TAP Vol 2 Issue 14

Oncology drug shortage 10

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National Cancer Policy Forum 14

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VOLUME 2, ISSUE 14

FDA Update 24-26, 34

SEPTEMBER 15, 2011

ASCOPost.com

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

Lymphoma

We Can Conduct Clinical Trials of Protons

FDA Approves Brentuximab Vedotin in Two Lymphoma Indications

By Matthew Stenger

T

he antibody-drug Brentuximab Vedotin conjugate brentuximab vedotin (Adcetris) ■■ Brentuximab vedotin received accelerated approval for the treatment of was granted accelerated relapsed or refractory Hodgkin lymphoma and systemic anaplastic large approval on August 19 for cell lymphoma, based on two pivotal trials. the treatment of relapsed ■ ■ In Hodgkin lymphoma, brentuximab produced an objective response or refractory Hodgkin in 73% of patients with a median duration of 6.7 months, and complete lymphoma and systemic remission in 32% with a median duration of 20.5 months. anaplastic large cell lym■■ In anaplastic large cell lymphoma, brentuximab produced an objective phoma. Brentuximab veresponse in 86% of patients with a median duration of response of 12.6 dotin is the first new drug months, a complete response in 57% with a median duration of 13.2 months, to be approved in Hodgand a partial response in 29% with a median duration of 2.1 months. kin lymphoma in more ■■ Adverse effects with brentuximab vedotin are primarily hematologic, than 30 years. neurologic, and constitutional, with the most frequent toxicities being In Hodgkin lymphoneutropenia and peripheral sensory neuropathy. ma, the drug is indicated for use in patients with tion after at least two multiagent chemotherapy regiprogressive disease after autolomens have failed. In anaplastic large cell lymphoma, gous stem cell transplantation and it is indicated for use in patients after failure of at least SEE PAGE 43 continued on page 6 in those ineligible for transplantaCost of Care

Palliative Care, Quality of Life, and Cost ore than half of our nation’s patients with cancer are Medicare beneficiaries, making the entitlement program ground zero in the heated debate on healthcare spending. Total Medicare expenditures attributable to beneficiaries in their last year of life runs upward of 30%; this statistic serves as a rallying point for the charge that too much expensive care is used in advanced cancer.

However, according to nationally regarded palliative care

A

great deal has been written about proton therapy, with a good deal of heat and only a modest amount of light. I would like to comment on an aspect of the proton vs photon controversy that I believe has not been adequately addressed: Should we run clinical trials that would allow us to prove that proton therapy is superior? This becomes a general question of how do we assess “new” technologies that are “clearly” superior to the “old” technology, because “new” is always better (at least in the United States).

The Physics For the purposes of this opinion piece, the physics can be easily summarized. High-energy photons (x-rays) spare the skin but travel through the body beyond the tumor (called the “exit dose”). Treatment plans deliver a higher dose to the tumor than to the surrounding normal tissue by the use of multiple beams that intersect on the tumor. Protons deposit their dose over a narrow continued on page 2

By Ronald Piana

M

By Theodore S. Lawrence, MD, PhD

expert, Diane Meier, MD, FACP, Director, Hertzberg Palliative Care Institute, Mount Sinai School of Medicine, New York, our fragmented delivery system is what we should be focusing on. Dr. Meier recently spoke with The ASCO Post, offering her perspective for our ongoing series on rising cancer costs.

Key Cost Driver in Cancer Care Several studies indicate increased hospital use among patients with cancer is becoming a key driver of costs. What’s your response to these findings?

It is an accurate assessment; however, increased hospitalizations are a symptom of a systemic problem.

Patients turn to the hospital because their needs are not being met in the community setting. There is no safety net in place, no appropriate support for caregivers and patients, so they

Dr. Lawrence is Professor and Chair, Department of Radiation Oncology, University of Michigan, Ann Arbor.

MORE IN THIS ISSUE Oncology Meetings Coverage Institute of Medicine National Cancer Policy Forum ��������������� 14 Best of ASCO Miami ������������������������������� 27 Direct from ASCO ��������������������������������������� 16 Integrative Oncology ���������������������������������� 28 Oncology Worldwide ���������������������������������� 29 Letters to the Editor ������������������������������������� 41

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A Harborside Press® Publication

The ASCO Post | SEPTEMBER 15, 2011

PAGE 2

Opinion

Clinical Trials of Protons continued from page 1

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology 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 Miami

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Robert W. Carlson, MD Stanford University Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

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

Stanley H. Winokur, MD Singer Island, Florida

Jay S. Cooper, MD Maimonides Medical Center

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

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

INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina 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 Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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sources are not infinite, and we should ask for data to support our beliefs so that resources can be applied rationally.

But does that new data need to come from a randomized trial of “old” technology vs “new” technology? Proton advocates claim that it is unethical to run a trial of photon vs protons. Even if it is not unethical, they say it will be impossible: People will demand the better technology.

region that depends on their energy (the Bragg peak); there is no exit dose. In order to treat a tumor (which is typically at least a few centimeters in width), several energies are used (the “smoothed-out Bragg peak”). Because there is no exit dose, protons should deliver less overall radiation to the normal tissues than photons for the same tumor dose.

I have just given The Questions you the definition of The big question is, Now we come “protons are better to the point of my than photons” for where is the evidence essay. It may sura medical physicist that protons can be prise some to find and many radiation out that the field oncologists. In fact, used to safely deliver of radiation oncolthere are a number a higher dose of ogy has asked this of technical issues general question that are beyond the radiation than photons before, but we did scope of this brief to, for example, it in the 1980s and opinion piece that 1990s with regard may make protons the prostate? to the then new inferior to photons three-dimensional in some settings.

(3D) treatment planning. How could But let’s ignore these and assume that the we ask if 3D, which was more labor pure physics advantage of protons can intensive and required complex softbe exploited, if not now, then in the near ware, was worth the effort compared to future. standard 2D? The question was broken The Controversy down into two steps, forming the basis Given the physics (and ignoring curof what was known as the “3D hypothrent technical limitations), why would esis”: 1. Can the dose be escalated with the there be any controversy? Unfortunew technology? Indeed, with 3D nately, protons are at least four times as (and, subsequently, intensity-modexpensive as photons, so it would seem ulated radiation therapy, or IMRT), that in the era of comparative effectiveone could escalate the dose to most ness, a theoretical advantage should not tumors, with the most studied exbe a sufficient reason to justify the far ample being prostate cancer. In the greater expense. To make matters worse, 2D era, 68 to 70 Gy was the maxithere is at this time no convincing clinimum dose before encountering cal evidence that protons are superior to unacceptable rectal toxicity. 3D and photons in any disease, especially prosIMRT permitted the dose to be estate cancer, the cancer that accounts for calated to approximately 78 Gy. the great majority of proton treatments.

2. Does that escalated dose improve loSome have written that it is so obcal control and/or survival? This vious that proton therapy is superior question has been resoundingly to photon therapy that it would be unanswered yes, with at least four ethical to conduct studies that address randomized trials demonstrating the question of whether protons are, in continued on page 3 fact, superior. I disagree. Health-care re-

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

Write to The ASCO Post at editor@ ASCOPost.com.

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

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 3

News

Novel BRAF Inhibitor Receives FDA Approval in Metastatic Melanoma BRAF targeting reduces mortality by 63%.

By Caroline Helwick

V

emurafenib (Zelboraf) received FDA approval on August 17, 2011, for treatment of metastatic or unresectable melanoma, based on the results of the phase III BRIM3 trial.1 BRIM3 compared vemurafenib to dacarbazine in 675 untreated patients with the BRAF V600E mutation. Vemurafenib targets the mutation, which is present in approximately 50% of patients with advanced melanoma. A companion diagnostic test called the cobas 4800 BRAF V600 Mutation Test was concurrently approved.

Omid Hamid, MD, of The Angeles Clinic and Research Institute (www. theangelesclinic.org), Los Angeles, re-

viewed data from BRIM3 and BRIM2 at the Best of ASCO meeting in Miami, Florida.1,2 “With vemurafanib we see an initial separation between the arms [vemurafenib vs dacarbazine] that continues. There are durable and ongoing responses. The data in both the first-line [BRIM3] and second-line [BRIM2] settings seem extremely promising,” said Dr. Hamid.

BRIM3 enrolled 675 patients, including 337 patients who were assigned to vemurafenib, 960 mg orally twice daily, and 338 who were assigned to dacarbazine, 1,000 mg/m2 intravenously,

W

ith two effective new treatments for advanced melanoma, the question has become how to best use them and how to manage their toxicities.

Vemurafenib (Zelboraf) and ipilimumab (Yervoy)1 have different pharmacokinetics, which lend themselves to different patient types. Omid Hamid, MD, of The Angeles Clinic and Research Institute, Los Angeles, who discussed the two agents at the Best of ASCO meeting in Miami, Florida, said he uses vemurafenib first in patients Omid Hamid, MD who are symptomatic or have a high tumor burden.

“Response with ipilimumab may be delayed, but response can be rapid with vemurafenib,” he noted. Vemurafenib might reduce the tumor burden and set the patient up for a better response when switching to ipilimumab.

In patients with minimal symptoms and low tumor burden, ipilimumab might be preferred first-line. “The goal is durable benefit. Definitive progression should trigger a switch to vemurafenib,” Dr. Hamid said.

“Both agents require experience and commitment by the physician and patient in the management of the unique toxicities, which can be life-threatening,” he emphasized. “We are nowhere near the end of the road with these agents.”

■

Reference 1. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2526, 2011.

continued from page 2

improved local control of prostate cancer at the higher dose. These randomized trials were successful because they were focused on dose, not technology (but only the improved technology could safely deliver the higher dose).

A corollary to this approach comes from tumors that are already fairly well controlled with current treatment (such

■■ Vemurafenib received FDA approval for treatment of patients with

unresectable or metastatic melanoma with the BRAF V600E mutation as detected by the cobas 4800 BRAF V600 Mutation Test.

■■ First-line treatment with the BRAF inhibitor vemurafenib reduced the risk of death by 63% and risk of progression by 74%.

■■ The most common adverse reactions (≥ 30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea.

Pivotal BRIM3 Trial

Using the New Melanoma Drugs in the Clinic

Clinical Trials of Protons

Vemurafenib in Advanced Melanoma

as head and neck cancer), with the goal of delivering the same tumor dose while using the better technology to decrease dose to the normal organs and, thereby, to preserve normal organ function (eg, parotid and other salivary glands).

Here, too, it has been shown that IMRT is superior to older techniques.

The Bottom Line Thus, the big question is, where is the evidence that protons can be used

every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal.

All patients had an ECOG performance status of 0 or 1, and 95% of patients had metastatic disease. The major endpoints of the trial were overall and progressionfree survival.

Survival Data The first interim analysis found progression-free survival to be 5.3 months with vemurafenib vs 1.6 months with dacarbazine, a 74% reduced risk (P < .0001). Overall survival at 6 months was 84% vs 64%, respectively, a 63% reduction (P < .0001). Overall responses were observed in 48.4% vs only 5.5%, respectively, and all subgroups benefited.

The most common grade 3 adverse event in patients treated with vemurafenib was cutaneous squamous cell carcinoma, which was treated by excision. Other common adverse reactions were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea.

Next Steps

and cytotoxics. Simultaneous inhibition of BRAF and MEK has been associated with resumption of response in patients who progressed on a prior BRAF inhibitor.

The recommended dose of vemurafenib is 960 mg orally twice daily.

■

Disclosure: Dr. Hamid reported receiving consulting and speaking fees from BristolMyers Squibb and Roche, and research funding from Bristol-Myers Squibb, GlaxoSmithKline, and Roche.

References 1. Chapman PB, Hauschild A, Robert C, et al: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine in patients with V600E BRAFmutated melanoma. 2011 ASCO Annual Meeting. Abstract LBA4. Presented June 5, 2011.

2. Ribas A, Kim KB, Schuchter LM, et al: BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma.

2011 ASCO Annual Meeting. Abstract 8509. Presented June 4, 2011.

What Will It Cost?

Future studies, Dr. Hamid said, should evaluate vemurafenib in combination, and sequentially, with MEK inhibitors, PI3K and mTOR inhibitors, insulin-like growth factor receptor inhibitors, immunomodulators,

According to Genentech, manufacturer of vemurafenib, cost of the drug will be approximately $9,400 per month with a total cost of approximately $56,400 for 6 months duration of treatment.

to safely deliver a higher dose of radiation than photons to, for example, the prostate? Or that the rectum and bladder can be better protected by protons at the same tumor dose? If proton facilities could generate such evidence, it could be used to support a trial testing whether the increase in tumor dose permitted by protons controls more tumors, or whether the decrease in dose to normal tissue decreases toxicity.

Our field has shown that random-

ized dose trials can be successfully conducted. In my opinion, proton facilities should not be permitted to continue to produce results that cannot be distinguished—except by the far greater price—from those produced by IMRT photons. Our patients deserve true improvements in outcome, rather than the hype and added expense that currently dominates the field.

■

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

The ASCO Post | SEPTEMBER 15, 2011

PAGE 4

Expert’s Corner

A Conversation with Monica Morrow, MD, FACS The Institute of Medicine issues guidelines on guidelines.

By Ronald Piana

Monica Morrow, MD, FACS

O

ver the past 15 years, practice guidelines have become an accepted tool to help physicians optimize patient care by offering informed assessment of the benefits and potential harms associated with various care options. However, a plethora of new guidelines have entered the market, many of which suffer from shortcomings in the development process. To ensure that organizations developing guidelines use objective, scientifically valid methods, the Institute of Medicine (IOM) assembled an expert committee to study the guideline development process. A year in the making , the IOM committee’s report (“Clinical Practice Guidelines We Can Trust”) was released in March 2011.1 The ASCO Post recently spoke about the consensus report with IOM committee member Monica Morrow, MD, FACS, Chief of the Breast Service at Memorial SloanKettering Cancer Center in New York.

Committee Process The IOM committee developed eight standards for guideline development.

What was the process like behind closed doors?

Developing the report was an extensive process. The committee comprised a diverse group representing multiple viewpoints, including experts on guideline development, pure methodologists, and guideSEE PAGE 43 line end users from the health plan and physician sides. We also had patient advocates, consumer representatives, and a legal representative.

A literature search was done to collect data on currently available state-of-the-art guidelines. We then

held a public forum and invited both individuals and organizations to comment on their experience with the guideline process and to offer their opinions about guidelines in general. After that, we had a series of committee meetings to hammer the information into a workable format, which was followed by another workshop to allow people and organizations with guideline expertise to address specific questions about challenges to guideline development and implementation.

On top of that, we commissioned four expert papers related to the guideline process. The first three papers covered adherence issues, implementation, and evaluation in the present and in the electronic future. The fourth outlined a current, best practice stateof-the-art process for guideline development. We then took all of that information and had committee meetings during which we argued our way, step by step, into the final report. Despite the wide variety of perspectives, we wound up with a report that satisfied all concerns and issues, so it was a successful process that took place over a year.

Oncology Representation Were you the sole representative from the oncology community?

Trustworthy Clinical Practice Guidelines

A ■■ ■■ ■■ ■■ ■■ ■■

ccording to the Institute of Medicine’s clinical practice guidelines report, trustworthy guidelines should: Be based on a systematic review of the existing evidence Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups Consider important patient subgroups and patient preferences, as appropriate Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest Provide a clear explanation of the logical relationships between alternative care options and health outcomes, and provide ratings of both the quality of evidence and the strength of recommendations Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations

guideline development, what does trustworthiness imply?

The term trustworthy was specifically used as part of the charge to the committee from the IOM. One problem identified by IOM was the sheer number of guidelines available to clinicians. To date, there are literally thousands of guidelines out in the system, and many of these instruments have conflicting recommendations. In many cases, the process by which they were developed is not transparent.

Today’s extremely busy clinicians don’t have time to scour the litera-

Conflict of interest issues must be balanced by the need to have a guideline committee composed of the best experts in all medical disciplines.

