase III study with about 300 enrollees, which would provide the kind of data needed for reschedul-ing and further work that will lead to the incorporation of psilocybin-assist-ed therapy into well-controlled clinical settings.”

In addition to the NYU Psilocybin Cancer Anxiety Study, work in this intriguing area is being conducted at the Harbor-UCLA Psilocybin Cancer Anxiety trial led by Charles Grob, MD,2 and the Johns Hopkins Universi-ty Psilocybin Cancer Anxiety trial. Ac-cording to the preliminary work from these studies, the psilocybin-assisted treatment model might offer a valuable approach to addressing the existential crisis that many cancer patients suffer.

Drs. Bossis and Guss have stressed that this treatment should only be used in the tightly controlled environ-ment of a clinical trial, and it is not a one-size-fits-all approach. Whether this inexpensive therapy will have the potential to significantly improve the quality of life and psychospiritual well-being of cancer patients will only be determined in the context of a phase III clinical trial. n

Disclosure: The Heffter Research Institute sponsored the NYU trial. Drs. Bossis, Ross, and Guss reported no potential conflicts of interest.

References1. New York University: NYU Psilo-

cybin Cancer Anxiety Study. Available at http://www.nyucanceranxiety.org/index.html. Accessed March 24, 2015.

2. Grob CS, Danforth AL, Chopra GS, et al: Pilot study of psilocybin treatment for anxiety in patients with advanced-stage can-cer. Arch Gen Psychiatry 68:71-78, 2011.

The substance that we use has never had anything to do with the 180 or so different types of hallucinogenic mushrooms that exist. It is synthesized in an organic chemistry lab. It is quite pure, coming in a powder form. It is organically compounded psilocybin.

—Jeffrey Guss, MD

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Important Safety Information• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fi ssures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of infl ammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening infl ammatory or infectious complications. Dose modifi cations for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• A predefi ned retrospective subset analysis of Study 3 further identifi ed a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated profi ciency in the specifi c technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identifi cation of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix®

treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix®

administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fi brosis have been observed in patients treated with Vectibix®. Pulmonary fi brosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confi rmed.

• In patients with a history of interstitial pneumonitis or pulmonary fi brosis, or evidence of interstitial pneumonitis or pulmonary fi brosis, the benefi ts of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the fi rst-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the fi rst 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal infl ammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4

• The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone

• Prespecifi ed major effi cacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02)

• Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC• Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm

(n = 331) (HR = 0.83; 95% CI: 0.70, 0.98)• There were no OS or PFS benefi ts in Vectibix®-treated patients with mutant KRAS/RAS mCRC

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-afl ibercept) prescribing information, sanofi -aventis.

Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page.

©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1 Visit www.vectibix.com

IndicationVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As fi rst-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fl uoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapyLimitation of UseVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

RAS is defi ned as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.”

mCRC = metastatic colorectal cancer; OS = overall survival.

WARNING: DERMATOLOGIC TOXICITYDermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

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APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Important Safety Information• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fi ssures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of infl ammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening infl ammatory or infectious complications. Dose modifi cations for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• A predefi ned retrospective subset analysis of Study 3 further identifi ed a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated profi ciency in the specifi c technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identifi cation of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix®

treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix®

administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fi brosis have been observed in patients treated with Vectibix®. Pulmonary fi brosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confi rmed.

• In patients with a history of interstitial pneumonitis or pulmonary fi brosis, or evidence of interstitial pneumonitis or pulmonary fi brosis, the benefi ts of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the fi rst-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the fi rst 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal infl ammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4

• The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone

• Prespecifi ed major effi cacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02)

• Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC• Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm

(n = 331) (HR = 0.83; 95% CI: 0.70, 0.98)• There were no OS or PFS benefi ts in Vectibix®-treated patients with mutant KRAS/RAS mCRC

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-afl ibercept) prescribing information, sanofi -aventis.

Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page.

©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1 Visit www.vectibix.com

IndicationVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As fi rst-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fl uoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapyLimitation of UseVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

RAS is defi ned as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.”

mCRC = metastatic colorectal cancer; OS = overall survival.


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Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION


INDICATIONS AND USAGEMetastatic Colorectal CancerVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)].• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-,

and irinotecan-containing chemotherapy [see Clinical Studies (14.1)].Limitation of UseVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)].RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.”DOSAGE AND ADMINISTRATIONPatient SelectionPrior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.Recommended DoseThe recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].Dose ModificationsDose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion

reaction for the duration of that infusion.• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the

severity and/or persistence of the reaction, permanently discontinue Vectibix®.Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose.• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses

of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently

discontinue Vectibix®.Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.Preparation and AdministrationDo not administer Vectibix® as an intravenous push or bolus.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSDermatologic and Soft Tissue ToxicityIn Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRCA predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)]. Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®.Electrolyte Depletion/MonitoringProgressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.Infusion ReactionsIn Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].Acute Renal Failure in Combination with ChemotherapySevere diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.Pulmonary Fibrosis/Interstitial Lung Disease (ILD)Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.PhotosensitivityExposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.Ocular ToxicitiesKeratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and ChemotherapyIn an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and

Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]• Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)]• Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)]• Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)]• Photosensitivity [see Warnings and Precautions (5.7)]• Ocular Toxicities [see Warnings and Precautions (5.8)]• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and

Chemotherapy [see Warnings and Precautions (5.9)]Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC.Vectibix® MonotherapyIn Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).Infusion ReactionsInfusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.• Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal

bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]

• Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)]DRUG INTERACTIONSNo formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Nursing MothersIt is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Pediatric UseThe safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.Geriatric UseOf the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.OVERDOSAGEDoses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.Patient Counseling InformationAdvise patients to contact a healthcare professional for any of the following:• Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings

and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)]• Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage

and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)]• Diarrhea and dehydration [see Warnings and Precautions (5.5)]• Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings

and Precautions (5.6) and Adverse Reactions (6.1)]• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]Advise patients of the need for:• Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)]• Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for

2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)]• Adequate contraception in both males and females while receiving Vectibix® and for 6 months

after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

Study 1Vectibix® Plus

Best Supportive Care(N = 229)


SYSTEM ORGAN CLASS Preferred Term

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

EYE DISORDERSGrowth of eyelashes 13 (6)

GASTROINTESTINAL DISORDERSNausea 52 (23) 2 (< 1) 37 (16) 1 (< 1)Diarrhea 49 (21) 4 (2) 26 (11)Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1)Stomatitis 15 (7) 2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Fatigue 60 (26) 10 (4) 34 (15) 7 (3)Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1)

INFECTIONS AND INFESTATIONS Paronychia 57 (25) 4 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS

Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Erythema 150 (66) 13 (6) 2 (< 1)Pruritus 132 (58) 6 (3) 4 (2) Acneiform dermatitis 131 (57) 17 (7) 2 (< 1) Rash 51 (22) 3 (1) 2 (< 1) Skin fissures 45 (20) 3 (1) 1 (< 1) Exfoliative rash 41 (18) 4 (2) Acne 31 (14) 3 (1) Dry skin 23 (10) Nail disorder 22 (10) Skin exfoliation 21 (9) 2 (< 1)Skin ulcer 13 (6) 1 (< 1)

Vectibix® Plus FOLFOX(n = 322)

FOLFOX Alone(n = 327)


Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

EYE DISORDERSConjunctivitis 58 (18) 5 (2) 10 (3)

GASTROINTESTINAL DISORDERSDiarrhea 201 (62) 59 (18) 169 (52) 29 (9)

Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1)


Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1)Asthenia 79 (25) 16 (5) 62 (19) 11 (3)


INVESTIGATIONS

Weight decreased 58 (18) 3 (< 1) 22 (7)

METABOLISM AND NUTRITION DISORDERS

Anorexia 116 (36) 14 (4) 85 (26) 6 (2)Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1)Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5)

Dehydration 26 (8) 8 (2) 10 (3) 5 (2)


Epistaxis 46 (14) 30 (9)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)


Rash 179 (56) 55 (17) 24 (7) 1 (< 1)Acneiform dermatitis 104 (32) 33 (10)Pruritus 75 (23) 3 (< 1) 14 (4)Dry skin 68 (21) 5 (2) 13 (4)Erythema 50 (16) 7 (2) 14 (4)Skin fissures 50 (16) 1 (< 1) 1 (< 1)Alopecia 47 (15) 30 (9)Acne 44 (14) 10 (3) 1 (< 1)Nail disorder 32 (10) 4 (1) 4 (1)Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1)

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14.Vectibix® (panitumumab)Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 USAPatent: http://pat.amgen.com/vectibix/© 2006-2014 Amgen Inc. All rights reserved.80748-R2-V1 – v22 10/14

S:9.25”S:13”

VECT14CDNY6408_B_JA_LOU_Update_King_BS_r10.indd 1 10/30/14 9:29 AM


Expert’s Corner

Bombarded With Changes in Health Care and Beyond, Gynecologic Oncologists Prepare for the Challenges Ahead By Charlotte Bath

Physicians are being “bombarded” with changes in health care and be-

yond, Richard R. Barakat, MD, FACS, noted in his Presidential Address at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer. These changes are being precip-itated by steeply rising health-care costs amid federal funding cuts, restructuring of clinical trials, and targeted therapies that pack power but also have “signifi-cant and profound” toxicities.

“What is the impact of these changes in health care on the practice of gyneco-logic oncology and how well positioned are we as individuals and as a society to meet these challenges head on?” Dr. Barakat outlined the challenges and what SGO is doing to meet them. “Para-mount and perhaps most important is the need to provide affordable care to all segments of the population, as dis-parities clearly still exist in the United States of America,” he said.

Dr. Barakat, a gynecologic oncology surgeon, served as Chief of the Gyne-cology Service at Memorial Sloan Ket-tering Cancer Center in New York for 12 years. In 2013, he was appointed Deputy Physician-in-Chief for the Me-morial Sloan Kettering Cancer Center Regional Network and Alliances.

The SGO Annual Meeting on Wom-en’s Cancer drew 2,064 participants, including 952 gynecologic oncologists, 169 fellows-in-training, 137 residents, and 72 medical oncologists, as well as other physicians and allied health-care practitioners. During the meeting in Chi-cago, the SGO surpassed its 2,000-mem-ber milestone for the first time.

Era of Targeted TherapiesNoting that President Barack

Obama “directed the National Cancer Institute to spend $70 million for preci-

sion medicine in oncology,” Dr. Barakat stated that we are in the era of precision medicine and targeted therapies. “Are we prepared to handle that? Are we pre-pared to deliver those agents?”

“Administration of these drugs is no easy task. If you look at the toxicities that occur, they differ from standard cytotoxic chemotherapy,” Dr. Barakat said. Citing a trial with ipilimumab (Yervoy), he noted that at the initial dose of 10 mg/ kg, 25% of patients had grade 3 or 4 toxicities. “They are rolling toxicities that occur at vari-ous time points—skin rash at 2 to 3 weeks, gastrointestinal/hepatotoxicity at 6 to 7 weeks,” Dr. Barakat said.

But they are not the usual toxici-ties expected with chemotherapy. “The gastrointestinal toxicity that occurs with this agent can be severe. These side effects are significant. They are powerful drugs.”

In an interview with The ASCO Post, Dr. Barakat said that oncologists “have got to learn what it means to give these drugs” and to function as both an on-

cologist and an internist in managing toxicities. Patients will need to go to physicians “who are qualified to handle these agents.”

Solo Practitioners Increasingly Rare

“One of the most important tools available to inform physicians, hospital administrators, industry insurers, and women’s cancer care teams about the cur-rent, present, and future state of gyneco-logic oncology is the 2015 SGO member practice survey,” Dr. Barakat said. He pre-sented “a snapshot” of the results.

Overall, 462 SGO members re-sponded to the survey, a response rate of 45% of the membership at the time of the survey. That level of response “is unheard of in a professional society and shows the commitment of the mem-bers of this society to our specialty,” Dr. Barakat said.

“There is a steady decline in the

number of gynecologic oncologists who consider themselves to be in solo practice to just 9% in the 2015 survey,” Dr. Barakat said. “It is going to be very rare to find solo practitioners.”

“There is a corresponding increase in respondents who either work with a group practice or belong to a multispe-cialty practice or clinic,” he continued. Although “almost one-quarter” of re-spondents reported being with a prac-tice that is part of or associated with an accountable care organization, “amaz-ingly, 31% of us did not even know if our practice was associated with an accountable care organization. If you don’t know, you need to know,” Dr. Barakat said.

‘First Foray Into Bundled Payments’

“Just 16% of gynecologic oncolo-gists” responding to the SGO survey “indicated their practice or hospital had bundled payment arrangements with private insurance companies last year for professional services, whereas 50%

did not know. You cannot not know,” Dr. Barakat stressed. “This will affect you. It will affect your bottom line. As a society, this indicates to me that we need to start focusing on these issues, because they are here; they are now; they are real.”

The issue of bundled payments is one of the priority issues being con-sidered by the SGO’s Task Force on Physician Payment Reform. “Research has shown that bundled payments can provide incentives for providers, including hospitals, physicians, and post-care providers, allowing them to work closer together across all special-ties,” Dr. Barakat noted.

“As part of a broader federal push to reward hospitals and doctors for value, rather than volume, of the services they provide,” the Centers for Medicare and Medicaid Services (CMS) “is inviting oncology practices and solo practitioners to join a 5-year

test set to begin in the spring of 2016,” Dr. Barakat said. SGO has developed a new alternative payment model for endometrial cancer patients, Dr. Barakat reported. “This is our first foray into bundled payments.”

Impact of Restructuring Clinical Trials

“Almost one-half of the members who answered the survey indicated that the number of clinical trials in which they participate has decreased over the past 5 years. On the other hand, one-quarter said that the number of trials in which they participate has increased,” Dr. Barakat said. “Many of those who answered reported that the changes in the National Cancer Institute (NCI) structure had led to a downsizing in their clinical trials infrastructure.”

The transformation of the NCI’s “long-standing cooperative group pro-gram into the new National Clinical Trials Network was based on the 2010 Institute of Medicine (IOM) report on the need for reinvigorating the NCI cooperative group mechanism,” Dr. Barakat noted. “The recommendations and feedback from the IOM and oth-ers emphasized the need for a more efficient and streamlined system that could more rapidly respond to scien-tific opportunities.” Describing frustra-tions with trying to open trials under the previous program, Dr. Barakat said, “I understand the need for being more nimble in getting trials open.”

“The program that emerged from this restructuring, the National Clinical Tri-als Network, has a different focus than its predecessors. Efficiency is stressed and mandatory time lines are now in place for protocol development,” Dr. Bara-kat added. The National Clinical Trials Network is “organized to take maximum advantage of the opportunities afforded by the improved understanding of tumor biology, as well the improved efficiencies created by the centralization and stream-lining of many critical functions.”

In addition to restructuring, de-creases in funding for NCI “over the past decade, have taken a toll on clini-cal trials,” Dr. Barakat noted. “Money has been “channeled into 30 sites that receive the lead academic participat-ing grants, which are given mostly to NCI-designated cancer centers that

Issues in Oncology

Richard R. Barakat, MD, FACS

Perhaps most important is the need to provide affordable care to all segments of the population,

as disparities clearly still exist in the United States of America.

—Richard R. Barakat, MD, FACS


Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION


INDICATIONS AND USAGEMetastatic Colorectal CancerVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)].• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-,

and irinotecan-containing chemotherapy [see Clinical Studies (14.1)].Limitation of UseVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)].RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.”DOSAGE AND ADMINISTRATIONPatient SelectionPrior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.Recommended DoseThe recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].Dose ModificationsDose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion

reaction for the duration of that infusion.• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the

severity and/or persistence of the reaction, permanently discontinue Vectibix®.Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose.• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses

of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently

discontinue Vectibix®.Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.Preparation and AdministrationDo not administer Vectibix® as an intravenous push or bolus.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSDermatologic and Soft Tissue ToxicityIn Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRCA predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)]. Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®.Electrolyte Depletion/MonitoringProgressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.Infusion ReactionsIn Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].Acute Renal Failure in Combination with ChemotherapySevere diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.Pulmonary Fibrosis/Interstitial Lung Disease (ILD)Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.PhotosensitivityExposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.Ocular ToxicitiesKeratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and ChemotherapyIn an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and

Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]• Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)]• Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)]• Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)]• Photosensitivity [see Warnings and Precautions (5.7)]• Ocular Toxicities [see Warnings and Precautions (5.8)]• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and

Chemotherapy [see Warnings and Precautions (5.9)]Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC.Vectibix® MonotherapyIn Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).Infusion ReactionsInfusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.• Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal

bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]

• Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)]DRUG INTERACTIONSNo formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Nursing MothersIt is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Pediatric UseThe safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.Geriatric UseOf the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.OVERDOSAGEDoses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.Patient Counseling InformationAdvise patients to contact a healthcare professional for any of the following:• Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings

and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)]• Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage

and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)]• Diarrhea and dehydration [see Warnings and Precautions (5.5)]• Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings

and Precautions (5.6) and Adverse Reactions (6.1)]• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]Advise patients of the need for:• Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)]• Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for

2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)]• Adequate contraception in both males and females while receiving Vectibix® and for 6 months

after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

Study 1Vectibix® Plus




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

EYE DISORDERSGrowth of eyelashes 13 (6)

GASTROINTESTINAL DISORDERSNausea 52 (23) 2 (< 1) 37 (16) 1 (< 1)Diarrhea 49 (21) 4 (2) 26 (11)Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1)Stomatitis 15 (7) 2 (< 1)


Fatigue 60 (26) 10 (4) 34 (15) 7 (3)Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1)



Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7)


Erythema 150 (66) 13 (6) 2 (< 1)Pruritus 132 (58) 6 (3) 4 (2) Acneiform dermatitis 131 (57) 17 (7) 2 (< 1) Rash 51 (22) 3 (1) 2 (< 1) Skin fissures 45 (20) 3 (1) 1 (< 1) Exfoliative rash 41 (18) 4 (2) Acne 31 (14) 3 (1) Dry skin 23 (10) Nail disorder 22 (10) Skin exfoliation 21 (9) 2 (< 1)Skin ulcer 13 (6) 1 (< 1)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

EYE DISORDERSConjunctivitis 58 (18) 5 (2) 10 (3)

GASTROINTESTINAL DISORDERSDiarrhea 201 (62) 59 (18) 169 (52) 29 (9)

Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1)


Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1)Asthenia 79 (25) 16 (5) 62 (19) 11 (3)


INVESTIGATIONS

Weight decreased 58 (18) 3 (< 1) 22 (7)

METABOLISM AND NUTRITION DISORDERS

Anorexia 116 (36) 14 (4) 85 (26) 6 (2)Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1)Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5)

Dehydration 26 (8) 8 (2) 10 (3) 5 (2)


Epistaxis 46 (14) 30 (9)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)


Rash 179 (56) 55 (17) 24 (7) 1 (< 1)Acneiform dermatitis 104 (32) 33 (10)Pruritus 75 (23) 3 (< 1) 14 (4)Dry skin 68 (21) 5 (2) 13 (4)Erythema 50 (16) 7 (2) 14 (4)Skin fissures 50 (16) 1 (< 1) 1 (< 1)Alopecia 47 (15) 30 (9)Acne 44 (14) 10 (3) 1 (< 1)Nail disorder 32 (10) 4 (1) 4 (1)Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1)

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14.Vectibix® (panitumumab)Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 USAPatent: http://pat.amgen.com/vectibix/© 2006-2014 Amgen Inc. All rights reserved.80748-R2-V1 – v22 10/14

S:9.25”

S:13”

VECT14CDNY6408_B_JA_LOU_Update_King_BS_r10.indd 1 10/30/14 9:29 AM


Expert’s Corner

accrue large numbers of patients, with the funding effectively raising the per patient reimbursement level to help support the research staff required to manage this effort,” Dr. Barakat said.

“This is an important issue for our members. Our members feel these changes and want something done about them. Eighty percent of our members who responded believe that SGO should advocate for increased clinical trials availability for its mem-bers,” Dr. Barakat related.

“Ultimately, clinical trials drive the field forward,” Dr. Barakat observed. “It is the groundbreaking discoveries of the Gynecologic Oncology Group that helped position us where we are today, and that needs to continue un-der the new system.”

Molecular Profiling and Basket Trials

“The types of trials, however, that we will be participating in are chang-ing,” Dr. Barakat noted. “In 2014, the NCI launched a pilot study, the M-PACT trial, to assess whether assign-ing cancer patients treatment based on the genetic characteristics of their disease can improve outcomes for pa-tients with advanced metastatic solid tumors.” This is one of the first trials “to use a randomized design to assign treatment based on specific mutations, and the results are due in 2017,” Dr. Barakat said.

“Trials will no longer focus exclu-sively on disease sites but rather on mutational profiles and the presence

of actual targets,” Dr. Barakat noted. For example, he cited a trial at Memo-rial Sloan Kettering Cancer Center with vemurafenib (Zelboraf). “It’s a basket trial where we looked for mutations in the BRAF V600 gene across tumor sites, across lung cancer, ovarian cancer, co-lon cancer, etc, and patients are entered into the trial based on mutational sta-tus, not their disease site.”

“This had to come,” Dr. Barakat told The ASCO Post, because the days of the 1,500-patient randomized trial are over. The way that clinical trials for advanced and recurrent disease are heading is toward basket trials with a focus on precision medicine and targeted therapy. It is all about precision medicine and targeted ther-apy.” Dr. Barakat said.

Extending Results Into the Community

Another important issue concern-ing clinical trials “is how do we extend access to these trials to the commu-nity? Large cancer centers have access to these agents, but a lot of practitio-ners in the community may not. And the fact of the matter is that more than 80% of cancer care delivered in the United States is delivered by commu-nity oncologists,” Dr. Barakat noted. “We need to get those treatments out to benefit patients in the community much more rapidly.”