I believe that I was. Interestingly, most of the people who have been engaged in guideline development have been from the nononcology internal medicine and pediatric sector. However, the IOM committee was intentionally represented by a wide variety of people, organizations, and clinical perspectives, to capture the most accurate and up-to-date recommendations that would help clinicians select the best care possible for their patients.

ture to evaluate the strength of every guideline recommendation, so from a practical point of view, they really need to know which guidelines have been developed by a thorough evidence-based process. That’s where the term trustworthy comes into the guideline development process. The doctors who use guidelines need to trust that they have been developed by a meticulous and unbiased process.

Guideline Trustworthiness

Why did conflict of interest issues garner so much attention in the guideline standards?

The word “trustworthy” was central to the committee’s mission. In the context of

Conflict of Interest

■

There were two reasons. First, some guidelines have been developed with fairly egregious conflicts of interest in play, such as a guideline funded by a drug company whose own drug was designed for the particular disease that was the subject of the guideline. That’s an example of a flagrant conflict of interest.

The other type of situation, which is much more difficult to deal with, involves clinical content experts who tend to have an inherent bias. For example, if an expert is involved in developing a guideline for a disease in which the alternative treatments are surgery or radiation, and that expert makes a major part of his or her income by doing surgery for this particular disease, would the viewpoint be completely unbiased?

But potential conflict of interest issues must be balanced by the need to have a guideline committee composed of the best experts in all medical disciplines involved in disease management weighing in on the clinical challenges during the development process. We concluded that we should recognize the more subtle forms of conflict of interest that may help explain why guidelines from separate groups reach different conclusions.

One needs to be clear about disclosing potential conflicts. Ideally, the chair of a guidelines committee should be more of a methodology person instead of a clinical specialist, and a macontinued on page 6

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E AR S UR V IVAL R ATE I S 17 % F O R PATIENTS W ITH M E TAS TATIC S OF T TIS S UE SA RC OMA , YE T S I G N I F ICANT THER APEUTIC A D VAN CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001

The ASCO Post | SEPTEMBER 15, 2011

PAGE 6

Expert’s Corner

Monica Morrow, MD, FACS continued from page 4

jor part of the chair’s role should be to ensure that potential conflicts are managed in a transparent fashion.

but CER-driven decisions could certainly spring from data in guidelines if you have two treatments with equal strengths of evidence and outcomes.

That said, cost was not a core focus of this committee.

Comparative Effectiveness Research

Future Role of Guidelines

Given the current economic issues in health care, was comparative effectiveness research (CER) part of the development process?

In order to make a guideline, you need to do a systematic review, and as it happens, the title of the committee from the IOM that was looking at systematic review was Standards for Systematic Reviews of Comparative Effectiveness Research. Regarding CER, we didn’t advocate one way of the other,

Speaking from your experience on the committee and as a practicing clinician, what place do guidelines have in the future of health care?

The difficulty in implementing guidelines is that many clinicians would like guidance in areas where high-quality evidence doesn’t exist, and that’s why there’s confusion. However, there are numerous examples in oncology and other disciplines of highquality evidence about certain clinical

Brentuximab Vedotin

from the anti-CD30 monoclonal antibody brentuximab and the antitubulin agent monomethyl auristatin E (vedotin), joined by an enzymecleavable dipeptide linker. The conjugate is designed to be stable in the circulation. After binding to CD30 via brentuximab, the conjugate is rapidly internalized and transported to lysosomes, wherein the linker is selectively cleaved. Vedotin is released into the cell and binds to tubulin, resulting in breakdown of microtubules, G2/M (gap 2 phase and mitosis) cell-cycle arrest, and apoptosis (Fig. 1).

continued from page 1

one prior chemotherapy treatment.

“Early clinical data suggest that patients who received [brentuximab vedotin] for Hodgkin lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

Mechanism of Action CD30, a defining marker of Hodgkin lymphoma, is expressed on the surface of Hodgkin Reed-Sternberg cells as well as cells in anaplastic large cell lymphomas, embryonal carcinomas, and select subtypes of B-cell-derived nonHodgkin lymphomas and mature T-cell lymphomas. The restriction of normal expression of CD30 to this relatively small population of activated B cells and T cells and a small portion of eosinophils makes the molecule an attractive therapeutic target. Anti-CD30 antibodies alone have thus far shown little clinical activity in Hodgkin lymphoma.

Brentuximab vedotin is formed

What Will It Cost?

According to Seattle Genetics, manufacturer of brentuximab vedotin, the cost of the new intravenous drug is $4,500 per vial. In the pivotal trials, patients received a median of three vials per dose, which translates to $13,500 per dose, and a median of seven to nine doses over duration of treatment (approximately $100,000 per treatment course).

Two Pivotal Trials Approval of brentuximab vedotin in both settings was based on findings in two pivotal, open-label, singlegroup clinical trials in which overall response rate was assessed by an independent review facility as the primary endpoint. Brentuximab vedotin was administered intravenously at a dose of 1.8 mg/kg over 30 minutes once every 3 weeks. The study in Hodgkin lymphoma included 102 patients (median age, 31 years; range, 15 to 77 years; 53% female, 87% white) who had received a median of five prior therapies including autologous stem cell transplantation. Objective response occurred in 73% of patients, with a median duration of response of 6.7 months. Complete remission occurred in 32%, with a median response duration of 20.5 months and responses that were ongoing at the time of the analysis (range, 1.4 to 21.9+ months), and partial remission occurred in 40%, with a median duration of 3.5 months (range, 1.3 to 18.7 months).

procedures and treatments that should be standard of care but to some extent are not being used. It is vital that we offer providers high-quality guidelines documenting evidence-based strategies if we expect to hold our healthcare system accountable regarding adherence to proven medical care.

On the other hand, it is not appropriate to hold providers accountable to guidelines based on who had the loudest voice in the development committee room. That’s where the balance in the IOM development process comes into play. The standards put forth by the committee are extremely rigorous.

Admittedly, doing what is described in our report takes time and resources, but the end results are worthwhile.

To me, it is more productive for our

health-care system to have a smaller number of truly trustworthy, highquality guidelines than what we currently have—a giant load of instruments, some good but many awful.

The mission of the IOM report was just that: to provide the framework for developing clinical guidelines that end users can trust as a tool in their medical care decisions.

■

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

Reference 1. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines: Clinical Practice Guidelines We Can Trust. Washington, DC; Institute of Medicine, 2011. Available at www.iom. edu.

Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD30 monoclonal antibody

ADC binds to CD30 ADC-CD30 complex traffics to lysosome

MMAE is released MMAE disrupts microtubule network

G2/M cell cycle arrest Apoptosis

Fig. 1: Brentuximab vedotin mechanism of action. The antibody-drug conjugate (ADC) brentuximab vedotin works by binding to CD30 proteins on the surface of Hodgkin lymphoma cells. The ADC then forms a complex with CD30 and enters the cell. Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell. Source: NCI Cancer Bulletin. December 14, 2010. Available at www.cancer.gov.

The study in systemic anaplastic large cell lymphoma included 58 patients (median age, 52 years; range, 14 to 76 years; 57% male, 83% white) who had relapsed after (50%) or were refractory on (50%) their most recent prior therapy. Patients had received a median of two prior therapies, with 26% having received prior autologous stem cell transplantation. Approximately 72% of patients were anaplastic lymphoma kinase (ALK)-negative.

Objective response occurred in 86% of patients, with a median duration of response of 12.6 months. Some responses, including complete and partial responses, were ongoing at the time of analysis (range, 0.1 to 15.9+ months). Complete response occurred in 57%, with a median duration of response of 13.2 months (range, 0.7 to 15.9+ months), and partial response

occurred in 29%, with a median duration of 2.1 months (range, 0.1 to 15.8+ months).

Toxicities Adverse effects with brentuximab vedotin are primarily hematologic, neurologic, and constitutional. In Hodgkin lymphoma, the most common adverse events (> 20%) were neutropenia (54%), peripheral sensory neuropathy (52%), fatigue (49%), upper respiratory tract infection (47%), nausea (42%), diarrhea (36%), anemia (33%), pyrexia (29%), thrombocytopenia (28%), rash (27%), abdominal pain (25%), cough (25%), and vomiting (22%). The most common grade 3/4 events were neutropenia (15%/6%), anemia (8%/2%), thrombocytopenia (7%/2%), peripheral sensory neuropathy (8% grade 3),

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; SEPTEMBER 15, 2011

PAGE 7

News Lymphoma

Important Benefit for Small Population Is a Major Milestone in Lymphoma

By Anas Younes, MD

T

he approval of brentuximab vedotin (Adcetris) is a major milestone for the treatment of patients with relapsed Hodgkin lymphoma and anaplastic large cell lymphoma. It represents an excellent example of personalized cancer therapy. Patients are preselected based on a predictive biomarker that is expressed by tumor cells, which is the CD30 receptor. This CD30 biomarker identifies approximately 11,000 newly diagnosed patients with Hodgkin lymphoma and

Anas Younes, MD

anaplastic large cell lymphoma out of a larger pool of patients, almost 80,000, who are diagnosed annually in the United States with different types of lymphomas. Both Hodgkin lymphoma and anaplastic large cell lymphoma are highly curable types of lymphoma, and it is estimated that less than 2,000 patients will not respond to or relapse from the intended curative therapy. It is this smaller pool of patients with CD30expressing Hodgkin lymphoma and anaplastic large cell lymphoma who stand to benefit from the current FDA-approved indication.

Given the high cost of drug development for cancer, it is therefore not surprising that for decades pharmaceutical companies neglected drug development for this relatively narrow indication and small market. In fact, the last drug approved by the FDA for the treatment of Hodgkin lymphoma was almost 34 years ago. However, and peripheral motor neuropathy (4% grade 3).

In systemic anaplastic large cell lymphoma, the most frequent adverse events were neutropenia (55%), peripheral sensory neuropathy (53%), anemia (52%), fatigue (41%), nausea continued on page 8

many of us, including myself, believe that because of the high response rates achieved with brentuximab vedotin with relatively low toxicity, in patients with multiply relapsed Hodgkin lym-

phoma and anaplastic large cell lymphoma, it has the potential of making a larger impact in future trials that will incorporate this drug in front-line regimens. Patients and doctors are encour-

aged to participate in the planned front-line studies so we can asses the impact of brentuximab vedotin on the natural history of these rare lymphomas.

â&#x2013;

The ASCO Post | SEPTEMBER 15, 2011

PAGE 8

Issues in Oncology

Cost of Care continued from page 1

have no alternative but to call 911.

More than 70% of patients with cancer who are admitted to the hospital enter through the ER. This is just one fact that illustrates how fundamentally broken our health-care system is.

Whole-person Care Short of scrapping the system and starting over, how can we fix the broken part of the cancer care component?

It has been repeatedly demonstrated that if you deliver high-quality, patientcentered palliative care focused on providing quality of life and an extra layer of support to caregivers, patients, and their oncologists, patients’ needs are met in a timely manner so that they do not have to go through the kind of crises that SEE PAGE 43 send them to the ER. Plus they have fewer psychosocial issues such as depression, stress, and worry, and, perhaps as a result, are more likely to complete their cancer treatments.

It’s a no-brainer that if the whole person—and I include the patient and family as the unit of care—has his or her respective needs met comprehensively and continuously throughout the course of illness, we can anticipate, prevent, and manage costly crises, such as emergency hospitalizations and all the inpatient treatments that follow. An emergency hospitalization is good for no one; patients are better off (and safer) at home, and the costs of using the hospital as the crisis default are astronomical.

What you described sounds like it should be standard of care. Why isn’t it?

In short, because we do not have a payment system in place that promotes whole-person care. The current payment system rewards highly specialized and fragmented medical care. We

Brentuximab Vedotin continued from page 7

(38%), pyrexia (38%), rash (31%), diarrhea (29%), and pain (28%). The most common grade 3/4 events were neutropenia (12%/9%), thrombocytopenia (5%/5%), peripheral sensory neuropathy (10% grade 3), pain (5% grade 4), fatigue (2%/2%), and pain in extremity (2%/2%).

Ongoing Trials Several studies of brentuximab

are throwing money out the window by the handfuls. Unnecessary hospital admissions are an example, not only for costly ER stays, but because hospitals are dangerous places for immunocompromised patients with cancer who are highly susceptible to nosocomial infections. So if we really want to improve quality of care and, as a side effect, markedly reduce spending, we will move these patients and provide the care they need back in the community—basically, into their homes.

Changing Policy How can we make that kind of transformation in cancer care?

We need a new payment model that promotes quality of care instead of the current system that promotes quantity of care. We need to pay for doctors, nurse practitioners, social workers, and others

trained and skilled and rewarded for meeting the whole patient’s needs in the home setting, thus avoiding unnecessary hospitalizations. It’s a systems problem, not a patient or cancer problem; we designed the delivery system based on financial incentives that are misaligned. That needs to change.

‘End-of-life Care’ Medicare spending for end-of-life cancer care is one area that policymakers single out for cuts. What’s your take on this issue?

In our ongoing dialogue, it is very important not to frame the issue as “end-of-life care” because that suggests we are giving treatment that we know will not help to patients who we know are dying, and that is simply not the case. An oncologist doesn’t know if a patient is going to be in the 50% of

Palliative care, which includes expert symptom management and comprehensive communication, should be provided to all patients with serious disease, from the time of diagnosis and independent of prognosis. to come to the house and be available on a 24/7 on-call basis. For example, if on a Saturday night a family caregiver suddenly realizes that pain meds will run out the next morning, or that the patient hasn’t had a bowel movement in 6 days and has abdominal pain, a call to the oncologist would probably elicit this advice: “Go to the ER.” However, if a palliative medical care home team is contacted, they would know which 24-hour pharmacy delivers in that area or could get a nurse to the house right away to administer enemas. Two phone calls and an emergency department visit, and hospitalization is averted.

Palliative care team members are

those who survive 3 to 4 years with non–small cell lung cancer, or in the 50% who die sooner.

Retrospectively citing a cost statistic attached to the phrase “end-oflife care” suggests that we know with certainty which patients should fall into that category, and the fact is, we don’t. As doctors, we have to give 100 patients the same treatment to capture the 50 who will respond and live an extra 3 to 4 years. The other 50 may not make it, but we don’t and can’t know that in advance. We need to give all our patients who could realistically benefit the same opportunity to have the best care possible.

vedotin are ongoing. The AETHERA trial (ADC Empowered Trial for Hodgkin to Evaluate PRogression after ASCT) is a phase III randomized, double-blind trial comparing brentuximab vedotin plus best supportive care vs placebo plus best supportive care in patients with Hodgkin lymphoma at high risk of relapse after autologous stem cell transplantation. A phase II trial is evaluating the potential for retreatment with brentuximab vedotin in

patients who have relapsed after discontinuing previous brentuximab vedotin therapy.

A phase I, two-arm, open-label, dose-escalation study is investigating the combination of brentuximab vedotin with multiagent chemotherapy in front-line treatment of Hodgkin lymphoma. The treatment arms consist of brentuximab vedotin in combination with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or with AVD (doxorubicin, vinblas-

Productive Conversations Is part of treating the whole patient and, in turn, delivering more cost-effective care, attained by developing better communication about realistic goals when the patient moves from the curative option setting, as articulated in the recent ASCO policy statement?

Once again, I would drop the qualifier “curative option” when we begin to have honest conversations with our patients. Here’s an example: A recent editorial I coauthored with Dr. Otis Brawley1 began with a case history of a young woman with leukemia who had terrible physical, psychological, and spiritual symptoms, as did her family. Her goal, and that of her oncologist, was cure. She received a bone marrow transplant, and fortunately she responded. Six years later, she’s still alive. It’s worth noting that she received very aggressive palliative care in harmony with very aggressive and effective oncology care.

So care—including a plan for when to initiate productive conversations—is not about either “curative” or “not curative.” One problem I had with the original ASCO policy statement was that it suggested we should not initiate conversations about realistic options until it is clear the patient is going to die. I do not agree with that. Palliative care, which includes expert symptom management and comprehensive communication, should be provided to all patients with serious disease, from the time of diagnosis and independent of prognosis. Our patients will benefit; so will our health-care system.