Doing so requires collaborative part-nerships. “That is what we are doing at Memorial Sloan Kettering,” as well as at other institutions, such as MD Anderson Cancer Center in Houston, Dr. Barakat said. As Deputy Physician-in-Chief for

the Memorial Sloan Kettering Regional Care Network and Cancer Alliance, Dr. Barakat is working to set up partner-ships with community cancer centers. “We have to maintain the identity of those community cancer centers,” he said, while helping them “assure coordi-nated cancer care for all of their patients and support the structure of multidisci-plinary teams at each hospital across the entire system. Ultimately, we have to en-hance access to cutting-edge clinical tri-als in the community.”

The Cancer Alliance has already es-tablished a relationship with Hartford HealthCare Cancer Institute, a five-hos-pital system in Connecticut. “It’s been a fantastic experience,” Dr. Barakat said. “We are in the process of opening MSK clinical trials at the Hartford Health-Care Cancer Institute.” (Dr. Barakat de-scribed the Cancer Alliance in detail in an article published in the November 1, 2014, issue of The ASCO Post.)

Other Important InitiativesAnother important initiative is the

SGO Clinical Outcomes Registry. Twenty sites, with more than 1,600 patients, have already enrolled, “and these sites will provide a standardized format for collection of clinical data in the areas of ovarian, endometrial, and

cervical cancers,” Dr. Barakat said. “The registry provides members with an ef-fective tool to measure quality improve-ment and clinical outcomes research. Members who participate in the reg-istry will be able to compare their in-dividual physician or institution’s data with regional or national benchmarks, which will help identify areas for qual-ity improvement.”

“The ultimate goal of the SGO Clini-cal Outcomes Registry is the submis-sion of performance measures to the

National Quality Forum for endorse-ment as a CMS-approved registry for submission of Physician Quality Re-porting System measures,” Dr. Barakat said. “I think it is critical that we do this.”

The reorganization of the SGO’s government relations functions “will bring SGO priorities into sharper fo-cus,” Dr. Barakat said. “You can expect more grassroot initiatives, with mem-bers encouraged to contact congressio-nal representatives and policy makers. When you get those blast e-mails, do me a favor,” he implored. “Take 5 min-utes out of your time and respond. Send out those notices to your representa-tives. It makes a difference. In Washing-ton, clearly numbers count.” n

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

Richard R. Barakat, MD, FACScontinued from page 35

The days of the 1,500-patient randomized trial are over. The way that clinical trials for advanced and recurrent

disease are heading is toward basket trials, with a focus on precision medicine and targeted therapy.

—Richard R. Barakat, MD, FACS

Download The ASCO Post iPad App

FREE from iTunes today!

For more from the SGO Annual Meeting, see page 15.


Issues in Oncology

approved last year by the U.S. Food and Drug Administration (FDA), more than 771 promising new cancer thera-pies are in the development pipeline.

However, the increase in the number of cancer survivors (and their need for long-term monitoring for late compli-cations or side effects from treatment and secondary cancers) coupled with an aging population driving up cancer incidence (a 45% increase in cancer inci-dence is expected by 2030) are resulting in a growing demand for cancer care. In addition, the report’s findings show that in 2014, the first year of implementation of the Affordable Care Act, nearly 8 mil-lion Americans signed up for health in-

surance and millions more are obtaining access to insurance through the expan-sion of Medicaid and other programs, and those numbers are expected to rise significantly as full implementation of the new law takes effect. The consequences of all these factors, said the report, are adding pressure to an already strained and fragmented health-care system.

This year’s report also singled out the rise in obesity—more than one-third of adults and nearly one-fifth of children in America are now considered obese—as a major contributor to an ad-ditional 500,000 cancer cases over the next 15 years. Another emerging public health concern cited in the report is the use of electronic cigarettes, which ex-perts fear may create new smokers.

Disparities in CareDespite advances in more effective

diagnostic strategies and treatment in cancer care, not all Americans are ben-efiting from the progress. For example, the ASCO report finds that African Americans are 2.5% more likely to de-velop cancer than whites and are 19.5% more likely to die from their disease.

“This is unconscionable when you think about it,” said Dr. Stella during the press briefing. “We’ve got to be able to start to focus on these issues not only scientifically, but in terms of access to care as well.”

Troubling TrendsAlthough ASCO reported that the

number of hematologists and/or medical oncologists providing care in the Unit-

ed States grew a modest 1.6% to about 11,700 from the previous year, several troubling trends are projected to derail patient access to care. They include:• An aging oncology workforce—Nearly

20% of oncologists are 64 or older.• Poor oncology coverage in rural ar-

eas—Although more than 59 mil-lion Americans live in rural areas of the country, just 600 hematologists and medical oncologists (5.5%) serve those communities.

• The rise of professional burnout—Data in the report show that one-third of oncology fellows experience high lev-els of professional burnout (at least one event per week) and do not plan to work as many hours as senior col-leagues. Failure to address physician

burnout and other quality-of-life is-sues, warns the report, could lead oncologists to reduce their patient volume or retire at an earlier age. “Oncology is a very demanding field emotionally and intellectually,” said Dr. Zon. “We are dealing with pa-tients who have a serious disease and may be dying, and are struggling to keep up with the pace of a rapidly ad-vancing field.”

• Growing concerns over cost of care and financial sustainability of oncology practices—ASCO’s 2014 Oncology Census2 of more than 10,000 oncolo-gists in community practices, hos-pitals, and academic facilities found that cost and payer pressures were the

most pressing practice concerns, es-pecially among physician-owned and hospital-based practices. Rising drug prices, growing administrative bur-dens caused by insurance issues (re-sulting in reduced time available for patient care), and practice consolida-tion (one-quarter of all community-based oncology practices report the likelihood of becoming affiliated with a hospital over the next year) have all added to practice uncertainty about the ability to stay in business.“With regard to practices, no mat-

ter where we are, we are experiencing rough waters, and we don’t see it get-ting better any time soon,” said Dr. Zon. “In the time I’ve been in practice over the past 17 years, I’ve seen a shift in the landscape of where oncology is prac-ticed. The survey shows that we have a serious problem. The reason we are so concerned about small community practices is because they really are the backbone of the U.S. cancer care deliv-ery system, caring for more than one-third of all patients newly diagnosed with cancer.”

Quality and ValueThe escalating cost of cancer care—

according to the ASCO report, direct medical costs of cancer care are currently at $86 billion annually and could increase

by as much as 39% by 2020—and ques-tions about the sustainability of the U.S. cancer care delivery system continue to dominate concerns among both oncolo-gists and patients. In response, ASCO is developing a framework for evaluating the value of new cancer treatment op-tions across three domains: treatment efficacy, toxicity, and cost.

The Society aims to provide oncolo-gists with tools needed to assess value of interventions and use these in dis-cussing treatment options with their patients.

“As we move to addressing value, we’ve been interested in this area for some time,” said Dr. Schilsky. “ASCO has had a Cost of Care Task Force since 2007, and a couple of years ago, we transformed that [task force] into the Value in Cancer Care Task Force, because we realized that it is not all about cost. There are often times when very costly therapies are well justified and have high value because they have high impact. We still don’t have as many of those in cancer as we would like, but clearly it is a value proposition more so than strictly a cost proposition.”

Preliminary information about the initiative is available at asco.org/value.

Recommendations for Countering These Challenges

Overcoming the challenges outlined in the ASCO report will take effort from everyone involved in oncology care, in-cluding clinicians, researchers, and the broader cancer community, said Dr. Schilsky. “The solution has got to be that every one of us in the health-care system has to do our part to deliver the best-quality, evidence-based care, and to do it in a way that ensures access to all members of our population,” he said.

ASCO is recommending the follow-ing strategies to help address the chal-lenges described in the report. They include:

Ensuring that all publicly funded in-surance programs offer consistent and ap-propriate benefits and services for patients with cancer• The Centers for Medicare & Med-

State of Cancer Carecontinued from page 1


The reason we are so concerned about small community practices is because they really are the backbone of the U.S. cancer care delivery system,

caring for more than one-third of all patients newly diagnosed with cancer.

—Robin Zon, MD, FACP, FASCO

We’ve got to be able to start to focus on these issues not only scientifically, but in terms of access to care as well.

—Philip Stella, MD

Left to right: Philip Stella, MD, Robin Zon, MD, FACP, FASCO, and Richard L. Schilsky, MD, FACP, FASCO. Courtesy of ASCO Connection.


Issues in Oncology

icaid Services (CMS) should stan-dardize benefits and other program elements in Medicare and Medicaid.

• Congress should eliminate incon-sistencies in coverage and benefits in Medicaid patients enrolled pre– and post–Affordable Care Act and ensure that Medicaid coverage in-cludes clinical trials.Pilot testing multiple innovative pay-

ment and care delivery models to identify feasible models that promote high-quality, high-value cancer care • CMS should expand efforts to pilot al-

ternative payment models to identify innovative strategies that allow prac-tices flexibility to deliver high-quality, high-value care while containing cost.

• Congress should provide a fair, ad-equate, and stable payment envi-ronment for oncology practice, in-cluding repealing and replacing the sustainable growth rate (SGR) for-mula. [Editor’s note: The Medicare Access and CHIP Reauthorization Act of 2015, which eliminates the 21% cut in Medicare reimburse-

ment, was passed by the House of Representatives on March 26 and by the Senate on April 14; President Barack Obama signed the bill into law on April 16.]

• Oncology professionals should en-gage in testing and evaluating new payment and care delivery models and in developing measures of ac-countability for the care delivered.

• Private insurers should partner with CMS, patients, and providers to test

promising new payment and care delivery models to determine the impact of alternative strategies on the cancer care delivery system.Promoting high-value care by advanc-

ing and supporting transparency and shared decision-making with patients• CMS should make every effort to

improve its publicly released data

and provide appropriate informa-tion to help the public understand the context of the data.

• Congress should require that health information vendors create products that promote interoperability and enable researcher use of standard-ized data in a secure environment to advance high-quality health care.

• Oncology professions should dis-cuss personal goals of care, potential treatment options, expected ben-

efits, and the physical and financial impacts of treatment options with every patient with cancer.

• Private insurers should ensure that publicly shared information about providers is accurate, in context, and meaningful to the intended audience.

• Professional organizations should offer tools and information that fa-

cilitate and incorporate shared deci-sion-making into practice.

Restoring Research FundingDr. Schilsky ended his remarks with

an appeal to Congress to increase fund-ing for the National Institutes of Health (NIH). “We are asking for support in appropriations of at least $32 billion for the NIH and $5.32 billion for the National Cancer Institute (NCI) for FY2016,” said Dr. Schilsky. “There is nothing more important to the future of our country than predictable, sus-tainable, inflation-adjusted increases in the NIH and NCI budgets.” n

Disclosure: Drs. Schilsky, Stella, and Zon reported no potential conflicts of interest.

References1. Kirkwood MK: The state of cancer care

in America, 2015: A report by the American Society of Clinical Oncology. J Oncol Pract. March 17, 2015 (early release online).

2. ASCO Oncology Census: Continuing Practice Adaptation. Available at www.asco.org/practice-research/cancer-care-ameri-ca-2015/asco-oncology-census-continuing-practice-adaptaton. Accessed April 21, 2015.

State of Cancer Carecontinued from page 37

There is nothing more important to the future of our country than predictable, sustainable, inflation-adjusted

increases in the NIH and NCI budgets. —Richard L. Schilsky, MD, FACP, FASCO

FDA Update

FDA Approves Ramucirumab for Metastatic Colorectal Cancer

The U.S. Food and Drug Admin-istration (FDA) today approved

ramucirumab (Cyramza) for use in combination with FOLFIRI (leuco-vorin, fluorouracil, irinotecan) for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab (Avastin)-, oxaliplatin- and fluoropy-rimidine-containing regimen. Ramuci-rumab is a recombinant human mono-clonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), pre-venting the interaction of VEGF-R2 to its ligands.

RAISE TrialThis approval is based on the results

of the phase III RAISE trial, a ran-domized, double-blind, multinational trial enrolling patients with metastatic colorectal cancer that progressed dur-ing or within 6 months of discontinua-tion of bevacizumab-, oxaliplatin- and

fluoropyrimidine-based combination chemotherapy.1

The clinical trial accrued 1,072 pa-tients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N = 536 per arm). Treatment cycles on both arms were repeated every 2 weeks, and ramucirumab was administered at a dose of 8 mg/kg by intravenous infu-sion every 2 weeks. Ramucirumab was continued until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall survival. Treatment assignment was stratified by geographic region (North America vs Europe vs other regions), KRAS status (wild-type vs mutant) and time to progression for the beginning of first-line treatment (< 6 months vs ≥ 6 months).

The median age of the study popu-lation was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. A statistically signifi-

cant overall survival improvement was observed in patients receiving FOLFIRI plus ramucirumab com-pared to those receiving FOLFIRI

plus placebo (hazard ratio [HR] = 0.85; 95% confidence interval [CI] = 0.73–0.98; P = .023, stratified log-rank test). Median overall survival was 13.3 and 11.7 months for patients on the FOLFIRI-plus-ramucirumab and FOLFIRI-plus-placebo arms, re-spectively. Progression-free survival was also significantly improved in pa-tients who received ramucirumab in combination with FOLFIRI (HR = 0.79; 95% CI = 0.70–0.90; P < .001). Median progression-free survival was 5.7 and 4.5 months, respectively.

In general, the safety data were con-

sistent with the known safety profile established in previously approved in-dications. However, hypothyroidism was reported in 2.6% of patients based on thyroid monitoring in patients with metastatic colorectal cancer.

The recommended dose and sched-ule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizu-mab-containing regimen is 8 mg/ kg ad-ministered every 2 weeks as a 60-min-ute intravenous infusion. n

Reference1. Tabernero J, Cohn AL, Obermannova

R, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carci-noma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A ran-domised, double-blind, multicentre, phase 3 study. Lancet Oncol. April 10, 2015 (early release online).

Take a bite out of G-CSF acquisition costsBased 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.

GRANIX® is an option in short-acting G-CSF therapy» A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)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

» The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1

» Now offering a new presentation for self-administration

Indication» GRANIX 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.

» 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.

» Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

» 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.

» 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® (tbo-� lgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

K Job Number: 21089Revision No: 0Date: 01/20/15

YMC724-41865 Page 1 DIGITAL

http://www.granixhcp.com/?utm_source=ASCOPost&utm_medium=DigitalEdition&utm_campaign=Journal


Announcements

Robert Coleman, MD, Begins SGO and Foundation Presidency

Robert L. Coleman, MD, Profes-sor, Department of Gynecologic

Oncology and Reproductive Medi-cine at The University of Texas MD Anderson Cancer Center, started his 1-year term as the 47th President of the Society of Gynecologic Oncology

(SGO) and 5th President of the Foun-dation for Gynecologic Oncology. These terms began at the conclusion of the Society’s 46th Annual Meeting on Women’s Cancer, March 28–31, 2015.

Dr. Coleman, who is also Vice Chair of Clinical Research, Ann

Rife Cox Chair in Gynecology, and Deputy Chair in the Department of Gynecologic Oncology and Repro-ductive Medicine at MD Anderson, commented that SGO’s newly formed Health Policy & Socioeconomic Committee, and the task forces cre-

ated within it, will address important quality and payment issues that are specific to the subspecialty of gyne-cologic oncology.

Dr. Coleman’s research interests include novel therapeutics for ovar-ian, uterine, and cervical cancers; clinical trial development and statisti-cal design; surgical innovations; and graduate education. In partnership

with his department’s faculty, he has established a translational medicine pipeline, which fosters, facilitates, and vets promising compounds and treatment strategies from preclinical to clinical investigation. He is MD Anderson’s NRG Oncology Principal Investigator (PI) and is PI or Co-PI for several NRG Oncology prospec-tive clinical trials. He has been in-strumental in representing SGO in conversations with the U.S. Food and Drug Administration on rethinking trial designs to allow for continued drug development in the ovarian can-cer space.

“I am excited to be president at a time when SGO continues to align its resources to meet the ever-changing needs of the members in their prac-tices. These issues directly impact the care we provide to our patients and how that is valued by the federal government and insurers,” said Dr. Coleman. “As health care practitio-ners across the country adapt to the changes brought about by the Afford-able Care Act, SGO needs to be the voice of our subspecialty.” n

As health care practitioners across the

country adapt to the changes brought about by

the Affordable Care Act, SGO needs to be the voice of our

subspecialty. —Robert L. Coleman, MD

BRIEF SUMMARY OF PRESCRIBING INFORMATION FORGRANIX® (tbo-fi lgrastim) injection, for subcutaneous useSEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEGRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically signifi cant incidence of febrile neutropenia.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Splenic RuptureSplenic rupture, including fatal cases, can occur following administration of human gran-ulocyte 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 gran-ulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infi ltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.5.3 Allergic ReactionsSerious 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 fi lgrastim or pegfi lgrastim.5.4 Use in Patients with Sickle Cell DiseaseSevere 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 ben-efi ts 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 Capillary Leak SyndromeCapillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.5.6 Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe 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 REACTIONSThe 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)]• Capillary Leak Syndrome [see Warnings and Precautions (5.5)]• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and

Precautions (5.6)]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 ExperienceBecause 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 refl ect the rates observed in clinical practice.GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved fi lgras-tim product were used as controls. Both GRANIX and the non-US-approved fi lgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least fi ve 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 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 fi lgrastim product).LeukocytosisIn 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 attribut-able to leukocytosis were reported in clinical studies.Additional Adverse ReactionsOther adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.6.2 ImmunogenicityAs 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 per-formed.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 consid-ered when interpreting bone-imaging results.8 USE IN SPECIFIC POPULATIONS 8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-fi lgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substan-tially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus.Animal DataIn an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-fi lgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-fi lgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embry-ofetal fi ndings 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 (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-fi lgrastim dose of 5 mcg/kg/day.8.3 Nursing Mothers It is not known whether tbo-fi lgrastim 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 ImpairmentThe safety and effi cacy 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 ImpairmentThe safety and effi cacy of GRANIX have not been studied in patients with hepatic impair-ment.10 OVERDOSAGENo case of overdose has been reported.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd.Manufactured by: Distributed by:Sicor Biotech UAB Teva Pharmaceuticals USA, Inc.Vilnius, Lithuania North Wales, PA 19454U.S. License No. 1803Product of IsraelGRX-40581 January 2015This brief summary is based on TBO-004 GRANIX full Prescribing Information.

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Patient’s Corner

Cancer Has Left an Indelible Mark on MeAlthough there is a good chance my breast cancer will never recur, the fear is always with me.By Barb Young, as told to Jo Cavallo

Even though today I’m cancer-free, the experience of getting a can-

cer diagnosis and going through treat-ment leaves an indelible mark on your psyche—as well as your body—that time doesn’t erase. Once you have cancer, you become a cancer survivor, and that status doesn’t change. I’ve known many people who weren’t as fortunate as I am, so I’m grateful to wear the moniker, even as I struggle to come to terms with it.

Two years ago, I found a lump in my right breast during a self-exam and in-stinctively knew something wasn’t right. I have fibrocystic breasts, so I’m used to feeling lumps of various sizes and shapes, but this one felt different, so I immedi-ately saw my gynecologist. Although the mammogram he suggested I have didn’t show any suspicious mass, the follow-up ultrasound I had did, and a biopsy of the tissue confirmed stage II triple-negative invasive ductal carcinoma.

I immediately had a lumpectomy, and even though the margins of the tis-sue removed were clear for malignant cells and there was no sign of metasta-sis, because my type of cancer is so ag-gressive, I was prescribed four rounds of ACT (Adriamycin [doxorubicin], cy-clophosphamide, and Taxol [paclitax-el]) and four additional rounds of pa-clitaxel alone. I then underwent 33 days

of radiation therapy. Despite 7 months of treatment and their subsequent side effects, hair loss, chemobrain, neuropa-thy in my feet (which I still have), and body-crushing fatigue, I managed to continue working and consider myself lucky to have coped so well.

The Fear of Cancer RemainsEven though I’m through treatment

and my prognosis is good, I still can’t help but worry the cancer will come

back, and I look at life differently than I did before my diagnosis. I’ve learned to let go of the things that used to stress me, and although I’m just 48, I’m more aware of my mortality now, trying not to waste time or get caught up in the day-to-day petty circumstances of life I can’t change. I also have a greater appre-ciation of the importance of family and

am determined to make more frequent trips to Hawaii to visit my daughter and her husband and to try to have more fun and be conscious of what is truly impor-tant to me.

Looking for AnswersI admit that the thoughts of cancer

are never far from my mind. I see my oncologist every 6 months for follow-up monitoring and always ask about my prognosis. My medical team uses a

predictive computer model, which cal-culates the probability of breast cancer recurrence for an individual patient, and according to the model’s predic-tion, my risk for recurrence is low. Still, I wish there was a more accurate meth-od to determine my specific chance for recurrence, so I could feel assured that I’ll never have to deal with this cancer

again. I guess I’m looking for statistical absolutes, even though I know with this disease none exists.

Nevertheless, at every office visit, I ask my oncologist if anything in my im-aging scans or blood tests has changed that might indicate recurrence, and I usually have some health issues to dis-cuss with him. I know my oncologist is extremely busy—at every appointment every seat in his waiting room is tak-en—but I often feel that he dismisses my complaints as just the normal after-effects of having cancer and its treat-ment, and his behavior bothers me. All cancer survivors should feel confident that their concerns are being listened to and addressed appropriately, and I don’t always feel that way.

Getting Distance From CancerIt may be that I need a few more

years into my survivorship before I can begin to put having cancer into better perspective and, hopefully, gain confi-dence that my cancer is gone for good. In the meantime, I’m trying to worry less and enjoy life more, which is not just a good creed for cancer survivors to live by but for everyone else as well. n

Barb Young teaches high school in Boyertown, Pennsylvania.