■

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

Reference 1. Meier D, Brawley O: Palliative care and the quality of life. J Clin Oncol 29:2750-2752, 2011.

tine, dacarbazine). Another phase I trial is evaluating brentuximab vedotin given sequentially and concurrently with multiagent chemotherapy as front-line treatment in patients with systemic anaplastic large cell lymphoma. Brentuximab vedotin is being given sequentially with cyclophosphamide, prednisone, doxorubicin, and vincristine and in concurrent and sequential combination with cyclophosphamide, doxorubicin, and prednisone.

■

The case for Vectibix® Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION: Vectibix® is indicated as a single agent for the treatment of occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus

epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical irinotecan-containing chemotherapy regimens. studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing pulmonary fibrosis and resulted in death. The second patient had symptoms of mCRC is based on progression-free survival. Currently, no data demonstrate an pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently improvement in disease-related symptoms or increased survival with Vectibix®. discontinue Vectibix® therapy in patients developing interstitial lung disease, Retrospective subset analyses of metastatic colorectal cancer trials have not shown pneumonitis, or lung infiltrates. a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in In a randomized, controlled clinical trial, median magnesium levels decreased by codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring cancer with these mutations. oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred Important Safety Information, including Boxed WARNINGS: 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and treatment (eg, oral or intravenous electrolyte repletion) as needed. were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months (5.1), and Adverse Reactions (6.1)]. after the last dose.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have patients. Fatal infusion reactions occurred in postmarketing experience. [See been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis.

Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Interrupt or discontinue Vectibix® for acute or worsening keratitis.

Reactions (6.1, 6.3)].

Adequate contraception in both males and females must be used while receiving In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to transmitted from the mother to the developing fetus and has the potential to cause the development of severe dermatologic toxicities, infectious complications, including fetal harm when administered to pregnant women. sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and Discontinue nursing or discontinue drug, taking into account the importance of the drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening drug to the mother. If nursing is interrupted, it should not be resumed earlier than dermatologic toxicity and monitor for inflammatory or infectious sequelae.

2 months following the last dose of Vectibix®.

Terminate the infusion for severe infusion reactions.

The most common adverse events of Vectibix® are skin rash with variable presentations, Vectibix® is not indicated for use in combination with chemotherapy. In an interim hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including analysis of a randomized clinical trial, the addition of Vectibix® to the combination of diarrhea resulting in dehydration. ® bevacizumab and chemotherapy resulted in decreased overall survival and increased The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion adverse reactions occurring at a higher rate in patients treated with Vectibix® included reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration Please see brief summary of Prescribing Information on next page.

(16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Reference: 1. Vectibix® (panitumumab) stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade prescribing information, Amgen.

3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

©2011 Amgen Inc. All rights reserved. 04-11 MC48257-B

The ASCO Post | SEPTEMBER 15, 2011

PAGE 10

News Issues in Oncology

Oncology Drug Shortage: An Unintended Consequence of the Medicare Modernization Act and Free-market Forces?

By Ronald Piana

O

ncology has a drug shortage problem, and the FDA says that it is getting worse. Drug shortages are not a new phenomenon, but over the

past few years we have seen a rapidly growing number of shortfalls that are Trim: 7.875” limiting providers’ ability to care for Live: 7” their patients. In 2004, the FDA re-

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

there are currently almost 200 drugs in shortage situations—more than triple the amount from 7 years ago.

In a recent statement, the FDA explained that the injectable drug crisis is fueled by a number of factors: shortages of raw materials, drug makers discontinuing older, off-patent

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. 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. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 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 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. 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 several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As 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 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). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy – 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 Reproductive and Developmental Toxicology]. 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 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It 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) in Full Prescribing Information].

Pediatric Use: The 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 Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • 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].

This brief summary is based on the Vectibix® prescribing information v11, 3/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-E

Walter Kalmans

drugs in favor of newer agents, and recalls of drugs due to quality problems.

Are consolidation, manufacturing, and regulatory issues the key culprits?

Partially, but according to health-care economics expert, Walter Kalmans, the main cause for the drug shortage crisis is economics. Mr. Kalmans is President of Lontra Ventures, a life science consulting firm that specializes in the drug commercialization process, with particular focus in the oncology sector.

Trim: 10.75” Live: 10”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information].

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • 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, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Do not administer Vectibix as an intravenous push or bolus.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported.

Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4).

Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (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 4%) 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. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

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

Ocular Toxicities: 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 therapy for acute or worsening keratitis.

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because 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 available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial.

The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

ported 58 drug shortages; in 2010, the agency reported 178 shortages.

According to the American Society of Health-System Pharmacists (ASHP),

Profits Dictate Production Regulatory and manufacturing issues slow production, and on occasion, the FDA shuts down an active pharmaceutical ingredient supplier. It takes time before a manufacturer can certify a new active ingredient. These problematic production issues occur far more frequently with lower-priced generic drugs, Mr. Kalmans pointed out.

“It should not come as a surprise that most of the drugs at the top of the shortage list are lower-priced generics.

Manufacturing companies have finite capacity. Naturally, there is more profit

The Language of Drug Pricing ■■ ASP = average selling price ■■ AWP = average wholesale price ■■ MMA = Medicare Modernization Act

ASCOPost.com | SEPTEMBER 15, 2011

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incentive to produce higher-priced drugs. It is simply a case of the free market at work,” said Mr. Kalmans.

One would think that drug manufacturing companies would see a window of opportunity and step in to fill the shortage, pricing the drugs accordingly. “First, it takes a long time to file and obtain approval for an abbreviated new drug application for generics with the FDA, as well as substantial time to construct and inspect a new manufacturing line and process,” said Mr. Kalmans.

Unintended Consequences Signed into law in 2003, the Medicare Modernization Act (MMA) worked as intended—it lowered reimbursement for IV drugs and created more transparency in pricing. Before MMA, IV drugs were reimbursed as a percentage of the average wholesale price (AWP), but the AWP was not a transparent way to understand the actual price paid for these medicines.

“Pre-MMA, the AWP might be $1,000 per vial. However, providers could acquire the drug for $150 per vial and receive reimbursement of 95% of AWP or $950 per vial. That was what lawmakers wanted to eliminate,” Mr. Kalmans said.

But under MMA, IV drugs are reimbursed as a percentage of the average selling price (ASP), which includes all discounts, rebates, and allowances provided in the sale. Manufacturers of generic drugs exchange significant margin for guaranteed sources of demand from a small pool of wholesalers.

Moreover, unlike AWP, which is static, ASP is updated quarterly to more accurately reflect the drug acquisition price (Fig. 1), but with a 6-month delay between collection of sales data and change in reimbursement rate.

Mr. Kalmans explained that, at least for injectable drugs, the Medicare ASP model makes it difficult for drug companies to raise prices more than 6% per year. “If companies were to raise prices more than 6%, it would leave some chemotherapy drugs ‘underwater’ [ie, for a 6-month period, the cost to the practice would be more than the Medicare payment rate] every time they were administered in an oncology office.”

Market competition drives down the price of generic drugs, and the MMA legislation has accelerated the rate and pace of these price declines, creating de facto price controls. “However, once product margins drop too far, drug manufacturing

MMA ‘Short-Circuits’ Free Market: Shortages Persist Free-market Scenario

■■ If a competitor leaves the market, remaining players gain a larger share and raise price to reach a new equilibrium.

■■ Higher prices attract new entrants to enter the market and increase capacity.

MMA Scenario

■■ If a player leaves the market, remaining players have to find

manufacturing capacity for a low-margin product. Because of average sales price constraints, they cannot raise price.

■■ Low margins, abbreviated new drug application fees, and inability to

raise price are several reasons why new entrants choose not to enter the market.

Visit

MMA Legislation Lowered Reimbursement and Created More Transparency in Drug Pricing Lowered Reimbursement Pre-MMA AWP = $1,000/vial Reimbursement = 95% of AWP = $950/vial

Post-MMA ASP = $150/vial Reimbursement = 106% of ASP = $159/vial

Pricing Transparency Pre-MMA: AWP is static and does not change Post-MMA: ASP changes quarterly to reflect changes in market price

Q1 Manufacturer submits Q1 ASP data to US Government

Q2 US Government calculates and publishes Q3 ASP

Q3 New ASP becomes effective beginning of Q3

Fig. 1: Effect of Medicare Modernization Act (MMA) on drug pricing and reimbursement, with change from average wholesale price (AWP) to average selling price (ASP). Courtesy of Lontra Ventures.

companies exit or choose to focus additional capacity on more profitable products. The remaining companies cannot increase prices more than 6% per year due to ASP constraints, and they have little incentive to increase manufacturing capacity for low margin products, and voilà, we have drug shortages,” said Mr. Kalmans.

Possible Solutions Mr. Kalmans enumerated three potential solutions that could address the unintended consequences of MMA:

Solution 1:

■■ Raise reimbursement for some/ all generic drugs to higher than ASP+6% for a certain period of time after a drug has lost exclusivity.

■■ Result: Generic drug margins could be increased to create an incentive for manufacturing.

Solution 2:

■■ Waive abbreviated new drug application fees and accelerate corresponding reviews for certain generic drugs.

■■ Result: Lower the cost and time

needed for new entrants to the manufacturing process.

Solution 3:

■■ Offer manufacturers a financial stipend to help ensure steady supply of product.

■■ Result: Manufacturers receive fees from government that do not affect ASP.

Conclusion The current generic drug shortage will continue unless its underlying root causes are addressed. Economics aside, these shortages are limiting access to life-sustaining drugs for cancer patients.

“As pointed out, this serious issue is largely an unintended consequence of MMA 2003, and unless steps are taken to rectify sections of the bill that incentivize drug-manufacturing companies not to produce lowerpriced injectable generic therapies, we can expect this situation to continue. Every option to fix the problem should be considered—lives are at stake,” concluded Mr. Kalmans.

■

Disclosure: Mr. Kalmans is President of Lontra Ventures LLC, a life science consulting firm that specializes in the drug commercialization process with particular focus in the oncology sector.

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NCCN Guidelines Panel Members – Breast Cancer

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Drug Development

Developing Targeted-agent Combinations: Business and Regulatory Issues, and Legal Obstacles

By Margot J. Fromer

T

he Institute of Medicine’s National Cancer Policy Forum recently convened a public workshop, “Facilitating Collaborations to Develop Combination Investigational Cancer Therapies,” to address the promises and challenges involved in the development of combination oncologic drug therapies. In the September 1 issue of The ASCO Post, we explored the concept that combining investigational products early in their development may be a promising strategy for identifying effective therapies, especially when a combination targets multiple pathways, or more than one step in a pathway, conferring greater benefit than a therapy directed at a single target.

In the concluding installment of this report, we consider scientific challenges and opportunities in the codevelopment of investigational therapies; the regulatory environment for codevelopment, including the recent FDA draft guidance on this topic; and legal issues that influence collaboration.

Challenges and Opportunities in Clinical Development Drug developers will be faced with the need to change their mindset from competition to collaboration if these new combinations are to go forward. They won’t like it, but it can be done. For example, the Biomarkers Consortium, a public-private partnership was established in 2010. It comprises NIH, FDA, patient groups, and pharmaceutical and biotech companies and initiated a groundbreaking trial known as I-SPY 2 that predicted drug responsiveness in SEE PAGE 43 breast cancer based on the presence or absence of genetic and biologic markers. The trial continues to evaluate tumor response to a variety of investigational drugs, albeit not in combination.

Stuart Lutzker, MD, PhD, Vice President for Oncology Early Development, Genentech, presented an industry perspective. “Most conventional oncology drug development follows the paradigm of first identifying a biologic feature unique to cancer cells as compared to normal ones, identifying a drug-able target, and generating candidates with ac-

ceptable preclinical pharmacology and toxicology. Then we assess safety, pharmacokinetics, and efficacy as a single agent or in combination with standard of care, which is most often chemotherapy,” Dr. Lutzker said.

Stuart Lutzker, MD, PhD

tions have the greatest impact: in metastatic disease or in the adjuvant or neoadjuvant setting?” she asked. “And what are the risks of studying both the individual agents and drug combinations at the wrong clinical stage?”

Patricia LoRusso, DO

“This is a relatively straightforward process but has several limitations: First, there is a high failure rate due to inability to combine with standard of care therapy. Second, efficacy may be limited due to failure to fully suppress the pathway or biologic process, the pathways may be resistant from the outset, or resistance may be rapidly induced,” he continued.

With rational combinations of two targeted therapies, many of these problems may be overcome. However, these combinations require both a strong scientific rationale and pharmacologically compatible molecules. It is often difficult and time-consuming to identify an optimal dose and dose schedule for these rational combinations, and many combinations turn out to be more toxic than thought.

“An early emphasis on pharmacodynamics markers is seen to be key in making correct phase II dose and schedule decisions,” Dr. Lutzker said.

Clinical Trial Considerations Pharmaceutical companies are talking about collaboration, but the challenges appear daunting.

Especially in phase I trials, said Patricia LoRusso, DO, Director of Experimental Medicine, Barbara Ann Karmanos Cancer Institute. She asked whether, based on our current knowledge, we may be moving into drug combinations too quickly. Since often we lack appropriate molecular signatures, we don’t know that best in class is important when selecting agents in combination.

“Where will these new combina-

Robert F. Leibenluft

Clinicians’ challenges, she said, are to find the best drugs to use in combination. But how many combinations of similar targets need to be tested, and what are the moral obligations of identifying and using the most appropriate of each class selected for combination therapy? And can the use of many of these combinations as proof of concept—despite not having the clinically best in class of each agent combined—slow or even negatively impact clinical drug development of selected targeted combinations?

And if the drugs are not optimal or if tumor types with appropriate targets are not selected, then what?

“Does this also limit targeting similar combinations, should we use them as proof of concept only, and does it slow clinical development?”

Dr. LoRusso said that patient selection is critical but difficult because selection tools are currently less than effective and very expensive. However, is investing dollars in the development of these selection tools more time-efficient and financially efficient? Despite all these obstacles and unanswered questions, she continues to conduct phase I studies.

“Our expectations are different from traditional monotherapy in terms of acceptable response and use of assays to define tumor effects. Often we focus on surrogates, which, although identifying target effect in select tissues, may actually lead to false hope when it comes to target effect at the tumor site—the true tissue target for the agents under investigation.”

Regulatory Concerns There has been a good deal of concern in industry and academia about how FDA would regulate testing and approval of targeted combinations.

The agency panel was chaired by Richard Pazdur, MD, Director, Office of Oncology Drug Products. He was joined by Rachel Sherman, MD, Associate Director for Medical Policy, Center for Drug Evaluation and Research, Robert Temple, MD, Deputy Director for Clinical Science, CDER, and others.

In response to the concern, FDA has developed a draft guidance for development of combination therapy. In general, basic requirements of safety and efficacy apply, but the draft guidance addresses several unique issues: ■■ Whether codevelopment is appropriate. It usually provides less information about safety and efficacy, with resultant increased risk.

Therefore it should be undertaken under only limited circumstances, that is, for difficult-to-treat disease.

■■ Whether the biologic rationale is plausible (clearly advantageous over monotherapy) and whether the model developed should be compared to its individual components.

■■ The need to demonstrate that each component of the combination contributes to the treatment effect.

This could require a large clinical trial in a multiarm design, unless such a study is unethical because it might promote resistance and render the new therapy ineffective.

■■ Preclinical testing for proof of concept and safety.

■■ Criteria for clinical safety and efficacy, first in healthy volunteers if possible, and if not, in early phase I studies.

■■ The need for phase II studies to demonstrate the contribution of each component of the combination as to efficacy and dosing. The amount and types of clinical data needed will vary depending on the nature of the combination, the disease, and other factors.

■■ The need for phase III studies to demonstrate the contribution of each component, compare the combination to standard of care, and fine-tune the dosing.

ASCOPost.com | SEPTEMBER 15, 2011

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Drug Development

■■ Assurance that drugs in a combination be used only together.

Legal Concerns This new enterprise carries potential antitrust concerns, said Robert F. Leibenluft, Partner in the Washington law firm Hogan Lovells. “It is possible that if pharmaceutical companies, who are otherwise competitors, coordinate their activities to develop drugs, the result will be higher prices, lower quality, and reduced innovation, which could in turn have an effect on the future market for products, services, technology, and innovation,” he said.