All cancer survivors should feel confident that their concerns are being listened to and addressed appropriately, and I don’t always feel that way.

—Barb Young

Patient Guides Available Through ASCO University Bookstore• ASCO Answers: Managing the Cost of Cancer Care explains the various

costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resourc-es available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges sur-vivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the

oncology community.

Write to The ASCO Post at [email protected]

www.ASCOPost.com Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street

Cold Spring Harbor, NY 11724

BRIEF SUMMARY OF PRESCRIBING INFORMATION FORGRANIX® (tbo-fi lgrastim) injection, for subcutaneous useSEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEGRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically signifi cant incidence of febrile neutropenia.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Splenic RuptureSplenic rupture, including fatal cases, can occur following administration of human gran-ulocyte 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 gran-ulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infi ltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.5.3 Allergic ReactionsSerious 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 fi lgrastim or pegfi lgrastim.5.4 Use in Patients with Sickle Cell DiseaseSevere 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 ben-efi ts 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 Capillary Leak SyndromeCapillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.5.6 Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe 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 REACTIONSThe 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)]• Capillary Leak Syndrome [see Warnings and Precautions (5.5)]• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and

Precautions (5.6)]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 ExperienceBecause 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 refl ect the rates observed in clinical practice.GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved fi lgras-tim product were used as controls. Both GRANIX and the non-US-approved fi lgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least fi ve 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 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 fi lgrastim product).LeukocytosisIn 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 attribut-able to leukocytosis were reported in clinical studies.Additional Adverse ReactionsOther adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.6.2 ImmunogenicityAs 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 per-formed.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 consid-ered when interpreting bone-imaging results.8 USE IN SPECIFIC POPULATIONS 8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-fi lgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substan-tially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus.Animal DataIn an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-fi lgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-fi lgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embry-ofetal fi ndings 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 (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-fi lgrastim dose of 5 mcg/kg/day.8.3 Nursing Mothers It is not known whether tbo-fi lgrastim 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 ImpairmentThe safety and effi cacy 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 ImpairmentThe safety and effi cacy of GRANIX have not been studied in patients with hepatic impair-ment.10 OVERDOSAGENo case of overdose has been reported.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd.Manufactured by: Distributed by:Sicor Biotech UAB Teva Pharmaceuticals USA, Inc.Vilnius, Lithuania North Wales, PA 19454U.S. License No. 1803Product of IsraelGRX-40581 January 2015This brief summary is based on TBO-004 GRANIX full Prescribing Information.

KJob Number: 21089Revision No: 1Date: 01/26/15

724_41865 Page 2 DIGITAL V2


Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With NeuroblastomaCompiled by Liz Janetschek

PILOT

Study Type: Pilot/interventionalStudy Title: 124I-Metaiodobenzyl-

guanidine (MIBG) PET/CT Diagnos-tic Imaging and Dosimetry for Patients With Neuroblastoma: A Pilot Study

Study Sponsor and Collaborators: University of California, San Francisco

Purpose: To describe organ dosimetry and acute toxicities using no carrier added and carrier added 124I-MIBG PET/CT in patients with relapsed or refractory neuro-blastoma who are currently enrolled on a treatment protocol with 131I-MIBG

Eligible Ages: 3 years or olderEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures: • Measurements of organ dosimetry us-

ing high specific activity (no carrier added) 124I-MIBG PET/CT (time frame: PET/CT scans on days 0-week 7)

• Measurements of organ dosimetry using low specific activity (carrier add-ed) 124I-MIBG PET/CT (time frame: PET/CT scans on days 0-week 7)

• Change from baseline of blood pres-sure measurements at week 7 (time frame: safety assessments on days 0- week 7)

• Number of participants with grade 3 or 4 imaging-related toxici-ties (time frame: from baseline up to 6 weeks post final imaging)

• Change from baseline of pulse measurements at 7 weeks (time frame: safety assessments on days 0-week 7)

Principal Investigator: Katherine Matthay, MD, University of California, San Francisco; 415-476-3831, [email protected]

For More Information: Visit clini-caltrials.gov and refer to this study by its identifier: NCT01583842

OBSERVATIONAL

Study Type: Observational Study Title: Neuroblastoma Biol-

ogy StudiesStudy Sponsor and Collaborators:

Children’s Oncology Group, National Cancer Institute

Purpose: To study biomarkers in tumor tissue samples from patients with newly diagnosed neuroblastoma or ganglioneuroblastoma

Eligible Ages: up to 30 yearsEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures: • Factors currently used for risk-group

assignment (time frame: up to 3 years) • Prevalence of 1p, 11q, 14q, and 17q

allelic status (time frame: up to 3 years)• MYCN copy number by quantitative

PCR(time frame: up to 3 years) • Expression pattern of neurotrophin-

related genes in diagnostic neuroblasto-ma tumors (time frame: up to 3 years)

• Presence of rare tumor cells in biolog-ic specimens by RT-PCR (time frame: up to 3 years)

• Database of the known biologic prognostic factors for patients on thera-peutic studies (time frame: up to 3 years)

Principal Investigator: Michael Hogarty, MD, Children’s Oncology Group; 215-590-3931, [email protected]


PHASE I

Study Type: Phase I/interventional/single-group assignment

Study Title: Pilot Study to Determine the Utility of [18F] 3'-Deoxy-3'-Fluoro-thymidine-Positron Emission Tomogra-phy in Monitoring Patient Response to Chemotherapy in Neuroblastoma

Study Sponsor and Collaborators: Barbara Ann Karmanos Cancer Insti-tute, Children’s Hospital of Michigan

Purpose: To gain knowledge about how best to diagnose and treat tumors, how tumors affect normal tissue, and how treatment of tumors with radiation thera-py and chemotherapy affect tumors

Eligible Ages: up to 21 yearsEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures: To

determine whether 18F-FLT-PET is a sensitive tool to image neuroblastoma

(time frame: 1st PETtt diagnosis) Principal Investigator: Anthony F.

Shields, MD, PhD, Barbara Ann Kar-manos Cancer Institute; 313-576-8735, [email protected]


Study Type: Phase I/interventional/nonrandomized/single-group assignment

Study Title: Autologous Activated T Cells Transduced With a 3rd Genera-tion GD-2 Chimeric Antigen Receptor and iCaspase9 Safety Switch Adminis-tered to Patients With Relapsed or Re-fractory Neuroblastoma (GRAIN)

Study Sponsor and Collaborators: Baylor College of Medicine; Center for Cell and Gene Therapy, Baylor College of Medicine; Texas Children’s Hospital; The Methodist Hospital System; Solv-ing Kids’ Cancer; The EVAN Founda-tion; National Cancer Institute

Purpose: To determine the highest dose of iC9-GD2-CD28-OX40 (iC9-GD2) T cells that can safely be given to patients with relapsed/refractory neuroblastoma.

Eigible Ages: N/AEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures: Dose-

limiting toxicities at 6 weeks post T-cell infusion (time frame: 6 weeks after infu-sion of the last dose of iC9-GD2 T cells)

Principal Investigator: Andras A. Heczey, MD, Baylor College of Medi-cine; contact Helton D. Cruz, 832-824-1798, [email protected]


PHASE I/II

Study Type: Phase I/II/interven-tional/single-group assignment

Study Title: Phase I/II Trial of a Bi-valent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral ß-glucan for High-Risk Neuroblastoma

Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center

Purpose: To test the safety and effects treatment with a vaccine against neuro-blastoma has on the patient and the cancer

Eligible Ages: up to 21 yearsEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures:

• To determine the maximally tol-erated dose of OPT-821 in a vaccine containing two antigens abundantly expressed on neuroblastoma (phase I; time frame: 2 years)

• To improve event-free survival of patients who are in second (or later) complete/very good partial remission (phase II; time frame: 2 years)

• To assess anti-NB activity of the bivalent vaccine plus oral β-glucan in patients who are enrolled with evidence of minimal residual disease by molecu-lar biological testing of bone marrow (phase II; time frame: 2 years)

Principal Investigator: Brian Kushner, MD, Memorial Sloan Ketter-ing Cancer Center; 212-639-6793


Study Type: Phase I/II/interven-tional/single-group assignment

Study Title: Treatment of Neuro-blastoma and GD-2 Positive Tumors With Activated T Cells Armed With OKT3 X Humanized 3F8 Bispecific An-tibodies (GD2Bi): A Phase I/II Study

Study Sponsor and Collaborators: Barbara Ann Karmanos Cancer Insti-tute, National Cancer Institute

Purpose: To study the side effects and best dose of activated T cells armed with GD2 bispecific antibody and how well they work in treating patients with neuroblastoma, osteosarcoma, and oth-er GD-2 positive solid tumors

Eligible Ages: 13 months to 29 years Eligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures:

Maximum tolerated dose of GD2Bi-aATC [(time frame: 35 days)

Principal Investigator: Maxim Yankelevich, MD, Barbara Ann Karma-nos Cancer Institute; 313-745-5516, [email protected]


PHASE II

Study Type: Phase II/intervention-al/single-group assignment

Study Title: Phase II Study of Pro-ton Radiation Therapy for Neuroblas-toma

Study Sponsor and Collaborators: Massachusetts General Hospital, Na-tional Cancer Institute

The information contained in this Clinical Trials Resource

Guide includes actively recruiting clinical studies for patients with newly diagnosed or relapsed or re-fractory neuroblastoma. The studies include pilot, observational, phase I, phase II, and phase III trials investi-gating single-agent and combination chemotherapies, immunotherapies, treatment toxicity, radiation therapy, T-cell transplantation, and proton therapy. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.


Clinical Trials Resource Guide

Purpose: To evaluate the effective-ness of using proton radiation in the treat-ment of neuroblastoma to reduce side ef-fects associated with radiation treatment, and to assess late side effects experienced by participants in the treatment group

Eligible Ages: 3 25 yearsEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures: To de-

scribe late complications of radiation ther-apy delivered with proton radiotherapy in place of photon radiation (time frame: 5 years); and to evaluate acute and subacute toxicities of proton radiotherapy in place of photon radiation (time frame: 5 years)

Principal Investigator: Shannon MacDonald, MD, Massachusetts Gen-eral Hospital; 617-726-2000, [email protected]


Study Type: Phase II/intervention-al/single-group assignment

Study Title: Neuroblastoma Proto-col 2012: Therapy for Children With Advanced Stage High-Risk Neuroblas-toma

Study Sponsor and Collaborators: St. Jude Children’s Research Hospi-tal, Cookies for Kids’ Cancer, CURE Childhood Cancer Inc

Purpose: To study the efficacy of two initial courses of cyclophospha-mide and topotecan combined with hu14.18K322A (4 doses/course fol-lowed by GM-CSF) in previously un-treated children with high-risk neuro-blastoma.