“On the other hand, research and development collaborations among competitors can be efficient and are not uncommon. Most such efforts are undertaken without serious antitrust scrutiny.”

Contact The ASCO Post EDITOR IAL CORR ESPONDENCE James O. Armitage, MD Editor-in-Chief email: Editor@ASCOPost.com Cara H. Glynn Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

R IGHTS AND PER MISSIONS email: Permissions@harborsidepress.com

Mr. Leibenluft said that the Federal Trade Commission and the Department of Justice have few antitrust concerns where the following issues are accounted for: ■■ There is no intent to harm competition by raising prices, reducing output or quality, or thwarting innovation.

■■ There are other comparable research and development efforts in addition to those of the collaboration that would ultimately compete with them—in other words, competition is preserved.

■■ Collaborators do not already have entrenched products similar to the type to be developed.

■■ Collaboration is limited to core research, with collaborators free to commercialize independently.

■ ■ The benefits of collaboration are very convincing and likely could not be achieved independently.

■

Disclosure: Dr. Lutzker is an employee of Genentech.

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Abstract Submitter Now Open Submit an abstract for the 2012 Genitourinary Cancers Symposium where the latest clinical and scientific strategies in prevention, screening, evaluation and management of genitourinary (GU) cancers will be discussed. The Meeting’s discussion-based, open format allows for debate and exchange of the most current updates in the diagnosis, treatment and care in GU cancers.

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

To submit an abstract or to review guidelines, visit www.gucasym.org This live activity has been approved for AMA PRA Category 1 Credit™.

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The ASCO Post | SEPTEMBER 15, 2011

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Direct from ASCO

ASCO Support of Training Expands in Parallel with Growth of Oncology as Subspecialty Forward-thinking ASCO programs foster, support fellowship training.

I

n the early 1970s, the number of residents choosing medical oncology as a subspecialty was far below the number going into cardiology, gastroenterology, or pulmonology—established subspecialties that were created in the 1940s. The first medical oncology training programs had begun to appear in the 1960s, at institutions such as Memorial Sloan-Kettering and Stanford School of Medicine, and the first oncology board exam was not given until 1973. Founded in 1964 itself, ASCO recognized that fellows going into the nascent field of medical oncology needed support, as did their training programs.

the organization launched the Young Investigators Awards to spotlight and financially support research being carried out by trainees and junior faculty.

“At the time, there were no other society-organized granting programs, and this was really a pioneering effort,” says Dr. Mayer, who remembers that there were just 29 applicants that first year. Today, the program has hundreds of applicants, and 54 researchers received a Young Investigator Award in 2011. Through that award and additional award and grant programs aimed at medical students, residents, and fellows, ASCO and its philanthropic arm, the Conquer Cancer Foundation, have given out millions of dollars, clearly demonstrating the emphasis and support that ASCO gives to training and associated research.

Free Meeting Registration, ASCO Membership Added to Benefits for Fellows Robert J. Mayer, MD

In the late 1970s, ASCO launched the Training Program Directors’ Breakfast, providing a forum for leaders of fellowship programs to compare notes, ideas, war stories, gripes, and best practices each year at the ASCO Annual Meeting. It was a smashing success that filled a much-needed gap, remembers R ­ obert J. Mayer, MD, a Past President of ASCO and a fellowship director for 36 years of his career. Dr. Mayer is now the Faculty Vice President for Academic Affairs at Dana-Farber Cancer Institute, and Stephen B. Kay Family Professor of Medicine at Harvard Medical School.

“The hot topics included dealing with the relationship with the American Board of Internal Medicine, which certifies subspecialists, and figuring out ways to encourage more people to enter the field,” recalls Dr. Mayer, who chaired some of those breakfast meetings.

Pioneering Research Grant Program Next, ASCO focused on the fellows themselves. In the early 1980s,

Continuing to focus on ways to support trainees, in the 1990s ASCO started its current membership program that allows fellows to become full-fledged ASCO members for free and, after training, reduces membership fees during the first few years in practice.

In addition, ASCO began offering steep discounts to the usually cashstrapped fellows to register for the Annual Meeting. Not surprisingly, the number of fellows attending the meeting expanded, so ASCO created ways to enhance the experience for them.

ASCO developed special fellow-focused tracks, established the trainee lounge, and created the educational session “On the Shoulders of Giants.”

Dr. Mayer notes that the session allows trainees to learn about matters such as the history of lung cancer treatment, or systemic treatment of colon cancer, directly from oncology’s old guard who made that history.

In-training Exam Launched In the early 2000s, observing that fellowship program directors needed a way to know that their programs were doing all they could for trainees, ASCO leaders developed

the In-training Exam, now used by virtually all oncology training programs. “It allows trainees to identify areas in which they still need more work, and allows program directors to identify areas where their teaching is in need of reengineering, restructuring, and refocusing,” says Dr. Mayer. Several international programs have since adopted the concept.

Oncology now has a much higher profile, as advocacy groups have greatly increased public awareness and molecularly derived drugs have began to change how oncologists approach the diseases that constitute cancer, Dr. Mayer points out. Oncology has begun to overtake cardiology in popularity among residents choosing a subspecialty.

Responding to the groundswell of focus and demand, in 2007 ASCO organized all of its fellowship training support under the umbrella of a new Professional Development Committee, whose staff of five supports the full spectrum of career-development needs of oncologists, from those just entering the field to those with mature careers.

Michael Kosty, MD

Annual Training Directors Retreat Added In the late 2000s, it became clear that fellowship program directors needed more time to network than their breakfast at the Annual Meeting was affording them. Michael Kosty, MD, Medical Director at Scripps Cancer Center and Chair of ASCO’s Oncology Training Program Subcommittee at that time, urged ASCO to support a second annual get-together for program directors.

ASCO agreed, and Dr. Kosty helped

launch a fall retreat for directors. It’s now going into its third year and has been very well attended.

“It really is a practical, hands-on opportunity for program directors to get some didactic information, and it’s an also an open forum and a chance to network,” said Dr. Kosty.

Fellows’ Reduced Fee for ASCO University Access Aids Training One recent outcome of discussions at the retreat and the breakfast was agreement among program directors that fellows should be allowed access to ASCO University’s education modules for a reduced ra te. They pointed out to ASCO that this concept would aid both fellows and directors. ASCO agreed, and now fellows have access for a nominal fee.

Dr. Kosty comments, “I can say, ‘OK, everybody go and do the pharmacology module by the end of September,’ and it helps me satisfy a lot of ACGME requirements. It’s a great boon and one less wheel that I have to invent. Also, it lets fellows know what ASCO has to offer and inculcates them into the culture of lifelong learning.”

Another ASCO program that was launched for trainees just this year is the Quality Oncology Practice Initiative (QOPI) for fellows. The slightly modified version of ASCO’s robust practice-based quality improvement program lets fellows get results on the quality of the work they’re doing and compare themselves to their peers as they seek ways to improve.

Taken together, ASCO’s efforts to support fellowship training have helped countless fledgling oncologists, and the organization continues to keep its ear to the ground for new ways to do so.

“There are few other groups who do this to such an extent,” notes Dr. Mayer. “ASCO has been tremendously forward-thinking in its efforts to support fellows, who, after all, are the specialty’s future.”

■

© 2011. American Society of Clinical Oncology. All rights reserved.

Direct from ASCO continued on page 18

NOW AVAILABLE

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

CRI00127C/280420

Š 2011 Pfizer Inc.

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August 2011

The ASCO Post | SEPTEMBER 15, 2011

PAGE 18

Direct from ASCO Philanthropy Spotlight

ASCO’s Immediate Past President Helps Build Future of Cancer Research and Care by Supporting Conquer Cancer Foundation

George W. Sledge, Jr, MD

G

eorge W. Sledge, Jr, MD, has been treating patients with breast cancer, and pursuing research in the field, for more than 30 years—the last few electrified by a rapid proliferation of knowledge.

work early in his career, and culminating with the completion of his tenure as President in June. At every level, he has found the organization a nourishing source of inspiration.

“Science is not a solitary enterprise,” Dr. Sledge says. “It requires immense amounts of collaboration.

The wonderful thing about ASCO is that you can bring people together very easily to talk about new goals, new research, whatever’s on your mind. At the ASCO Annual Meeting, you can stand on a corner for 20 minutes and see everyone in your field walking by,” he notes.

“Having grown up in Wisconsin,” he says with a chuckle, “I think of ASCO as a great smorgasbord. It offers lots of tasty things, and you always go home fulfilled.”

I see less fear, and I see a lot of people who are very hopeful. That’s a direct result of the progress we’ve made in both treatment and survivorship— progress won through tireless advocacy and innovative, painstaking research.

—George W. Sledge, Jr, MD

“We have so much to offer our patients today,” says Dr. Sledge, who serves as Ballve-Lantero Professor in the Department of Medicine and as a Professor in the Department of Pathology at the Indiana School of Medicine, as well as Co-leader of the Breast Cancer Program at Indiana University’s Melvin and Bren Simon Cancer Center. “Advances in genomics, proteomics, computational biology, and other disciplines have come together all at once over the past decade, allowing us to leapfrog ahead at an incredible rate.”

Fostering Collaboration Dr. Sledge has helped lead the way in creating opportunities to use those new discoveries to advance cancer research and treatment. In addition to his own work in the clinic and in the laboratory, Dr. Sledge has been active in many roles within ASCO—starting with committee

Creating a World Free from the Fear of Cancer One of the most meaningful ways in which every ASCO member can come to the table, says Dr. Sledge, is by supporting its affiliated charitable arm, the Conquer Cancer Foundation.

“ASCO does a lot of important things, but if you ask me what is the most important thing we’ve done over the past 20 or 25 years—the most important, long-term contribution we make to society—it’s working through the Conquer Cancer Foundation to act as a catalyst for the careers of clinical and translational scientists. We’re building generations of researchers who are going to cure cancer one day.”

The Foundation’s mission is to conquer cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge, with the ultimate vision of creating

a world free from the fear of cancer.

It’s a goal that resonates deeply for Dr. Sledge.

“I see far fewer patients who have waited to seek care than I did 15 or 20 years ago,” he says. “I see less fear, and I see a lot of people who are very hopeful. That’s a direct result of the progress we’ve made in both treatment and survivorship—progress won through tireless advocacy and innovative, painstaking research.”

The Conquer Cancer Foundation supports the ASCO Annual Meeting, the award-winning website Cancer.Net, and other programs and initiatives that benefit ASCO’s 30,000-plus members and the patients they treat. The Foundation also supports a robust Grants and Awards Program that provides critical funding to researchers, with a unique emphasis on supporting the work of early-career clinical and translational investigators. In 2011, the Foundation awarded more than $7 million in grant funding to more than 70 investigators.

Seeding the Future of Cancer Care and Research

Many planned giving vehicles, including bequests, are available to help our community support the Conquer Cancer Foundation. For more information, please contact info@conquercancerfoundation.org.

received the Jane C. Wright award, and I was so proud that we had selected her—especially because, as a member of the Board, I had directly contributed to the award,” says Dr. Sledge. “She feels part of this wonderful tradition of excellence in research that is supported by the Foundation, and she really embodies our commitment to supporting the next generation.”

It wasn’t the first time Dr. Sledge had such an experience. “I often run into people who have received a Young Investigator Award. They frequently tell me that it was the first award they had ever received, and that it had had a huge impact in terms of convincing them to stay in the field. The Conquer Cancer Foundation has kick-started the careers of a lot of great junior faculty,” he says.

Dr. Sledge met one of those researchers at an NCI lecture earlier this year. Jung-min Lee, MD, who is researching sequencespecific DNA damage with PARP inhibition and carboplatin in women’s cancers at NCI, was the first recipient of the Jane C. Wright, MD Young Investigator Award, established in 2010 to honor ASCO Jane C. Wright, MD (left), and Jung-min Lee, MD cofounder and chemotherapy pioneer Jane C. Wright, MD. The “We raise money to support the award is funded by generous, pergrants, and we bring in top-notch insonal contributions from members ternational talent to review the work of the ASCO and Conquer Cancer of these outstanding folks—and the Foundation Boards of Directors. requirements we place on their host continued on page 20 “Dr. Lee was so proud that she had

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 19

Direct from ASCO

ASCO’s International Clinical Trials Workshop Educates Nascent Researchers on the Inner Workings of Clinical Trials

P

harmaceutical companies are increasingly conducting drug development research outside of the United States, Western Europe, and Japan. Attracted to the perceived lower costs, easier patient recruitment, and market potential, drug developers are now conducting more phase III clinical trials in areas such as China, India, Latin America, and Central and Eastern Europe.

But what of the doctors and nurses in these regions who now find themselves approached by pharmaceutical companies? Are they ready to conduct trials for the commercial drug industry? Do they know all they need to know about regulations, informed consent, and ethical issues, not to mention how to get paid properly for their work? And are they learning it from sources that aren’t the drug companies themselves?

which was begun in 2005. Each Advanced Cancer Courses implementation represents a partnership between ASCO and an international oncology society to provide high-level training to oncologists where there’s a perceived need. A mix of local faculty and faculty sent from ASCO present each course.

The International Clinical Trials Workshop has turned out to be among the program’s most popular offerings to date. Piloted in 2009 in Buenos Aires, the 2-day interactive workshop has taken place three times in 2011, in Egypt, Romania, and Uruguay. The courses had more requests for attendance than they were able to accommodate.

Other Advanced Cancer Courses programs are Cancer Care in the Older Population; Cancer Prevention; and EPEC-O: The Education in Palliative and End-of-life Care for Oncology Curriculum.

ASCO’s Advanced Cancer Courses Program Responds to Need

Not Enough Experienced Principal Investigators

To help address questions like these, ASCO has launched the International Clinical Trials Workshop as part of its Advanced Cancer Courses program,

According to Lucia Delgado, MD, President-Elect of the Federation of Latin American Cancer Societies, training is needed now because places

CONQUERING

such as India, Eastern Europe, China, and Latin America are seeing a huge influx of clinical trials, putting a strain on the limited number of experienced clinical investigators there.

“In Latin America, there are countries that are well prepared to conduct biomedical research. However we face some challenges, in particular regarding clinical trials, including making sure we have an appropriate number of well trained and experienced researchers,” said Dr. Delgado, local course chair and coordinator for the Uruguay workshop held in Punta del Este.

Seventy-six people attended the workshop that Dr. Delgado led, from principal investigators to research nurses, data managers, and clinical trial coordinators. The workshop delved into best practices in clinical trial implementation, trial design, patient recruitment, the tenets of good clinical practice, patient safety, and nuanced ethical and regulatory issues. It also answered frequently asked questions about publishing, said Dr. Delgado, who is a former ASCO International Affairs Committee member and Head of the Clinical Oncology Department

at the University of Uruguay.

Evaluation data collected at two of this year’s workshops showed that 77% of attendees intended to change their research practices based on what they learned at the workshop, and 61% made new relationships with other professionals involved in research, or strengthened the ones they already had.

Luis Ubillos, MD, was in that number. The young Uruguayan oncologist had worked on basic and translational research on molecular markers and immunotherapy as a medical student, but wanted to get more guidance before taking the plunge to become a principal investigator. He said that hearing lectures from very experienced local researchers and later getting to network with them was invaluable. Also of particular interest, he said, was the workshop’s focus on regulatory requirements in Latin American countries.

Focus: Not Just Big Pharma “Almost all the studies [coming to Latin America] are financed by the pharmaceutical industry, and in all cases there is minimal participation of continued on page 20

Cancer.

Together, anything is possible.

The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s pre-eminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

ConquerCancerFoundation.org

The ASCO Post | SEPTEMBER 15, 2011

PAGE 20

Direct from ASCO Conquer Cancer Foundation

Paying It Forward

continued from page 18

Dr. Sledge believes that one motivation for supporting the Conquer Cancer Foundation hits close to home. B:8.625 “In addition to its work in at the national and international T:7.625 in levels, theS:6.75 Conquer Cancer Founin dation is a major supporter of our state societies,” he notes. “Strong

institutions raise the bar in terms of mentoring,” Dr. Sledge continues.

“There’s not a lot of early-career funding available, especially for clinical and translational researchers, and it’s something the Conquer Cancer Foundation does uniquely well.”

state societies, which help us stand up for patients and provide physicians and allied health personnel with the recognition they deserve, are critical to our work.”

But there’s also the big picture.

“Like many scientists, I’ve always taken as a guiding principle the famous quote by Sir Isaac

To learn more about how the Conquer Cancer Foundation is working to create a world free from the fear of cancer, or to support the Foundation’s work by making an online donation, visit

www.conquercancerfoundation.org.

Newton: ‘If I’ve been able to see further, it was only because I stood on the shoulders of giants.’ We owe so much to those who came before us. But we also owe something to those who will follow. I view my support of the Conquer Cancer Foundation as an important means by which I can pay it forward,” says Dr. Sledge.

“We’re all links in a very long chain—a chain that’s far more valuable than any individual link.”

■

© 2011. American Society of Clinical Oncology. All Rights Reserved.

International Trials continued from page 19

an important escape pathway remains: MET Although advanced antitumor therapies have become available, many tumor types continue to evade treatment.1 Research has identified the MET pathway as one of the most critical escape pathways utilized by tumors. In most normal tissues, MET and its only known ligand, hepatocyte growth factor (HGF), are found in low levels. But in a range of malignancies—including thyroid, prostate, ovarian, lung, and breast cancers—MET is upregulated and drives more invasive and aggressive behavior of tumor cells, resulting in metastasis.2-7 Recent evidence also shows that inhibition of angiogenesis creates hypoxic conditions in the tumor that may further upregulate MET and ultimately promote disease progression.5,7 Exelixis is fully devoted to shutting down MET-driven escape in cancer. Therefore, we are investigating the dual targeting of the MET and VEGF pathways to simultaneously inhibit metastasis and angiogenesis in several cancers.

Visit www.METinhibition.com to learn more about the role of MET in tumor escape.

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. http://seer.cancer.gov/csr/1975_2008/. Accessed May 10, 2011. 2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth [draft manuscript]. 2011. Data on file, Exelixis, Inc. 3. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 4. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109:863-867. 5. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347-361. 6. Capdevila J, Argiles G, Rodriguez-Frexinos V, Nuñez I, Tabernero J. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med. 2010;9:153-162. 7. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207-2214.

© 2011 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 06/11

T:10.5 in

Despite advances in targeted cancer therapy,

B:11.25 in

S:9.75 in

local investigators in clinical trial conception, design, analysis, and reporting,” Dr. Delgado said. But she stressed that conducting clinical trials proposed by the pharmaceutical industry isn’t the workshops’ only focus. Each workshop also includes a presentation on how to stimulate more research from the local community, for the local community. To that end, she said, local or regional trials are necessary for developing therapeutic strategies that meet local and regional needs. “To achieve this, the implementation of academic courses like the International Clinical Trials Workshop is a significant contribution,” she added.

As for 2012, ASCO is teaming up with the Federation of Latin American Cancer Societies and the Brazilian Society of Clinical Oncology for a workshop in São Paulo in March, and collaborating with the Indian Cooperative Oncology Network to host a meeting in Mumbai in the summer. In addition, ASCO is exploring partnerships for conducting future workshops in China and Southeast Asia.

“I certainly recommend the workshop to young oncologists,” said Dr. Ubillos. “It is an excellent tool for beginning your career as a clinical investigator.”

■

© 2011. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 21

Direct from ASCO

New ASCO in Action Website:

One-stop Source for Policy News

F

or the past 2 years, ASCO members and others who have looked to ASCO for insight on policy issues have turned to the ASCO in Action section of the Society’s website for up-to-date information. Now, ASCO has launched a whole new website devoted entirely to policy issues and ASCO’s specific efforts to represent the best interests of oncologists and their patients. The ASCO in Action website was launched in September as a one-stop source for cancer policy news and information for ASCO members and other oncology professionals.

From legislative and regulatory developments impacting reimbursement, cancer research funding, access to care, and cancer care quality, ASCO in Action provides up-to-date information and resources about the issues impacting on-

cology practice and patient care.

“As policymakers work to address myriad issues facing our nation’s healthcare system, ASCO is tracking, monitoring, and responding to federal level initiatives to protect access to care,” said Allen S. Lichter, MD, ASCO’s Chief Executive Officer. “The new ASCO in Action is designed to help our members and others stay abreast of important cancer policy matters and offers an easy way to become an advocate on the critical issues that impact practice.”

Information and Feedback ASCO in Action presents at-a-glance as well as in-depth information on a variety of important topics including federal funding for research; Medicare and Medicaid reimbursement, rule-

making, and coverage issues; qualityof-care initiatives; and more.

In addition, ASCO in Action incorporates member polling to provide ASCO with a timely snapshot of members’ opinions. Dr. Lichter explains, “No one knows more about cancer care and delivery than ASCO members. Developing policy positions that best represent the profession requires direct input and feedback from our members.”

Other new features on the site ­include: ■■ Improved content organization, navigation, and search capability

Volume 29, Issue 15

May 20, 2011

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

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg

What the Latest Breast Cancer News Means for Patients

D

irect your patients to www.­ cancer.net/breastsymposium to learn about the research highlighted at the 2011 Breast Cancer Symposium in the special online newsletter, Cancer Advances: News for Patients from the 2011 Breast Cancer Symposium. Also,

your patients can listen to a podcast of the symposium highlights online or download it free of charge at www. cancer.net/podcasts.

■

© 2011. American Society of Clinical Oncology. All rights reserved.

Save the Date ASCO HIT/EHR SYMPOSIUM November 4-5, 2011 The Westin Peachtree Plaza Atlanta, Georgia

EORTC-NCI-ASCO Annual Meeting on Molecular Markers in Cancer October 27-29, 2011 Brussels Meeting Center Brussels, Belgium

Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

■■ Comprehensive links to related content ■■ Illustrative photos, graphics, and videos ■■ One-click accessibility to the ASCO ACT Network—ASCO’s grassroots action center Visit the new ASCO in Action website at ascoaction.asco.org. Visitors are encouraged to sign up for ASCO in Action’s RSS feed to stay abreast of current issues and policy news.

■

© 2011. American Society of Clinical Oncology. All Rights Reserved.

What’s Hot in

JCO

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

JCO.org 1. Is Breast Conservation Therapy Superior to Mastectomy for Women With Triple-Negative Breast Cancers?

Jean-Philippe Pignol, et al 29(21): 2841

7. Gain of Function: Empathy for the Uncertain Patient With Cancer Mark A. Lewis 29(22): 3103

2. Molecular Selection Trumps Clinical Selection Frances A. Shepherd 29(21): 2843

8. Clinical Development of Vascular Disrupting Agents: What Lessons Can We Learn From ASA404?

Patricia M. LoRusso, et al 29(22): 2952

3. Estrogen Receptor: A Never Ending Story?

Antonio C. Wolff, et al 29(22): 2955 4. Presurgical Progesterone in Early Breast Cancer: So Much for So Little?

Mitch Dowsett, et al 29(21): 2839 5. Prediction Models: Revolutionary in Principle, But Do They Do More Good Than Harm?

Andrew J. Vickers 29(22): 2951 6. A Time to Keep and a Time to Cast Away Categories of Tumor Response Michael L. Maitland, et al 29(23): 3109

9. A Time to Keep and a Time to Cast Away Categories of Tumor Response Michael L. Maitland, et al 29(23): 3111 10. Increased Risk of Locoregional Recurrence for Women With T1-2N0 Triple-Negative Breast Cancer Treated With Modified Radical Mastectomy Without Adjuvant Radiation Therapy Compared With BreastConserving Therapy Bassam S. Abdulkarim, et al 29(21): 2852

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004T

For more information: Please visit www.istodax.com or call 1-888-423-5436

The ASCO Post | SEPTEMBER 15, 2011

PAGE 24

FDA Update

FDA Grants Orphan Drug Status to MM-398, a Nanotherapeutic Encapsulation of Irinotecan, to Treat Pancreatic Cancer

M

errimack Pharmaceuticals, Inc, announced that the FDA has granted MM-398 orphan drug status for the treatment of pancreatic cancer. MM398 is a novel, stable nanotherapeutic

encapsulation of the marketed chemotherapy drug irinotecan. MM-398 is partnered with PharmaEngine, Inc, for development and commercialization in Taiwan under the designation PEP02.

Merrimack is a biopharmaceutical company discovering, developing, and preparing to commercialize innovative medicines paired with companion diagnostics for the treatment of

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

serious diseases. Merrimack currently has four targeted therapeutic oncology candidates in clinical development and a fifth expected to enter clinical development by the end of 2011.

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5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1.

Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 25

FDA Update

Action Date Set for Denosumab Supplemental Application

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mgen announced that the FDA will target a Prescription Drug User Fee Act (PDUFA) action date of April 26, 2012, for the supplemental Biologics License Application to expand the indication for denosumab (Xgeva) to treat men

with castrate-resistant prostate cancer to reduce the risk of developing bone metastases. If approved in this expanded indication, denosumab would become the first therapy licensed to prevent or delay the spread of cancer to bone.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

Denosumab is the only RANK ligand inhibitor approved by the FDA indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The drug is also approved in another dosage form as Prolia,

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

which is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture.

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The ASCO Post | SEPTEMBER 15, 2011

PAGE 26

FDA Update

FDA Clears Genetic FISH Panel for Leukemia Patient Prognosis

A

bbott announced it has received 510k clearance from the FDA for a new in vitro diagnostic test to aid in determining the prognosis of patients with chronic lymphocytic leukemia (CLL). Abbott’s Vysis CLL FISH Probe Kit is the

first FDA-cleared CLL test to aid in prognosis. The test detects genetic abnormalities in lymphocytes.

In CLL, abnormal lymphocytes are produced and can accumulate in the circulatory system, restricting normal cell function and weakening the

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus.

In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study.

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

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

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied.

Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

immune system.

CLL progresses more slowly than other types of leukemia and most patients diagnosed with CLL have early-stage disease. Up to 50% are at risk for accelerated progression while others live for many years and

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.

Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)].

• Patients should be instructed to read the patient insert carefully.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

often do not require therapy. Several published studies and the National Comprehensive Cancer Network (NCCN) guidelines suggest that chromosomal abnormalities associated with CLL are valuable prognostic tools.

The Vysis CLL FISH Probe Kit includes a panel of five individual FISH probes intended to detect deletion of the LSI TP53, LSI ATM and LSI D13S319 probe targets and gain of the D12Z3 sequence in peripheral blood specimens from untreated patients with B-cell CLL. The assay may be used to dichotomize CLL (the 13q-, +12, or normal genotype group vs the 11q- or 17p- group) and may be used as an aid in determining disease prognosis in combination with additional biomarkers, morphology, and other clinical information. The Vysis CLL FISH Probe Kit is not intended for use in selection of therapy or in monitoring of residual disease.

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Radium-223 Chloride Gets Fast Track Designation

B

ayer HealthCare Pharmaceuticals, Inc, announced that its investigational compound radium-223 chloride, which is exclusively licensed from Algeta ASA, has been granted Fast Track designation by the FDA for the treatment of castration-resistant (hormone-refractory) prostate cancer in patients with bone metastases.

Radium-223 chloride is an investigational pharmaceutical containing an alpha-particle–emitting nuclide in development for cancer patients with bone metastases. In September 2009, Bayer signed an agreement with Algeta ASA (Oslo, Norway) for the development and commercialization of radium-223 chloride.

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ASCOPost.com | SEPTEMBER 15, 2011

PAGE 27

Best of ASCO® Psychosocial Oncology

Lifestyle Changes Can Benefit Patients with Cancer But may often be ignored by oncology providers

By Caroline Helwick

O

ncologists may successfully manage their patients with cancer by following treatment guidelines, but they come up short when it comes to prescribing simple measures to enhance their patients’ health, according to Ann Partridge, MD, MPH, of Dana-Farber Cancer Institute, Boston, who spoke on the topic at the recent Best of ASCO meeting in Miami.

“This is the softer side of oncology, and we don’t pay as much attention to it as we should, but in our practices these are the things that patients often ask us about,” she said. “Helping patients modify health-related behaviors should be viewed as an important part of our job.”

Psychosocial Problems Are an Unmet Need Psychosocial problems and their accompanying impairments are common among patients and survivors.

“Some would argue that stress is the 6th vital sign,” she said. Psychosocial distress not only takes an emotional toll, but can also reduce treatment compliance, thus [resulting in poorer outcomes] as well,” she said.

But clinicians rarely look for signs of psychosocial distress. At most, 15% or so of clinicians report using validated scales. “We care about this on paper, but studies show SEE PAGE 43 we are not routinely screening,” she said. “We need to ask the patient, ‘How are you doing with this [distress]?’—the same way we ask about smoking.”

Guidelines and recommendations already exist to help clinicians identify psychosocial distress. “We just need to generate interest among providers in adopting them,” Dr. Partridge suggested.

Nutrition, Exercise: What Patients Should Know Oncologists might have one-third fewer patients if the public adopted

a healthier lifestyle, according to the American Institute of Cancer Research and the World Cancer Research Fund.

Their analysis has shown that about one-third of cancers are preventable through lifestyle modifications of diet, physical activity, body size, and alcohol intake—not including smoking, injection drug use, and bacterial/viral infections. The percentage that are preventable rises to 70% for endometrial cancer, 69% for esophageal cancer, and almost 50% for stomach and colon cancers.

In terms of nutrition, the bulk of the evidence pertains to primary cancer prevention, though data are emerging to show benefits in survivorship and guidelines are being developed to reflect that. In fact, the health benefits of good nutrition among cancer patients have gone from being hypothetical to becoming measurable and established, according to Kimberly Robien, PhD, who discussed the topic at an ASCO educational session.

For breast cancer, at least in the Nurses Health Study population, postdiagnosis weight gain was associated with a 40% to 60% increased risk of recurrence, breast cancer mortality, and all-cause mortality.1 In the Women’s Intervention Nutrition Study (WINS), an intervention counteracted this: A lowfat diet significantly reduced not only weight but recurrence rates, especially in the estrogen-negative population.2 While a lack of beneficial effect was seen for a low-fat diet in the Women’s Healthy Eating and Living (WHEL) study, a healthful diet at baseline may have been responsible for this.3 As for exercise, at least in colorectal cancer, moderate activity has been associated with a 40% to 50% reduction in recurrence, disease-specific mortality, and all-cause mortality.4 Altogether, according to Dr. Partridge, the evidence strongly suggests that a healthy diet protects against comorbidity and is probably beneficial in preventing recurrent or

progressive disease. There are possible effects on depression, fatigue, adverse body composition changes, and functional decline.

The data for the value of exercise are stronger: Clear effects are seen on adverse changes in body composition, functional decline, and comorbidity; probable benefits are observed on recurrence/ progression and fatigue; and possible benefits are seen in depression.

Oncologists can now, therefore, emphasize to cancer survivors the value of following dietary and physical activity guidelines, Dr. Partridge said.

“The problem is that although it’s a no-brainer to recommend that people try to eat well and exercise, it’s hard for our patients to do,” she acknowledged.

“We need to figure out how to help them.”

Alcohol and Supplements Reports of a link between alcohol and breast cancer have raised patients’ concerns; drinking has also been linked to renal and head and neck cancers. The data are conflicting regarding the effect of alcohol on breast cancer recurrence: some studies show little to no effect, while others show a dose-related effect of increasing alcohol intake on increasing risk of recurrence. To further confuse matters, alcohol may be cardioprotective.

“We generally recommend one glass of wine or less per day to our patients,” she said. She does not recommend vitamin supplements, as no reliable body of data yet show a beneficial effect for their use.

Unfortunately, despite excellent recommendations, the average patient

demonstrates unhealthy lifestyle practices and behaviors, Dr. Partridge concluded, citing the following prevalence rates:

Helping patients modify healthrelated behaviors should be viewed as an important part of our job.