Eligible Ages: up to 18 yearsEligible Genders: BothAccepts Healthy Volunteers: NoPrimary Outcome Measures:

Number of participants with complete or partial response (time frame: after two initial courses of chemotherapy; ap-proximately 6 weeks after enrollment)

Principal Investigator: Wayne L. Furman, MD, St. Jude Children’s Re-search Hospital; 866-278-5833, [email protected]


PHASE III

Study Type: Phase III/interven-tional/parallel assignment

Study Title: Phase III Random-ized Study of Chimeric Antibody 14.18 (Ch14.18) in High Risk Neuroblas-toma Following Myeloablative Therapy and Autologous Stem Cell Rescue

Study Sponsor and Collaborators: National Cancer Institute

Purpose: To study isotretinoin with dinutuximab, aldesleukin, and sar-gramostim, as opposed to isotretinoin alone, following stem cells transplant in treating patients with neuroblastoma

Eligible Ages: up to 30 yearsEligible Genders: Both

Accepts Healthy Volunteers: NoPrimary Outcome Measures:

Event-free survival (time frame: from study enrollment until the first occur-rence of an event or until last contact with the patient if no event occurs, as-sessed up to 3 years)

Principal Investigator: Alice Yu, MD, Children’s Oncology Group; visit

clinicaltrials.gov to see all study loca-tions and regional contacts.


Editor’s Note: The clinical trials pre-sented here do not represent all the trials listed on ClinicalTrials.gov. For the com-plete list, go to ClinicalTrials.gov. n

GoalIllustrate in presentations and manuscripts effective approaches to delivering coordinated, patient-centered cancer care and apply the evidence for effective cancer care teams

WhoApproximately 10 writing groups will be formed with the following participants: • Clinicians (physicians, nurse practitioners,

physician assistants and nurses) • Patient advocates • Researchers studying team effectiveness in

health care (not only oncology) US or Canada

WhatGroups including clinicians, patient advocates and team researchers will develop a presentation and manuscript applying principles of team-based care to a case within the cancer care continuum (prevention, screening, diagnosis, active treatment of curable and incurable disease, survivorship, end-of-life).

Important Dates • Applications Due – June 15, 2015 • Selection of Teams – July 17, 2015 • In-Person Meeting at ASCO offices

(Alexandria, VA) – August 28, 2015 • Presentations at NCI-ASCO Workshop –

February 25, 2016

Apply as individuals or teams at www.ASCO.org\TeamsQuestions: [email protected]

Call for Participants! NCI-ASCO Teams in Cancer Care Project

The National Cancer Institute and the American

Society of Clinical Oncology are collaborating

to illustrate models of team-based care at a

workshop and Journal of Oncology Practice

content. Teamwork involves delineating roles

and responsibilities for multi-disciplinary care

across many settings. At a time of increasing

expectations and pressure to demonstrate

value in oncology care, this project will

explore how oncology care can provide

an effective model.

http://www.asco.org/practice-research/nci-asco-teams-cancer-care-delivery-0


2015 Oncology Meetings 2015MayASCO Annual MeetingMay 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

2015 ASCO State Affiliates’ ReceptionMay 31 • Chicago, Illinois For more information: www.asco.org/about-asco/ state-affiliate-leadership-conference

June2015 Clinical Update: 21st Century Prevention of HPV-Associated CancerJune 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-Century-Prevention-of-HPV-Associated-Cancer

Society of Nuclear Medicine and Molecular Imaging Annual MeetingJune 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML)June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

Anticancer Drug Action and Resistance: From Cancer Biology to the ClinicJune 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

CAP-ACP 2015 Annual MeetingJune 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php

International Society on Thrombosis and Haemostasis Annual MeetingJune 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

MASCC/ISOO Annual Meeting on Supportive Care in CancerJune 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July

7th World Congress on Gastrointestinal CancerJuly 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/WGIC2015/index.asp

14th Annual International Congress on the Future of Breast Cancer®July 16-18 • Huntington Beach, California For more information: www.gotoper.com

The 13th Annual Scientific Meeting of JSMOJuly 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html

NRG Oncology MeetingJuly 16-19 • Denver, Colorado For more information: www.gog.org/meetinginformation.html

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-OncologyJuly 28-August 1 • Washington, DC For more information: www.apos-society.org

16th Annual International Lung Cancer Congress®July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/meetings/16th-International-Lung-Cancer-Congress

Best of ASCO® BostonJuly 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

AugustBest of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://boa.asco.org/

World Congress on Cancer and Prevention MethodsAugust 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/oncology-2015/

ASCO Multidisciplinary Cancer Management Course (MCMC)August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/international-programs/multidisciplinary-cancer-management-courses

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

European Society for Medical Oncology Academy 2015August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

SeptemberInternational Palliative Care WorkshopSeptember 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/international-palliative-care-workshops

For more information, visit http://www.lymphcon.ch


2015 Oncology Meetings 201525th World Congress of the International Association of Surgeons, Gastroenterologists and OncologistsSeptember 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

ILCA 2015 —The International Liver Cancer Association’s 9th Annual ConferenceSeptember 4-6 • Paris, France For more information: www.ilca2015.org

16th World Conference on Lung CancerSeptember 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

American Society of Head and Neck Radiology (ASHNR) Annual MeetingSeptember 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015)September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/childhood-cancer/CIPO-2015/

2015 Breast Cancer SymposiumSeptember 25-27 • San Francisco, California For more information: http://breastcasym.org

European Cancer Congress (ECC 2015)September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/European-Cancer-Congress-2015

October30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis and Immunology”October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/tumorcourse

Congress of the International Society of Pediatric OncologyOctober 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com

Palliative Care in Oncology SymposiumOctober 9-10 • Boston, Massachusetts For more information: http://pallonc.org

NCCN 10th Annual Congress: Hematologic Malignancies™October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/meetings/hematological/default.aspx

NOVEMBER 5-8, 2015JW MARRIOTT DESERT RIDGE

PHOENIX, ARIZONA

Advanced Practitioners

Learn more at jadprolive.com

This CE/CME/CEU accredited conference is jointly provided by:

in Oncology

A CE EVENT FOR

SAVE THE DATETell Your NP & PA to

http://jadprolive.com


In the Literature

Emerging Clinical Data on Cancer Management

OLDER PATIENTS

Chemotherapy Trial Results Overestimate Survival for Elderly Medicare Patients With Lung and Pancreatic Cancers

Results of clinical trials evaluating chemotherapy regimens for advanced pancreatic and lung cancers “tended to correctly estimate survival for Medicare patients aged 65 to 74 years but to over-estimate survival for older Medicare patients by 6 to 8 weeks,” Elizabeth B. Lamont, MD, MS, of Massachusetts General Hospital Cancer Center in Boston, and colleagues reported in the Journal of the National Cancer Institute. “These ‘real world’ results may help in-form treatment discussions between older patients with these common ad-vanced cancers and their oncologists,” the researchers wrote.

In the United States, “patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are of-ten younger, more functional, and have less comorbidity,” the investigators ob-served. “We compared survival follow-ing three chemotherapy regimens ac-cording to the setting in which the care was delivered (ie, clinical trial vs usual care) to determine generalizability of clinical trial results to unselected elderly Medicare patients.”

Using Surveillance, Epidemiology, and End Results Program (SEER)–Medicare data, the researchers esti-mated survival for 14,097 patients age 65 years or older with advanced

pancreatic or lung cancer who had re-ceived one of three guideline-recom-mended first-line chemotherapy regi-mens. Their survival was compared with that of 937 patients, without age restrictions, but with the same diagnosis and stage of disease, simi-larly treated in clinical trials. These patients treated with standard first-line chemotherapy regimens in the clinical trial setting were identified using data from the National Cancer Institute–sponsored cooperative clin-ical trial group Cancer and Leukemia Group B, now a part of the Alliance for Clinical Trials in Oncology.

The median age of the clinical trial patients was 9.5 years younger than the elderly Medicare patients. “For each tu-mor type, Medicare patients who were 75 years or older had median surviv-als that were 6 to 8 weeks shorter than those of trial patients,” the researchers reported.

Key DataSurvival times for patients with

advanced pancreatic cancer treated with single-agent gemcitabine were 4.3 months for the elderly Medicare patients vs 5.8 months (P = .03) for the clinical trial patients. Respective survival times were 7.3 vs 8.9 months (P = .91) for patients with stage IV non–small-cell lung cancer treated with carboplatin and paclitaxel and 8.2 vs 10.2 months (P ≤ .01) for patients with extensive-stage small cell lung cancer treated with cisplatin/etopo-side. For younger Medicare patients,

survival times were similar to those of clinical trial patients.

“In applying these findings to any age group, it is essential to recognize that there is heterogeneity in impor-tant attributes like functional status, comorbidity, and general health status. Experts in geriatric oncology therefore advocate for comprehensive geriat-ric assessments that take into account many of these factors and that can as-sist in selecting patients for treatment, including participation in clinical tri-als,” the authors noted. “Given the similarly in survival between Medicare patients aged 65 to 74 years and the tri-al patients we studied, physician selec-tion for usual-care treatment appears to have been reasonable.”

Lamont EB, et al: J Natl Cancer Inst 107:336, 2014 (print January 2015).

‘Frailty Profile’ Predicts Survival and Toxicities in Elderly Patients With Multiple Myeloma

A frailty score predicts mortality and the risk of toxicity in elderly pa-tients with multiple myeloma and can be used to determine more suitable therapies for these patients, the Inter-national Myeloma Working Group re-ported in Blood.

“Chronologic age, performance sta-tus, and physician’s clinical judgment are not sufficient to characterize the frail population,” the authors stated. Geriatric assessment “is a more sen-sitive predictor of clinical outcomes, and the proposed score may be ad-opted as a valid new standard to evalu-ate patients’ frailty. It could be used in everyday clinical practice as well as in the context of research to ensure an adequate representation of elderly pa-tients and to allow more precise cross-trial comparisons.”

The score is based on a pooled anal-ysis of data from 869 newly diagnosed elderly patients from three prospective international trials. “At diagnosis, a ge-riatric assessment had been performed to assess comorbidities, cognitive [sta-tus], and physical status,” the authors explained.

The median age of the patients was 74 years, and 46% were older than 75 years. The most frequent comorbidi-ties were diabetes without organ dam-age (13.2%), mild renal failure (7.4%), cardiopulmonary disease (10.4%), and peripheral vascular disease (5.8%). The most frequent abnormal parameters for activities of daily living were related to

transportation (38.0%), housekeep-ing (37.3%), shopping (33.9%), laun-dry (31%), independence in bathing (19.6%), transferring (13.7%), and dressing (12.1%).

“An additive scoring system (range, 0–5), based on age, comorbidities, cognitive and physical conditions, was developed to identify three groups: fit (score = 0, 39%); intermediate-fitness (score = 1, 31%), and frail (score ≥ 2, 30%),” the investigators reported.

At 3 years, 3-year overall survival was 84% among patients with a fit score, 76% among those with an intermedi-ate-fitness score (hazard ratio [HR], 1.61, 95% confidence interval [CI], 1.02–2.56, P = .042), and 57% in frail patients (HR, 3.57, CI 95%, 2.37–5.39, P < .001). The cumulative incidence of grade ≥ 3 nonhematologic adverse events at 12 months was greater among frail patients (34.0% vs 26.4% for inter-mediate-fit and 22.2% for fit patients). The risk of grade > 3 hematologic ad-verse events was not significantly differ-ent among the three groups.

“This analysis showed that a frailty score that combines age, functional status, and comorbidities can predict survival and toxicity and is useful to determine the feasibility of a treatment regimen,” the authors concluded. “The frailty profile was associated with an increased risk of death, progression, nonhematologic adverse events, and treatment discontinuation,” the au-thors noted.

Currently, more than 60% of mul-tiple myeloma diagnoses and nearly 75% of deaths occur in patients older than age 65, according to the Interna-tional Myeloma Working Group. Al-though novel agents have substantially improved outcomes, the authors noted, “patients over 70 years benefit less from new treatments, probably due to an in-creased treatment-related toxicity and worse biology.”

Palumbo A, et al: Blood 125:2068-2074, 2015.

END-OF-LIFE CARE

Escalation of Oncology Services at End of Life May Be Moderated by Coordinated Care

“Use of oncology-related services is increasingly scrutinized, yet precise-ly which services are actually rendered to patients, particularly at the end of life, is unknown,” noted an article in ©Tom Cheney/The New Yorker Collection/www.cartoonbank.com


In the Literature

the Journal of Oncology Practice. To address this knowledge gap, Eijean Wu, MD, of the Los Angeles County and University of Southern California Healthcare Network, and colleagues catalogued the end-of-life use of med-ical services by patients with gyneco-logic cancer at a large, urban safety-net hospital.

Study DetailsThe investigators retrospectively

reviewed medical and hospital records to systematically identify all regis-trants in their hospital-based gyneco-logic oncology clinic with document-ed deaths between December 2006 and February 2012.

“The clinic is part of a 600-bed, publicly funded teaching hospital that serves a mid to low socioeconomic status population within a major met-ropolitan area,” the authors stated. “The core population serviced by this institution is 71% Hispanic, 7% white/non-Hispanic, 8% black, and 11% Asian. A total of 83% and 80% of the outpatient and inpatient popula-tion, respectively, were county indi-gent or state funded, with only 4.9% and 6.1%, respectively, funded by Medicare.”

Among the 116 subjects, the me-dian age at diagnosis was 55 years, and the median age at death was 57 years. Most patients presented with stage III or IV disease. Cervical cancer ac-counted for most of the deaths (42%).

The researchers evaluated the pa-tients’ clinicopathologic oncologic history and metrics of medical use, such as hospitalizations, outpatient visits, invasive procedures, chemo-therapy infusions, radiology studies, and blood draws. Calculating the days between the last therapeutic interven-tion (surgery, radiation therapy, or chemotherapy) and death showed that 30% of patients received a therapeutic intervention within the last month of life, the researchers reported.

“The median time between a pa-tient’s last therapeutic intervention and death was 55 days. The median time between the last chemotherapy infusion and death was 76 days (range, 4–363 days). Although 8% of patients received no treatment during their last 12 months of life, 3.4% received che-motherapy within 30 days of death, and 1 patient received chemotherapy within 14 days of death.

“To determine whether or not pa-tients underwent or received more di-agnostic tests, interventions, and ther-apies simply as a result of increased

availability of these services over the 6-year study period, we conducted time-trend analyses for the use of each variable within our health-care use evaluation,” the investigators wrote. These analyses revealed that only che-motherapy infusions significantly in-creased over time, by approximately two additional infusions per year. Use

of each of the services, however, did increase significantly during the last year of a patient’s life (P < .001).

Patients who had been receiving continued care within the clinic for a longer period experienced overall fewer days of hospitalization and out-patient visits in their last months of life. Patients who had been under continu-

ous care for a longer period by the same medical team also had fewer blood draws, radiology studies, and chemo-therapy infusions in the last months of life. Patients registered in the health-care system for the shortest period were more likely to be admitted into the hospital at the end of life than to


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In the Literature

receive outpatient treatment and care. “Importantly, our data showed that

lengthier time in the same health-care system, with coordination and over-sight of care by a stable medical team, may favorably affect the efficiency of resource use in the inpatient and out-patient settings,” the authors conclud-ed. They also realized over the course of their study that there is a dearth of data concerning optimal timing for discussions about resuscitation/code status and how it would best fit into a model of comprehensive cancer care. “ASCO strongly suggests early inte-gration of palliative care services to facilitate these discussions, especially for patients in advanced stages of can-cer,” the authors noted.

“Despite improvements in end-of-life planning and growing endorse-ment of hospice care over the past decade, multiple reports still show that such decisions continue to be delayed to within moments of death,” the authors noted. “What drives this procrastination, whether appropriate or not, warrants further investigation.”

Wu E, et al: J Oncol Pract 11:e163-e169, 2015.

COLON CANCER

Lower 30-Day Mortality, Increased Likelihood of Adjuvant Chemotherapy With Laparoscopic vs Open Colectomy for Stage III Colon Cancer

“In routine clinical practice, lapa-roscopic colectomy is associated with a lower 30-day mortality, shorter length of stay, and greater likelihood of adjuvant chemotherapy initiation among stage III colon cancer patients when compared with open colecto-my,” according to an analysis of data from the National Cancer Data Base. The results were reported in the Jour-nal of the National Cancer Institute by Zhiyuan Zheng, PhD, of the Ameri-can Cancer Society, and colleagues from the University of Texas MD An-derson Cancer Center in Houston and the Alliance for Clinical Trials in Oncology Network and American College of Surgeons Clinical Research Program.

“Randomized clinical trials showed that laparoscopic colectomy is supe-rior to open colectomy in short-term surgical outcomes,” and “meta-analy-sis studies confirmed these findings,” the authors noted. They undertook

the current study to investigate wheth-er the findings could be generalized to patients outside clinical trials.

Using the National Cancer Data Base, the investigators identified stage I to III colon cancer patients aged 18 to 84 years in 2010 and 2011. “Pa-tients were limited to those who had adenocarcinoma and underwent ei-ther curative laparoscopic colectomy or open colectomy as their first course of treatment within 90 days after diag-noses,” the authors explained.

Among 45,876 patients analyzed, 18,717 (41%) had laparoscopic col-ectomy and 27,159 (59%) had open colectomy. After propensity score matching to avoid the effect of treat-ment selection bias, both groups had 18,230 patients well balanced on their covariables.

Patients who had laparoscopic col-ectomy had consistently lower 30-day mortality, 1.3% vs 2.3 % for patients with open colectomy (odds ratio [OR] = 0.59, 95% confidence inter-val [CI] = 0.49–0.69, P < .001). The median length of stay was 5 days with laparoscopic colectomy vs 6 days with open colectomy (incident rate ratio = 0.83, 95% CI = 0.8–0.84, P < .001). “Laparoscopic colectomy was also as-sociated with a higher rate of adjuvant chemotherapy use in stage III patients (72.3% vs 67.0%, P < .001)” and re-ceiving chemotherapy without delay, the researchers reported.

Laparoscopic colectomy was per-formed “at a wide variety of facil-ity types and among both low- and high-volume hospitals and surgeons, with more than 64% of laparoscopic colectomy cases performed in com-munity hospitals and more than 70% performed by low-volume surgeons, demonstrating the widespread avail-ability of the laparoscopic approach,” the researchers stated. “Laparoscopic colectomy was more likely to be per-formed by high-volume surgeons in high-volume hospitals, but there was no significant effect of the hospital/surgeon volume on short-term out-comes,” the authors added.

“We have demonstrated the gen-eralizability of the benefits of laparo-scopic colectomy found in random-ized clinical trials among real-world patients where the majority of colec-tomies were performed in community cancer programs. However, more than half of patients still undergo open resection,” the investigators noted. “Wider diffusion of laparoscopy at the population level with incentives to im-prove laparoscopic skills acquisition

through training and monitoring of outcomes, particularly among current high-volume surgeons who perform only open colectomy, may benefit patients and improve the efficiency of colon cancer care throughout the health-care system.”

Zheng Z, et al: J Natl Cancer Inst 107:dju491, 2015.

BREAST CANCER

Mammographic Density After Tamoxifen Initiation Linked to Improved Prognosis for Pre- and Postmenopausal Women With ER-Positive Breast Cancer

An improved prognosis for women with estrogen receptor (ER)-positive breast cancer who experience a large reduction in mammographic density following the initiation of tamoxifen treatment extends to premenopausal as well as postmenopausal women, re-searchers reported in the Journal of the National Cancer Institute. Although a previous analysis linked decline in mammographic density following ini-tiation of tamoxifen with improved survival in postmenopausal women, this more recent evaluation of change also showed improved survival in premenopausal women, “for whom tamoxifen is the primary antiendo-crine therapy,” Sarah J. Nyante, MD, and colleagues wrote. Dr. Nyante is currently affiliated with the Univer-sity of North Carolina but was pre-viously associated with the National Cancer Institute, which supported the study.

“Mammographic density reflects the fibroglandular composition of the breast, and women with the high-est levels have approximately fourfold higher breast cancer risk compared with women with the lowest density,” the investigators noted. “Emerging evidence,” they added, “indicates that density reductions specifically among tamoxifen users may predict treatment effectiveness in adjuvant and chemo-preventative settings, which could have value for planning long-term treatment.”

The case-control study includ-ed 349 estrogen receptor–positive breast cancer patients, aged 32 to 87 years, who were treated with tamoxi-fen at Kaiser Permanente Northwest in Portland, Oregon, between 1990 and 2008: 97 who died of breast can-cer (case patients) and 252 who did not (control patients), matched on age and year at diagnosis and disease

stage. The mean age at diagnosis was 59 years. Mammographic density in the unaffected breast was measured at baseline (with a mean of 6 months be-fore tamoxifen initiation) and again at a mean of 12 months after tamoxifen was started.

“Absolute change in percent den-sity ranged from a 41.7% reduction to a 17.2% increase, with smaller changes among case patients (mean, 3.1% reduc-tion) than control patients (mean, 5.2% reduction),” the researchers reported. Patients with the highest percentage of decline in mammographic density had a lower risk of breast cancer than did those with a lower percentage decline. The odds ratio (OR) for the highest tertile of decline in mammographic density (> 8.7%) vs the lowest tertile (< 0.5%) was 0.44 (95% confidence in-terval [CI] = 0.22–0.88). Results were similar after adjustment for baseline mammographic density (OR = 0.49, 95% CI = 0.23–1.02). Patients in the middle tertile of density change (0.5%–8.7%) did not have a lower risk of breast cancer death than did those in the lowest tertile.