—Ann Partridge, MD, MPH

■■ Overweight or obese: 59%–71% ■■ Diet includes < 5 daily servings of fruits and vegetables: 52%–58% ■■ Moderate to heavy alcohol intake: 16% ■■ Sedentary lifestyle: 70% These figures only accentuate the mandate for oncologists. “Cancer incites a teachable moment for lifestyle change,” she said. “We can have a positive impact on health behaviors of survivors and family members.”

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References 1. Kroenke CH, Chen WY, Rosner B, et al: Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23:1370-1378, 2005.

2. Blackburn GL, Wang KA: Dietary fat reduction and breast cancer outcome: Results from the Women’s Intervention Nutrition Study (WINS). Am J Clin Nutr 86:878S-881S, 2007.

3. Pierce JP, Natarajan L, Caan BJ, et al: Influence of a diet very high in vegetables, fruit and fiber and low in fact on prognosis following treatment for breast cancer: The Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA 298:289-298, 2007.

4. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al: Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Clin Oncol 24:3535-3541, 2006.

For more from Best of ASCO 2011, including coverage of news and data presented in Miami and Seattle, watch future issues of The ASCO Post, including a special supplement coming soon.

Visit The ASCO Post online at ASCOPost.com.

The ASCO Post | SEPTEMBER 15, 2011

PAGE 28

Multidisciplinary Care

Integrative Oncology Modalities Supported by Varying Levels of Evidence, but More Research Needed Overall

By Ronald Piana

O

ver the past couple of decades, unregulated nonstandard oncology approaches have gained growing popularity among cancer patients. The relatively new field of integrative oncology was established to promote a more holistic and multidisciplinary approach to cancer care and to encourage scientific and evidence-based evaluation and appropriate clinical integration of complementary therapies. Nationally regarded breast cancer specialist Debu Tripathy, MD, Professor of Medicine and Clinical Leader of the Women’s Cancer Research Program, University of Southern California and Norris Comprehensive Cancer Center, spoke with The ASCO Post about the current state of integrative oncology and the importance of further research in this area.

Important Nuance Dr. Tripathy stressed that differentiating the terms complementary and alternative is essential. He explained that the formal definition of integrative medicine is using complementary interventions that are not considered part of mainstream Western medicine and combining them with standard therapy, whereas alternative medicine

Accepted Integrative Modalities Dr. Tripathy explained that there is a wide range of modalities encompassed by integrative oncology, many of which have theoretical underpinnings indicating clinical benefit. These include mind-body, meditation, acupuncture, and group therapy. “It may also extend to systems-based forms of medicine such as Chinese or Ayurvedic medicine where there is a combination of lifestyle modification or in some cases herbal or even homeopathic medicine, for which we don’t have good evidence of efficacy at this time,” he said.

These diverse approaches have different levels of evidence associated with them, Dr. Tripathy noted. “Some approaches have a reasonable amount of data from randomized trials, such as acupuncture, which has clearly been shown to improve pain control in certain situations when side effects from other modalities are clinically significant. In fact, many payers now reimburse for acupuncture,” he said, adding that acupuncture has recently shown benefits in chemotherapy-induced nausea.

Health-care professionals should be able to provide evidence-based, patient-centered advice to guide patients regarding the benefits of certain proven integrative approaches, while counseling to avoid those that might be harmful.

—Debu Tripathy, MD

is taking nonstandard approaches and using them as the primary therapy, as an alternative to evidenced-based medicine.

“The concern is that unproven therapies that are harmful might be used instead of proven treatments. However, where evidence of benefit exists, we can integrate various complementary approaches into standard care, to improve quality of life and possibly even cancerrelated outcomes. So the term integrative has more or less replaced complementary, being a more holistic definition of the approach,” said Dr. Tripathy.

Higher Stakes Dr. Tripathy cautioned that although some herbal and botanical medicines might have potential benefits, these compounds could produce rare but dangerous side effects or adverse herb-drug interactions for patients undergoing chemotherapy. “We need prospective randomized trials to evaluate these approaches in a similar fashion to how any other drug is tested. Our group has obtained investigational new drug (IND) licenses from the FDA to conduct early trials with certain

herbs that might contain a mixture of compounds that work synergistically to confer anticancer benefits,” commented Dr. Tripathy.

From Theory to Trial “If you think about it in evolutionary terms, many plants and herbs evolved symbiotically with higher-level organisms. Beneficial health effects may have evolved over time such that many components found in an herb can make the host healthier, in some cases protecting them against infection or other disease, and this in turn allows the host to spread the seeds to propagate the plant,” said Dr. Tripathy.

Many currently used drugs come from natural products. “In our experience in the laboratory, we’ve isolated the anticancer activity of certain herbs, but with certain botanicals, when you begin to fractionate different compounds from the herbal extract either by size or charge, you begin to lose the activity. However, when you reconstitute the fractions, you regain the activity—suggesting several active compounds working in synergy. Clearly in some cases you therefore need to test the whole herbal extract, but that makes it very difficult to obtain regulatory approval, “ said Dr. Tripathy.

Ongoing Trials Dr. Tripathy’s group has worked in a couple of areas. One has been looking at the antitumor effects of an herb called Ban Zhi Lian (BZL 101), which has been used for centuries in Chinese medicine for both its antiinflammatory and purported antitumor effects. “We showed in the laboratory that the compound inhibited glycolytic pathways preferentially used by tumor cells and was selective against many different cancer cell lines, including breast and pancreatic cancer, compared with normal cells,” said Dr. Tripathy.

A safety study they initiated found some gastrointestinal side effects such as bloating and gas, probably due to the insoluble herbs, so we gave them a different preparation and reduced the fiber content. “We then conducted another phase I study and actually saw some minimal responses

on serial tumor scans. In fact, some patients just came short of a formal response, and we’ve just submitted a grant to conduct a phase II trial to assess efficacy.”

They are also looking at the herb Menerba, which has a targeted mechanism of action that activates only the estrogen receptor beta pathway, and can thereby inhibit hot flashes. “Unlike estrogen-based hormone therapy, Menerba does not activate the estrogen receptor alpha pathway, known to be implicated in both breast and uterine cancer development,” remarked Dr. Tripathy.

The trial—a randomized, doubleblinded, placebo-controlled study that enrolled 217 healthy postmenopausal women at six clinical sites— provided evidence that treatment with Menerba reduced the frequency of hot flashes in healthy postmenopausal women and the drug was well tolerated. A larger phase III trial is underway.

Conclusions “Integrative oncology is very young field, but we have laboratory data that show potential. We now need well-conducted studies to prove benefits, but there are two reasons funding is difficult to obtain,” said Dr. Tripathy.

First, government grants are subject to peer review from scientists who come from a strictly traditional view, and they tend to be skeptical about nonstandard approaches. And second, because you cannot patent these compounds, funding from the private sector is equally difficult to obtain. Consequently, most of the research in this area has been limited to very small pilot studies, which may indicate safety but are just too small to prove efficacy.

But until we have data from more definitive trials of botanical agents, Dr. Tripathy said, “health-care professionals should be able to at least provide evidence-based, patientcentered advice to guide patients regarding the benefits of certain proven integrative approaches, while counseling to avoid those that might be harmful.”

■

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

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 29

OncologyWorldwide Treating Cancer in Japan: A Conversation with Kensei Tobinai, MD

By Ronald Piana

Kensei Tobinai, MD

I

n this installment of Oncology Worldwide, internationally regarded lymphoma expert and cancer survivor, Kensei Tobinai, MD, Chief, National Cancer Center Hospital, Tokyo, sheds light on the Japanese oncology experience.

Medical Education What was the medical school experience in Japan like?

When I received my medical education at Tohoku University School of Medicine, in Sendai, Japan, the educational system comprised a 6-year course consisting of an initial 2 years for general education, followed by 2 years dedicated to basic research in medicine, and the last 2 years studying clinical medicine. At the 6th grade level in medical school, I decided to proceed to internal medicine, but at that time I was still wondering what field of internal medicine I should specialize in.

When I graduated from medical school, the most interesting field for me was endocrinology, probably because I felt it to be a more logical and scientific discipline compared with the remaining fields I had to choose from at that time.

Career Choice What influenced your decision to pursue a career in oncology?

After graduating from medical school in 1976, I worked as a clinical trainee initially, and subsequent to my trainee period I served as a staff physician for 4 years in Iwaki Kyoritsu General Hospital, Iwaki, Fukushima, which is only about

50 km (~31 mi) from the Fukushima Daiichi Nuclear Power Plant (the site of the March 2011 nuclear disaster).

I attended an initial 2-year rotating education program in various fields of internal medicine, including respiratory medicine, gastroenterology, hematology, cardiology, nephrology, and endocrinology/diabetes mellitus in this general hospital.

At that time, I realized that most hospitalized patients in the first three areas listed above were those with cancer.

In the late 1970s, in the wards of internal medicine in Japanese hospitals, most patients with advancedstage cancer had very unsuccessful clinical courses, even though they received the best chemotherapy regimens available. So I felt that the most significant unmet need in medicine

The New England Journal of Medicine in 1975. However, immunoblastic lymphadenopathy was later found to be a distinct entity of peripheral T-cell lymphoma and was renamed as angioimmunoblastic T-cell lymphoma.

In addition, I had one young male patient with acute lymphoblastic leukemia, bulky mediastinal mass, and bone marrow involvement. The tumor cells in his bone marrow had an “e-rosette” formation with sheep erythrocytes, one of the representative analytic methods for immunophenotyping at the time, indicating a T‑cell derived tumor. My experiences with these two characteristic patients with T-cell malignancy in Iwaki Kyoritsu General Hospital greatly influenced my decision to specialize in hematologic malignancies, especially lymphoma.

Medical costs for cancer care, especially the high costs of new agents, are becoming a significant issue in Japan. was cancer, and I pursued a career in oncology.

Lymphoma Specialist What drew your clinical and research interests to lymphomas?

Among patients with cancer, those with hematologic malignancies were the most difficult ones to manage in the late 1970s. I encountered many patients with acute leukemia, lymphoma, and myeloma who showed miserable treatment outcomes. At that time, I experienced one rapidly deteriorating patient with skin exanthema, hepatosplenomegaly, generalized lymphadenopathy, high fever, marked polyclonal hypergammaglobulinemia, and autoimmune hemolytic anemia. The pathologist who examined the biopsy specimen suspected “immunoblastic lymphadenopathy,” which had been proposed as a new disease entity of lymphoproliferative disorders by Drs. Robert Lukes and Barbara Tindle in

At medical school, I learned lymphoma classification as a simple three-disease structure, consisting of Hodgkin disease, lymphosarcoma, and reticulum cell sarcoma. However, the actual patients with lymphoid malignancies were very heterogeneous with regard to cellular origin and clinical behavior. I felt that there remained many important unsolved issues in lymphoma research.

After the initial 4-year training in Iwaki Kyoritsu General Hospital, I moved to Tokyo and became a resident in hematology/oncology at National Cancer Center Hospital, where I began to deeply involve myself in lymphoma research. During the resident course at the National Cancer Center between 1980 and 1983, an epoch-making discovery was made in oncology research—namely, that human T-cell lymphotropic virus type I, an RNA retrovirus, was found to be a causative agent of adult T-cell leukemia-lymphoma.

Notable Mentor Was there a mentor along the way who helped shape your career?

When I received training in hematology/oncology as a resident in the National Cancer Center Hospital, Dr. Masanori Shimoyama, who was a Chief of the Hematology/Oncology Division at that time, taught me the importance of reporting the results of laboratory and clinical research with scientific manuscripts. Since then, I have made continuous efforts to scrupulously report the findings of our own research.

Nowadays, to conduct a qualified research trial on lymphoma, cooperation with other investigators is essential in view of the need for cooperation between basic and clinical researchers—both intramural and extramural cooperation—including national and international multicenter trials. The National Cancer Center, where I have worked for 28 years, is one of the most suitable institutions to conduct such cooperative investigations in oncology in Japan.

Access to Care What’s the situation in Japan concerning patient access to cancer care?

Although I am not a specialist in this field, I feel that the National Health Insurance System, which covers all people who live in Japan, is still working adequately. Of course, there are many significant problems in the current Japanese health-care system for patients with cancer, including financial deficit, paucity of medical oncologists and radiation oncologists, “drug lag” (delay in the approval of new oncologic agents compared with North America and Europe), and inadequate (but developing) status of end-of-life care for patients with cancer.

In Japan, patients can visit the clinic of the doctor of their choice to receive consultation or disease management.

This may be a preferable system for patients, but it is somewhat problematic in terms of efficiency. For instance, more than half of the patients who visit my clinic are those who want second opinions. Medical costs for cancer continued on page 30

The ASCO Post | SEPTEMBER 15, 2011

PAGE 30

Oncology Worldwide

Kensei Tobinai, MD continued from page 29

care, especially the high costs of new agents, are becoming a significant issue in Japan.

Nevertheless, basically all patients who are registered in the National Health Insurance System in Japan can receive expensive oncologic agents such as rituximab (Rituxan), imatinib mesylate, ibritumomab tiuxetan (Zevalin), and allogeneic hematopoietic stem cell transplantation.

Obstacle to Care

National Cancer Center Hospital because an annual checkup revealed the presence of early gastric cancer.

My body weight decreased approximately 10% after gastrectomy, but my marginally abnormal findings in blood sugar and blood pressure were normalized, and my current health condition is very good. So I am a

healthy 5-year cancer survivor.

Finally, I would like to thank people all over the world, including those in the field of oncology, for all the kind and generous support we received after the disaster caused by the earthquake and tsunami on March 11, 2011, and subsequent nuclear accidents on the Pacific coast of east

Japan. Although a long time will be needed for a full recovery, I believe the situation in the affected areas is gradually improving, and most areas of Japan, including Tokyo, are functioning as normally as prior to the earthquake.

■

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

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

What is the greatest challenge to the Japanese cancer care system?

Considering the tremendous deficiency issues in the financial affairs of the Japanese national and local governments, and the increasing demands of Japanese patients with cancer and their families requesting more expensive, high-quality care, including end-of-life care, financial issues are the greatest challenge for the future of the Japanese cancer care delivery system.

Select ERBITUX + RT

Closing Thoughts Any last thoughts about the future of cancer care and survivorship in Japan?

Although problems in cancer care will continue to occur, based on my own experience of more than 30 years as a clinical oncologist, future cancer care will be further refined and become more sophisticated mainly due to advances in oncology research, including the incorporation of more effective new agents and less invasive surgical interventions.

As a matter of fact, I am a cancer survivor who has enjoyed successful cancer management. In 2006, I received a partial gastrectomy in the

Contact The ASCO Post ADVERTISING

Rates, reprints, or supplements Leslie Dubin email: Leslie@harborsidepress.com Phone: 631.935.7660

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 31

Journal Spotlight

Tissue of Origin Test Evaluated in Patients with Cancer of Unknown Primary

A

ccording to results of a study published in the Journal of Molecular Biomarkers and Diagnosis,1 the recently developed Tissue of Origin Test (Pathwork Diagnostics, Inc) aids in the diagnosis of challenging cancer cases such as those that are metastatic or that have

a complex clinical history, particularly those with cancer of unknown primary.

The test is a microarray-based gene expression array for determining the similarity of a tumor specimen to 15 known tumor tissue types.

In the study, the researchers retro-

spectively performed the Tissue of Origin Test on biopsy specimens from patients with cancer of unknown primary.

Assay results were correlated with clinical and pathologic features and treatment results. The Tissue of Origin test provided predictions of the primary site in 96% of

for Increased OVERALL SURVIVAL ERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT Survival in Combination With RT*1,2 ERBITUX + RT (n=211)

vs

RT alone (n=213)

Median overall survival 49.0 months

vs

29.3 months

vs

45%

19.7

month improvement

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confidence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

patients with cancer of unknown primary. Predictions were generally consistent with clinicopathologic features.