Study Implications“In this study, estrogen receptor–

positive breast cancer patients who experienced greater than an 8.7% ab-solute reduction in mammographic percent density after approximately 1 year of tamoxifen treatment had a 56% lower risk of breast cancer death,” the investigators stated. “Accounting for other factors, including early tamoxi-fen nonadherence, tamoxifen use duration, other adjuvant treatments, and antidepressant use, did not alter the results.

Furthermore, results were similar among younger (≤ 50 years) and older (> 50 years) women.” This similarity among younger and older women “re-inforces the clinical relevance of these findings, as tamoxifen is the primary antiendocrine treatment available to the former group, whereas use has diminished among the latter,” the au-thors noted.

Confirming these findings with studies involving large numbers of estrogen receptor–positive premeno-pausal women “could support moni-toring of mammographic density as an approach for assessing tamoxifen ef-fectiveness,” the investigators wrote. n

Nyante SJ, et al: J Natl Cancer Inst 107:dju425, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Emerging Clinical Datacontinued from page 47


Perspective

reimbursement models that reward the quantity rather than the quality of care delivered, the often inappropriate use of tumor-directed therapy near the end of life, and the sometimes desperate hopes and unrealistic expectations of patients and family members that lead clinicians to offer certain options despite lack of clear evidence of clinical benefit.

Cost vs ValueRising health-care costs are distrib-

uted throughout the broader economy by causing higher insurance premiums, increased cost shifting to patients in the form of higher deductibles and copay-ments, higher taxpayer burden, and stagnant wages. A resulting concern is that health care will become less and less affordable for Americans unless steps are taken to curb current trends.

Indeed, health-care expenditures are now cited as a major cause of personal bankruptcy, and the term “financial tox-icity” has been introduced to describe the financial distress that now often ac-companies cancer treatment. Patients experiencing high out-of-pocket costs have reported reducing their spend-ing on food and clothing, reducing the frequency with which they take pre-scribed medications, avoiding recom-mended procedures, skipping physician appointments, and having poor quality of life. But cost is only one component of a complex calculus that must weigh health outcomes against dollars spent to assess the true value of health care.

Value must be considered from the varying perspectives of consumers of health care, providers of health care, payers for health care, purchasers of health care, and innovators of health-care products. Many of these perspec-tives will be examined in two sessions at the upcoming 2015 ASCO Annual Meeting (see box).

Consumer’s ViewIn the United States, consumers with

insurance have typically been shielded from the full costs of their health care, as direct out-of-pocket costs are only a fraction of the total cost of their care. But as costs continue to rise, even in-sured patients are beginning to struggle with monthly out-of-pocket expendi-tures of thousands of dollars.

For consumers, value is defined pri-marily by health outcomes, eg, cure of disease, longevity, relief of symptoms, resumption of usual daily activities, im-provement in quality of life, and achieve-

ment of personal goals. Value is often de-fined in very personal ways, depending on individual preferences, work require-ments, comorbidities, family circum-stances, and financial realities.

Provider’s ViewOncologists and other members of

the cancer care team have a primary responsibility to deliver high-quality, evidence-based, efficient care to their patients. For providers, value can be cre-ated through a shared decision-making process that lays out prognosis, goals of treatment, treatment options, and ex-pected benefits and risks in the context of the patient’s preferences, values, and personal goals.

To make informed choices, patients also need information about the costs of their medical care and the relationship between the costs they will incur and the benefits they will receive for different treatment options. ASCO’s value frame-work, soon to be released for public com-ment, will provide the foundation for a tool that will help doctors and patients as-

sess the relative value of cancer therapies based on efficacy, side effects, and cost.

Payer’s ViewPayers focus largely on the distribu-

tion of illness and wellness in the cov-ered population, reduction in use of ex-pensive treatments and procedures not supported by medical evidence, elimina-tion of inefficiencies in health-care de-livery systems that lead to duplication of services, and enhanced communication among providers and between providers and patients to reduce unecessary emer-gency room visits or hospitalizations. For payers, achieving high value care depends not only on improving health outcomes but also on reducing waste, improving efficiency, and increasing ac-cess to the primary health-care team, all of which tend to drive down costs.

Purchaser’s ViewPurchasers of health care, whether

governments or private companies, often consider multiple factors when deciding whether or not to introduce a

new product or service as an option for their population. Purchasers typically have a fixed and limited budget, and considerations often include the com-peting health-care needs of the popula-tion, the extent of unmet medical need for a condition, available alternatives, and overall affordability of a new treat-ment as well as its incremental benefit and toxicity. Indeed, most developed countries other than the United States employ health technology assessments provided by a government-sanctioned entity to determine the value of a new therapeutic option and use this assess-ment to engage in price negotiations with the product manufacturer to ob-tain the lowest cost and best value.

Innovator’s ViewFor product innovators, value is de-

termined in the context of research and development investment and share-holder expectations. From the innova-tor’s perspective, value is often assessed over the life cycle of the product, as product performance varies across pa-tient populations, by line of therapy, and based on whether a biomarker se-lection strategy is employed.

Pricing and reimbursement typically depend on marketplace competition, region of the world, and duration of patent exclusivity and less so on treat-ment indication and magnitude of in-cremental benefit achieved. To be sure, cancer drugs take years to develop and billions of dollars in research invest-ment, and for every success, there are dozens of failures. Yet even drugs that successfully reach the market some-times produce only modest incremen-tal improvements in clinically impor-tant endpoints—nevertheless, they still enter the market with extraordinarily high prices.

Optimizing ValueFor all stakeholders, the definition of

value ultimately comes down to the price that must be paid to achieve meaningful-ly improved health outcomes at the level of individual patients or for the broader population of affected individuals. Op-timizing the value of a new product be-gins with innovation to address an un-met medical need followed by defining and achieving clinically meaningful im-provements in health outcomes through well-designed and efficiently conducted clinical trials. Effectiveness research is essential to determine how well the new product performs compared to available alternatives and in more diverse popula-tions than those typically included in the clinical trials used to establish efficacy.

Patient goals, preferences, and choic-es shape the real-world experience with a new product, and the direct and indirect costs of treatment to patients and their families impact its widespread adoption. Until their value is clearly established, new and costly products should be de-ployed judiciously by the medical com-munity after careful consideration of the goals of treatment; available options; and the unique needs, preferences, and goals of individual patients.

Research in many domains is neces-sary to improve the assessment of the value of new cancer treatments. New clinical efficacy endpoints—both pro-vider- and patient-reported—that accu-rately describe how a patient feels and functions must be developed and should reflect outcomes of value to patients other than survival, particularly in non-curative settings. Better predictive bio-markers can transform a drug of modest efficacy in an unselected population to one of high efficacy in a biomarker-de-fined subgroup and thereby contribute to improving the value of a treatment.

Regulatory and policy initiatives (such as adaptive licensing, value-based insurance, and indication-specific pric-ing, which impact marketing approval, reimbursement, and price, respective-ly) based on treatment effectiveness all deserve careful consideration. Further research must also be conducted to de-termine the impact of these initiatives on aligning cost with benefit while in-

Richard L. Schilsky, MD, FACP, FASCOcontinued from page 1


Together, we can and we must ensure that all patients have the opportunity to achieve optimal outcomes at affordable costs—ie, that patients receive high-value, not just high-cost, cancer care.

—Richard L. Schilsky, MD, FASCO

Sessions on Value in Health Care at the Upcoming ASCO Annual Meeting

■ ASCO–European Society of Medical Oncology (ESMO) Joint Session: Global Perspectives on Value (Saturday, May 30)

■ The Value Proposition in Oncology: Different Approaches to Understanding Value in Cancer Care (Sunday, May 31)


Perspective

suring patient access to life-prolonging therapies and continuing innovation in product development.

All Stakeholders AccountableAll stakeholders need to accept ac-

countability for improving the value of cancer treatment. Providers need to practice evidence-based medicine fo-cused on quality rather than quantity of care and engage in shared decision-making with their patients. Patients need a better understanding of treat-ment options, potential outcomes, and costs to help establish realistic goals.

Industry needs to responsibly price products to support true innovation but ensure access. Payers need to make well-informed, fair, and transparent coverage decisions. Purchasers of health care need to demand that the cost of a given

intervention bears a relationship to the beneficial impact it has on the patients who receive it.

Together, we can and we must en-sure that all patients have the oppor-tunity to achieve optimal outcomes at affordable costs—ie, that patients receive high-value, not just high-cost, cancer care. n

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

References1. Centers for Medicare and Medicaid

Services: National Health Expenditure Pro-jections 2010-2020. Available at www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/National-HealthExpendData/downloads/proj2010.pdf. Accessed April 15, 2015.

2. Mariotto AB, Yabroff KR, Shao Y, et al: Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 103:117-128, 2011.

Richard L. Schilsky, MD, FACP, FASCOcontinued from page 49

Physicians, researchers and healthcare professionals from over 100 countries are expected to attend ASCO’s 51st Annual Meeting later this month at the McCormick Convention Center. The theme for this year’s meeting is Illumination and Innovation, Transforming Data Into Learning.

Watch for comprehensive coverage of the meeting in future issues of The ASCO Post. Photo by © ASCO/Zach Boyden-Holmes 2012

2015 ASCO Annual Meeting, Chicago, May 29 – June 2, 2015

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Residual disease in myeloma goes deep.1-5

shouldn’t we stRive to go deepeR?

Growing evidence supports using a long-term treatment approach for continuous disease suppression and improved outcomes.6-8

Proteasomes regulate intracellular protein degradation. Their inhibition induces endoplasmic reticulum stress within myeloma cells and impacts support mechanisms within the bone marrow microenvironment.9-11

At Takeda, we’re committed to achieving a deeper understanding of multiple myeloma and helping to address the challenges patients face today and tomorrow.

Even after achieving complete response, myeloma cells can persist.1-5 It’s time to reconsider the way we approach myeloma:

Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited.Other trademarks are the property of their respective owners.

Copyright © 2015, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in the USA USO/NON/15/0002 January/15

ReFeRenCes: 1. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540-2547. 2. Paiva B, Vidriales MB, Cerveró J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023. 3. Biran N, Ely S, Chari A. Controversies in the assessment of minimal residual disease in multiple myeloma: clinical significance of minimal residual disease negativity using highly sensitive techniques [published online ahead of print September 16, 2014]. Curr Hematol Malig Rep. doi:10.1007/s11899-014-0237-y. 4. Munshi NC, Anderson KC. Minimal residual disease in multiple myeloma. J Clin Oncol. 2013;31(20):2523-2526. 5. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079. 6. Palumbo A, Niesvizky R. Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Leuk Res. 2012;36(suppl 1):S19-S26. 7. Girnius S, Munshi NC. Challenges in multiple myeloma diagnosis and treatment. Leuk Suppl. 2013;2(suppl):S3-S9. 8. Palumbo A, Gay F, Musto P, et al. Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints. J Clin Oncol. 32:5s, 2014 (suppl; abstr 8515). 9. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4(5):349-360. 10. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034-2042. 11. Borrello I. Can we change the disease biology of multiple myeloma? Leuk Res. 2012;36(suppl 1):S3-S12.

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