Site-specific Therapy Cancer of unknown primary accontinued on page 32

The ASCO Post | SEPTEMBER 15, 2011

PAGE 32

Journal Spotlight

Tissue of Origin Test continued from page 31

counts for approximately 2% to 5% of all cancer diagnoses. Although several clinical subsets with specific treatment implications have been identified, the majority of patients receive “broad-spectrum,” empiric chemotherapy, which is only modestly effective, producing median

survivals of 9 to 11 months.2-4 “As treatments improve for specific cancer types, it becomes more important to identify the tissue of origin in patients with cancer of unknown primary so that site-specific therapy can be administered,” explained lead researcher John D. Hainsworth, MD, Chief Scientific Officer, Sarah Cannon

Research Institute, Nashville. “Accurate identification could allow these patients to benefit as treatments targeted for specific malignancies improve.”

Study Data In the study, the Tissue of Origin test was successfully performed in 45 tumor specimens. In 43 of 45 assays (96%), a

specific tissue of origin was predicted.

The most commonly identified tissues of origin included lung (11), pancreas (6), sarcoma (6), ovary (5), and colon (4).

Most diagnoses were compatible with the clinical features, immunohistochemical staining, and response to treatment.

The Tissue of Origin Test results were also correlated with previous cancer of

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms.

Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients — Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 33

Journal Spotlight

unknown primary test results using a molecular 10-gene reverse transcriptase polymerase chain reaction cancer of unknown primary assay designed to detect six primary cancer sites. The Tissue of Origin test provided predictions in a higher percentage of patients than did the cancer of unknown primary assay (96% vs 53%). Agreement between

the Tissue of Origin test and the cancer of unknown primary assay was relatively low, possibly related to the limited number of genes assessed by the cancer of unknown primary assay.

■

References 1. Hainsworth JD, Pillai R, Henner WD, et al: Molecular tumor profiling in

the diagnosis of patients with carcinoma of unknown primary site: Retrospective evaluation of gene microarray assay. J Mol Biomark Diagn 2:106, 2011.

2. Hainsworth JD, Erland JB, Kulman LA, et al: Carcinoma of unknown primary site: Treatment with 1-hour paclitaxel, carboplatin, and extended schedule etoposide. J Clin Oncol 15:2385-2393, 1997.

3. Greco FA, Burris HA, Litchy S, et al:

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB05808

5/11

Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network study. J Clin Oncol 20:1651-1656, 2002.

4. Culine S, Lortholary A, Voigt JJ, et al: Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: Results of a randomized phase II study. J Clin Oncol 21:3479-3482, 2003.

The ASCO Post | SEPTEMBER 15, 2011

PAGE 34

FDA Update

Crizotinib plus Companion Diagnostic Test Approved in NSCLC

O

n August 26, 2011, the FDA granted accelerated approval to Pfizer’s crizotinib (Xalkori) for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-

positive as detected by an FDA-approved test. The FDA approved the first-of-its-kind Vysis ALK BreakApart FISH Probe Kit (Abbott Molecular) concurrently with the crizotinib approval. This companion diagnostic test is designed to detect

rearrangements of the anaplastic lymphoma kinase (ALK) gene in NSCLC. About 1% to 7% of those with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically nonsmokers.

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONs None.

WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

Key Trials The approval was based on two multicenter single-arm trials, study A (N = 136 patients) and study B (N = 119 patients). Crizotinib, 250 mg, was administered orally twice daily to a total of 255 patients with locally

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 0 9 1 Dyspepsia 14 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 Alanine Transaminase, high 43 2 21 1 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages 87 17 10 1 Acneiform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 35

FDA Update

advanced or metastatic ALK-positive NSCLC. Demographic analysis from the combined data of these trials noted that the median age was 52 years, 63% of patients were white, 30% were Asian, 48% were male, and 84% had an Eastern Cooperative Oncology Group

(ECOG performance status of 0 or 1.

Fewer than 3% of patients were current smokers. Approximately 96% had adenocarcinoma, 95% had metastatic disease, and 94% had received prior systemic treatment for NSCLC. The primary endpoint of both tri-

als was objective response rate as assessed by the investigator. In study A, the objective response rate was 50% (95% CI = 42%–59%) with a median response duration of 42 weeks.

In study B, the objective response rate was 61% (95% CI = 52%–70%)

with a median response duration of 48 weeks. Complete responses were observed in 1% of patients. No differences in objective response rate by performance status, the number of prior chemotherapeutic regimens, or the percentage of cells found to have the ALK gene rearrangement were noted.

Toxicities Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 8 10 18 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old.

No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A8

ER-B0001A-03-11

Rev March 2011

The most common adverse reactions (≥ 25%) observed in both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Vision disorders included visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia. Grade 3/4 adverse reactions in at least 4% of patients included increased alanine aminotransferase and neutropenia. Crizotinib has been associated with severe, lifethreatening, or fatal treatment-related pneumonitis with a frequency of 1.6% in clinical trials. All cases occurred within 2 months after the treatment initiation.

The recommended dose and schedule for crizotinib is 250 mg orally twice daily.

Accelerated Approval Crizotinib was reviewed under the FDA’s priority review program, and was approved under the FDA’s accelerated approval program.

“The approval of [crizotinib] with a specific test allows the selection of patients who are more likely to respond to the drug,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “Targeted therapies such as [crizotinib] are important options for treating patients with this disease and may ultimately result in fewer side effects.”

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Coming Next Month See next month’s issue of The ASCO Post for more FDA Updates along with comprehensive information on novel agents in metastatic melanoma, including how to use ipilimumab (Yervoy) and vemurafenib (Zelboraf ) in the clinic, and how to manage related toxicities.

The ASCO Post | SEPTEMBER 15, 2011

PAGE 36

In the News Radiation Oncology

Many Women Treated for High-risk Breast Cancer Do Not Receive Recommended Postmastectomy Radiation Therapy

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

D

espite major studies showing that postmastectomy radiation therapy improves survival for women with high-risk breast cancer and evidence-based guidelines supporting the use of postmastectomy radiotherapy, 45% of these patients do not receive such treatment, according to an analysis of data from more than 32,000 patients with breast cancer.

Benjamin D. Smith, MD

“There’s a clear gap between the scientific evidence demonstrating [postmastectomy radiotherapy’s] benefits and the proper use of the therapy in everyday clinical practice,” stated Benjamin D. Smith, MD, principal investigator of the study, which was published recently in the journal Cancer.1 Dr. Smith is Assistant Professor, Department of Radiation Oncology, at The University of Texas MD Anderson Cancer Center in Houston, and Vice Chairman of the American Society for Radiation Oncology clinical guidelines committee.

The study cites three landmark randomized controlled trials demonstrating that postmastectomy radiotherapy “decreased locoregional recurrence and improved survival among patients with high-risk breast cancer,” defined as stage T3–T4 and/or N2–N3.2-4 Previous research had shown that publication of these studies increased postmastectomy radiotherapy in these patients, and the recent study was intended to determine whether the use of

postmastectomy radiotherapy has increased in response to evidence-based guidelines. The researchers looked at data from 38,322 women aged ≥ 66 who underwent invasive breast cancer between 1992 and 2005. The percentage of patients with high-risk breast cancer who received postmastectomy radiotherapy increased from 36.5% to 57.7% between 1996 and 1998, when the landmark clinical trials were published. “However no further increase in [postmastectomy radiotherapy] use was observed between 1999 and 2005 despite publication of multiple guidelines endorsing its use; during this period, only 54.8% (2,729 of 4,978) of high-risk patients received [postmastectomy radiotherapy],” the authors reported.

The investigators used data for women 66 and older because more complete data—combined Surveillance, Epidemiology and End Results (SEER)-Medicare data—exists for these women, Dr. Smith told The ASCO Post. “With the SEER-Medicare data, you can look at claims for receipt of radiotherapy, so you can be relatively confident that you know who received radiation,” Dr, Smith said, “but the chief limitation of this data set is that it only allows you to look at women who are Medicare beneficiaries,” he said. “I would love to know what utilization rates are for women in their 30s, 40s, and 50s, but the only population-based data available with which to do that is the SEER data. SEER data systemically underreports use of radiation, so I don’t think you can really do this study with just the SEER data.”

Reasons for Nonadherence The authors offered several explanations for lack of adherence to evidence-based guidelines published by ASCO, NCI, and the National Comprehensive Cancer Network. The possible reasons include inadequate access to radiation resources, patient preference not to undergo radiation, passive rather than active dissemination of the guidelines, and gray areas where the guidelines may be open to interpretation.

“A specific subgroup within the study had larger tumors that were node-negative, T3N0, and in those

Expect Questions from Your Patients

W

omen who have already undergone mastectomy and chemotherapy may question why additional breast cancer treatment is needed.

Benjamin D. Smith, MD, of MD Anderson Cancer Center in Houston said that he frequently has patients referred to him who initially express their preference to avoid radiation after mastectomy.

“Ultimately if a patient makes that decision and is appropriately counseled and educated, I certainly respect that,” Dr. Smith said, “but part of my role as a radiation oncologist is to counsel patients so that they understand the risks and benefits of radiotherapy. I find that the vast majority of rational people, if they are appropriately counseled, will choose to receive radiotherapy.

Patients with stage III The literature from randomized breast cancer derive clinical trials is quite strong, convincing, and corroborated by our very meaningful own institutional experience, which improvements in is that patients with stage III breast cancer derive very meaningful imlocoregional disease provements in locoregional disease control and overall control and overall survival from receiving radiotherapy. That improvesurvival from receiving ment is on the same order of magniradiotherapy. tude as the benefit they receive from chemotherapy or endocrine therapy. So most women aren’t going to undergo a mastectomy, take endocrine therapy, and receive chemotherapy and not finish the course of recommended therapy once they understand what is at stake.”

Good Teamwork “Reviewing the literature with patients is very helpful,” Dr. Smith said. Also important is establishing and maintaining “good relationships with the other physicians in the multidisciplinary care team,” he continued. For patients going from chemotherapy to radiation therapy and being transferred from the care of one physician to another, having “a good system and a good team working together gives your patients a lot of assurance.”

At MD Anderson, weekly tumor boards and multidisciplinary clinics provide an opportunity for surgeons, medical oncologists, radiation oncologists, and others to discuss “patients with challenging or unusual problems, and to educate one another about new things going on in our fields,” Dr. Smith said. “At the multidisciplinary clinics, we work together to develop a treatment plan for patients… I think we are relatively well-versed in one another’s subspecialties and know when we need to send patients back and forth to one another.”

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patients there is some controversy about when radiotherapy is recommended,” Dr. Smith explained. “Some literature suggests that in patients who are just barely T3, with 5.5- or 6-cm tumors, if cancer has not spread to any lymph nodes and if there are no adverse prognostic factors, radiation is not always needed. But for the vast majority of patients with T3 breast cancer, radiation is recommended.

If you had a smaller tumor, but had four or more involved lymph nodes, we would definitely recommend ra-

diotherapy, and all the guidelines would concur with that. Or if you had a bigger tumor, but just one positive lymph node, again we would recommend radiotherapy, and all the guidelines would agree with that.”

Postmastectomy radiotherapy may be appropriately contraindicated in certain patients. “Radiation would be contraindicated if a patient had received prior radiotherapy for lymphoma or for a prior breast cancer, and then had a new breast cancer and a mastectomy, but that area of the chest

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 37

In the News

wall and lymph nodes had previously received radiotherapy. That would be the main absolute contraindication,” Dr. Smith explained, noting that such patients were excluded from the study.

Other relative contraindications, he said, include serious collagen vascular diseases like scleroderma or active lupus, and perhaps severe pulmonary disease.

Increasing Compliance The authors offered specific strategies to increase compliance with postmastectomy radiotherapy guidelines.

“Some of the suggestions we offered were attempts to include failsafe mechanisms in patient record systems,” Dr. Smith said. “It might be a care pathway or a checklist, or if you are using an electronic medical record, when you put the stage in for the patients, then a flag pops up and asks if you remembered to refer your patient for radiation therapy.”

Other suggestions include monitoring guideline adherence through internal audits and adding postmastectomy radiotherapy as an additional quality measure to the American College of Surgeons Commission on Cancer or the National Quality Forum. “Thousands of hospitals across the county participate in the Ameri-

can College of Surgeons Commission on Cancer. Hospitals want to be accredited by this entity because they feel it reflects well on the quality of care that they offer,” Dr. Smith noted.

“They can use that accreditation as they seek to maintain and establish their market share and the viability of their hospitals.”

Payers could use financial incentives to influence adoption of guidelines. “Pay for performance hasn’t really disseminated widely. It hasn’t permeated the health-care climate now, but there are lots of very smart people interested in figuring out how they can tweak the financial incentives for physicians to help promote quality of care,” Dr. Smith said. “Some sort of pay for performance will continue to trickle into the health-care system over the next decade, and we would advocate that if it trickles into breast cancer care, this would be a good treatment to incentivize, because it is known to be effective and it appears to be underused currently.”

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Disclosure: Dr. Smith reported that his group has received research funding from Varian Medical Systems.

References 1. Shirvani SM, Pan I-Wen, Buchholz TA, et al: Impact of evidence-based clini-

Higher Postmastectomy Radiotherapy Rates at NCCN Institutions

W

hile the investigators reported that overall only 54.8% of patients with high-risk breast cancer received postmastectomy radiation therapy, they also cited a report that 83.6% of high-risk patients treated at National Comprehensive Cancer Network (NCCN) institutions received such treatment. Benjamin Smith, MD, said that one reason for the higher postmastectomy radiotherapy rates is the amount of subspecialization at most NCCN cancer centers, including MD Anderson. “All I treat is breast cancer here. So that affords us the luxury of getting to be very good at treating one thing and to know the literature on that one disease site very well,” he said.

“I think people who come to NCCN institutions are usually seeking high quality of care. They tend to be a little bit more invested in their care than someone who may not have the resources to know the advantages of an NCCN institution,” he continued. “If a patient has managed to come here, that means she has the ability to navigate through the health-care system, get a second referral, and get into a place like MD Anderson. She has already passed through a few hoops, making it more likely that she will receive recommended treatment.”

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cal guidelines on the adoption of postmastectomy radiation in older women. Cancer.

June 27, 2011 (early release online).

2. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in highrisk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949955, 1997.

3. Ragaz J, Jackson SM, Le N, et al:

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956962, 1997.

4. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:16411648, 1999.

Genitourinary Cancer

Long-term Data Show Benefit of Degarelix Beyond 3 Years in Advanced Hormone-dependent Prostate Cancer PSA suppression and the effects on PSA progression free survival remained consistent over the long term.

D

egarelix (Firmagon) is effective and well tolerated beyond 3 years in patients with advanced prostate cancer, according to a recent study published in The Journal of Urology.1 The new study (CS21A) extends the conclusions of the pivotal phase III study (CS21) in which the risk of prostate-specific antigen

(PSA) failure or death was significantly lower in patients on degarelix compared to leuprolide up to 1 year.

The extension study has now shown that for patients who remained on degarelix, PSA suppression and the effects on PSA progression free survival (PFS) remained consistent over the long term (42 months).

Being able to delay castration resistance for as long as possible is an important outcome for any firstline therapy.

– E. David Crawford, MD

“Being able to delay castration resistance for as long as possible is an important outcome for any first-line therapy,” said study author E. David Crawford, MD, Head, Section of Urologic Oncology and Professor of Urologic and Radiation Oncology, University of Colorado Denver. “The data from the phase III extension study demonstrate that [degarelix] provided prostate cancer patients with fast and effective testosterone and PSA control over the long term, which may in turn delay castration resistance.

In addition, the study looked at patients who crossed over from leuprolide to degarelix after 1 year. At a median follow up of 27.5 months the data showed that the risk of PSA PFS had decreased (P = .003).1 CS21A was designed to collect ex-

tended safety and tolerability data on degarelix. Following the close of the phase III trial, all patients were SEE PAGE 43 offered the option to receive degarelix as part of the extension study. All patients who had received degarelix continued with their treatment and those who had previously been treated with leuprolide were switched to receive degarelix.

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Reference 1. Crawford ED, Tombal B, Miller K, et al: A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: Comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 186(3):889-897, 2011.

ASCO MEMBERS ONLY Early Registration and Housing for the 2012 ASCO Annual Meeting Opens in October, 2011 ASCO members have an exclusive advance window to secure hotel reservations and their first-choice of ticketed sessions for the 2012 Annual Meeting, to be held June 1-5 in Chicago.

Visit www.chicago2012.asco.org during the last week in October to make your hotel reservations, and register for the Meeting. Hotel reservations may be made without registering for the Meeting, but both processes are linked for your convenience.

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Collaborating to Conquer Cancer

ASCOPost.com | SEPTEMBER 15, 2011

PAGE 39

In the Literature

Emerging Clinical Data on Cancer Management THYROID CANCER Wide Variation in Use of Radioactive Iodine for Thyroid Cancer The proportion of patients with well-differentiated thyroid cancer who received radioactive iodine following total thyroidectomy increased significantly since 1990, and there is wide variation in the use of adjuvant radioactive iodine, according to a study in the Journal of the American Medical Association. Patients and tumor characteristics accounted for 21.1% of the variation and hospital type, and case volume accounted for 17.1%. “After adjusting for available patient, tumor, and hospital characteristics, 29.1% of the variance was attributable to unexplained hospital characteristics,” investigators from the University of Michigan reported.

The investigators analyzed data from a cohort of 189,219 patients with well-differentiated thyroid cancer treated at 981 hospitals associated with the U.S. National Cancer Database. Between 1990 and 2008, the proportion of patients receiving radioactive iodine after total thyroidectomy increased from 40.4% to 56% (P < .001). For tumors from 1.1 to > 4 cm, the percentage of patients treated with radioactive iodine increased from 55% to 67%. The proportion of smaller tumors treated with radioactive iodine “was lower but has also increased steadily over time,” the authors stated.

Multilevel analysis for patients treated between 2004 and 2008 showed “younger age and absence of comorbidity were associated with a small but significantly greater likelihood of receiving radioactive iodine after total thyroidectomy.” Female sex, African-American race, and lack of private or government insurance were associated with significantly less likelihood of receiving radioactive iodine.

The researchers also found a statistically significant difference in radioactive iodine use between American Joint Committee on Cancer stages I and IV, but not for stage II or III vs stage IV. Analyses of hospital case volume showed that radioactive iodine was more likely to be used as the volume of thyroid cancer cases treated increased.

Interpreting the Results “Even with the limitations inherent in a large database, the results of this

study have implications for patients, physicians, and payers,” the authors wrote. “There is a clear role for adjuvant therapy with radioactive iodine in iodine-avid, advanced-stage, well-differentiated thyroid cancer; however, there is unclear benefit to radioactive iodine use in low-risk disease because patients with low-risk disease have an excellent prognosis regardless of intervention.”

In addition to cost savings associated with not using radioactive iodine for low-risk thyroid cancer, limiting the use of radioactive iodine would decrease the risk of adverse effects. “Not only are there transient adverse effects on quality of life with the hypothyroidism typically required before radioactive iodine treatment, but radioactive iodine itself has long-term health risks,” they stated.

“In the interests of curbing the increasing health care costs and preventing both overtreatment and undertreatment of disease,” the authors concluded, “indications for radioactive iodine should be clearly defined and disease severity should become the primary driver of radioactive iodine use.”

Haymart, et al: JAMA 306:721-728, 2011.

PROSTATE CANCER Androgen Deprivation plus Radiotherapy Increases Survival in Men with Localized Prostate Cancer Adding short-term androgendeprivation therapy to radiotherapy “conferred a modest but significant increase in the 10-year rate of overall survival, from 57% to 62%,” in men with localized prostate cancer enrolled in Radiation Therapy Oncology Group (RTOG) trial 94-08. “This increase was accompanied by a significant reduction in 10-year disease-specific mortality, from 8% to 4%, as well as reductions in the secondary endpoints of biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years, the RTOG investigators reported in The New England Journal of Medicine.

The study involved 1,979 men with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostatespecific antigen (PSA) level ≤ 20 ng/ mL who were randomly assigned to radiotherapy alone (992 patients) or radiotherapy with 4 months of to-

tal androgen suppression starting 2 months before radiotherapy (987 patients). Androgen-deprivation therapy consisted of flutamide at 250 mg orally three times a day and either monthly subcutaneous goserelin (Zoladex) at 3.6 mg or intramuscular leuprolide at 7.5 mg for 4 months. Trial participants had not received any previous chemotherapy, radiation or hormonal therapy, cryosurgery, or definitive treatment for prostate cancer.

Greatest Benefit The RTOG investigators found that “the greatest clinical benefit” was to men in the intermediate-risk subgroup.” Men in this group had a baseline Gleason score of 7 or ≤ 6 with a PSA level > 10 and ≤ 20 ng/mL or clinical stage T2b.

“The efficacy gains were achieved with minimal temporary acute hepatic toxic effects and some decreased erectile function at 1 year, but with no increased risk of death from intercurrent disease, serious cardiovascular toxic effects, or acute or long-term gastrointestinal or genitourinary complications of radiotherapy,” the authors reported.

“The rate of erectile dysfunction observed in this study is similar to that reported in previous studies that involved the use of similar doses of radiotherapy.”

The authors noted that newer radiotherapy techniques permit “safer delivery of higher does of radiation than was possible when this study was conducted” and are associated with improved efficacy. A new study (RTOG 081-15) is looking at adding the value of short-term androgen-deprivation therapy in men with intermediate-risk cancers treated with these current irradiation methods.

Jones CU, et al: N Engl J Med 365:107118, 2011.

BREAST CANCER Comorbidities Can Be as Important as Stage in Predicting Breast Cancer Survival in Older Patients Comorbidities can be as important as stage in predicting survival among older women with breast cancer, according to a study in the Journal of the National Cancer Institute. While previous studies have combined comorbidities into a summary measure or comorbidity index, the current study assessed the individual associations

between 13 selected comorbidities and overall survival among patients with breast cancer aged 66 or older, using the Surveillance, Epidemiology, and End Results–Medicare database.

“Each of the 13 comorbid conditions examined was associated with decreased overall survival and increased mortality,” the authors reported. Comorbidities with the highest fully adjusted hazard ratios were liver disease (HR of death = 2.32), chronic renal failure (HR of death = 2.20), dementia (HR of death = 1.96), and congestive heart failure (HR of death = 1.70). Other comorbidities studied were previous cancer, myocardial infarction, peripheral vascular disease, cerebrovascular SEE PAGE 43 disease, chronic obstructive pulmonary disease, paralysis, diabetes, stomach ulcer, and rheumatoid arthritis. Among the 60,034 patients identified, 37,306 (58%) had none of these comorbid conditions, 28% had one, 8.8% had two, and 4.9% had three or more. Overall survival was estimated using age-specific KaplanMeier curves.

Key Findings “Across all of the comorbid conditions, patients aged 66 to 74 years with stage I tumors who had these conditions had survival curves similar to patients with stage II tumors who had no comorbidities. Similar trends were observed in the Kaplan-Meier survival curves for patients aged 75 to 84 years and 85 years or older.” the authors stated.

The most common survival pattern (seen in association with myocardial infarction, peripheral vascular disease, stroke, chronic obstructive pulmonary disease, and diabetes) for patients with earlier-stage cancers and comorbidities was to have survival outcomes shifted about one stage higher compared with patients without comorbidities. “For more severe comorbidities (eg, dementia, chronic renal failure, and liver disease), the survival outcomes of patients with stage I and stage II tumors who had the specific comorbid condition resembled that of patients with stage III and IV tumors who did not have the specific conditions,” the investigators noted.

Patnaik JL, et al: J Natl Cancer Inst 103:1101-1111, 2011. continued on page 40

The ASCO Post | SEPTEMBER 15, 2011

PAGE 40

In the Literature

Emerging Clinical Data continued from page 39

Patients with HER2-positive Breast Cancer Benefit from Trastuzumab plus Chemotherapy Adding trastuzumab (Herceptin) to standard anthracycline/taxane– based chemotherapy continued to

produce disease-free and overall survival benefits in patients with HER2positive breast cancer enrolled in the North Central Cancer Treatment Group (NCCTG) N9831 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials.

“These trials were designed simi-

larly, enabling a joint analysis of the two studies,” wrote the authors of the latest analysis, published in the Journal of Clinical Oncology. At 3.9 years of median follow-up, the new analysis confirmed results from two interim analyses showing reductions in disease-free survival events, defined as local, regional, or distant recurrence of breast

cancer; a contralateral breast cancer; a second primary cancer; or death as a result of any cause.

The first analysis, with a median follow-up of 2 years, found that the relative reduction in disease-free survival event rate was 52% (P < .001).

The second interim analysis, with a median follow-up of 2.9 years, demonstrated a continued reduction in the disease-free survival event rate and a statistically significant 35% reduction in mortality (P < .001).

Combined Analysis “With the additional follow-up, the relative reduction in disease-free survival event rate was 48% (P < .001), and the relative reduction in death rate was 39% (P < .001),” the authors wrote. “Thus, our data demonstrate long-term continued benefit with trastuzumab administered concurrently with chemotherapy (anthracycline/cyclophosphamide followed by paclitaxel plus trastuzumab, with 1 year of trastuzumab treatment). Absolute differences in disease-free survival increased by number of nodes; it was most pronounced for patients with 10 involved nodes, who had an unprecedented 27% absolute improvement.”

The N9831 and B-31 trials “assessed the efficacy and safety of adding 52 weeks of trastuzumab to standard anthracycline/taxane-based chemotherapy (doxorubicin plus cyclophosphamide [AC] followed by paclitaxel),” the authors explained.

The latest findings are based on all 4,045 patients enrolled in these treatment arms before enrollment ended. The women had to be older than 18 years with primary, operable, and histologically confirmed nodepositive (both trials) or high-risk node-negative invasive breast cancer (N9831 only), with no evidence of metastases, and strongly HER2-positive tumors.

“A number of adjuvant treatment combinations of chemotherapy with trastuzumab are now available, allowing physicians to select a regimen they consider most appropriate for patients with early-stage invasive HER2-positive breast cancer. Longer-term follow-up and identification of predictive biomarkers will provide further insight into optimal trastuzumab adjuvant therapies,” the authors concluded.

What role may MUC1 play in NSCLC

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

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Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

EMD Serono Oncology | Combination is key™

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Perez EA, et al: J Clin Oncol. July 18, 2011 (early release online).

003296_emddsa_dsa_tea_fa2.indd 1

7/28/11 4:40 PM

ASCOPost.com | SEPTEMBER 15, 2011

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Letters to the Editor

BREAST CANCER Unexpected Results May Push Breast Cancer Research toward More Productive Approaches Two recent articles on breast cancer prognostic factors in the Journal of Clinical Oncology “do not jibe with accepted—and profoundly influential— notions of malignant progression,” according to an editorial accompanying the articles in the Journal of Clinical Oncology. One of the articles found that very small tumors with four or more positive lymph nodes may predict for higher breast cancer–specific mortality than larger tumors, suggesting, according to the investigators, “that very small tumor size in the presence of extensive nodal disease may be a surrogate for inherent biologic aggressiveness.” The other article concluded that once there is evidence of lymph node metastasis, the number of positive lymph nodes may not affect prognosis in patients with triple-negative breast cancer.

SEER Data The study related to tumor size was based on findings from 50,949 female patients identified from SEER registry data and diagnosed between 1990 and 2002 with nonmetastatic T1/T2 invasive breast cancer treated with surgery and axillary lymph node dissection. Tumor size was classified according to the AJCC staging system.

Among patients with four or more positive lymph nodes, those with T1b tumors experienced significantly lower breast cancer–specific mortality relative to patients with T1a tumors (P = .02), the authors reported. Among those with one to three positive lymph nodes, they found no significant differ-

ence in breast cancer–specific mortality between patients with T1a tumors and those with T1b or T1c tumors.

“Although the conventional view of cancer spread is that cancer gains metastatic ability through an accumulation of mutations as they grow to large size, we hypothesize that very small cancers with extensive nodal spread represent a subset of cancers where the invasion/ metastases pathways are more prominent than those of ‘self-seeding to the primary tumor,’” they wrote.

Triple-negative Population The other study reviewed 1,711 patients with triple-negative breast cancer diagnosed between 1980 and 2009 at The University of Texas MD Anderson Cancer Center in Houston. The 5-year overall survival rates were 80% for nodenegative patients, 65% patients with 1 to 3 positive lymph nodes (N1), 48% for patients with 4 to 9 positive lymph nodes (N2), and 44% patients with 10 positive or more lymph nodes (N3; P < .0001). The 5-year relapse-free survival rates were 67% for N0, 52% for N1, 36% for N2, and 33% for N3 (P < .0001).

“Pairwise comparison by nodal status showed that when comparing N0 with node-positive disease, there was a significant difference in [overall and relapse-free survival] (P < .001 for all comparisons). However, when comparing N1 with N2 and N3 disease regardless of tumor size, there were no significant differences in [overall or relapse-free survival],” the investigators reported.

Clinical Enigmas “Simple anatomic reasoning— which has led to many advances in clinical oncology but also the clinical enigmas described above—may not be the

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Pathways Reconsidered: Let’s Not Stop ‘Thinking Outside the Box’

I

read “Are Clinical Pathways Inevitable in Oncology’s Future?” (The ASCO Post, July 15, 2011) including Lesli Lord’s interview with great interest and agree with most everything said in the article. However, I do want to make one comment: There is no specialty for which the 80/20 rule applies more than it does in oncology— that is, pathway recommendations may work for the majority of patients, but perhaps 20% of patients will be best served by using therapy that is divergent from these accepted pathways.

Our first and foremost obligation is to provide the best quality care for our patients at a reasonable cost.

Pathways and standards of care are useful and will reduce cost eventually while likely improving the quality of care. However, I have been in practice for close to 30 years and have learned the importance of “thinking outside most productive way forward in understanding the clinical behavior of cancers and hence prognostication,” the editorialists commented. “Elucidating the molecular mechanisms that underlie the biology of individual cancers would seem to be a more useful focus of our attention. Fortunately for us and for our patients, both technical and conceptual

the box.” I have had major successes with drugs that were not considered to be the standard of care for patients who I thought were appropriate candidates for such treatment.

I understand that reimbursement is a major issue in the current economic climate. I also concede that pathway development is ongoing, evolving, and will generally be a good thing. Nevertheless, I would like to see those of us who attempt to advocate for patients and think outside the box be given some recourse to treat our patients discordant with pathways on occasion, and when and if the physician feels strongly about the need to treat a patient differently.

As always, our first and foremost obligation is to provide the best quality care for our patients at a reasonable cost; hopefully, we won’t lose sight of the first concept while concentrating on the second. After all, if all we needed were pathways to decide on clinical treatments, we might as well just slip them into a computer with the patient’s record and go fishing.

—Stephen C. Fox, MD, FACP Paoli, Pennsylvania

■

improvements are now available and are resulting in headway. These, coupled with insightful clinical observations… herald a future of greater understanding and resulting clinical progress.”

■

Comen EA, et al: J Clin Oncol 292:6102612, 2011; Wo JA, et al: J Clin Oncol 292: 2619-2627, 2011; Hernandez-Aya LF, et al: J Clin Oncol 292:2628-2634, 2011.

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PAGE 43

Patient’s Corner

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

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Position your device in front of the code so that it fills about half your screen.

The code will scan automatically.

Keeping a Positive Attitude

Years of addiction recovery helped me get through my cancer diagnosis.

By Rich Longtin, as told to Jo Cavallo

I

’ve been in alcohol and drug recovery for 20 years, and my wife of nearly 50 years, Arlene, and I have been through a lot together during that time. So 2 years ago, when my doctor told us that I had stage III prostate cancer and a Gleason score of 8, we both looked at him and asked if we could still go on our planned vacation to Hawaii. That’s been our attitude through this whole ordeal—not that there haven’t been some scary moments along the way.

If the scan is successful, you will be rerouted to the targeted link.

lide to shrink the tumor and immediately developed menopausal-like symptoms, including severe hot flashes, which were so uncomfortable I had to take a 3-month medical leave from my sales position at a beach resort near my home in Santa Cruz, California. The hormone therapy was followed by 5 weeks of daily radiation therapy, which left me weak and fatigued. But by then, my oncologist said to me, “Rich, you’re not going to die,” and that was all I needed to hear. That’s when I really started to relax.

Rejecting Defeat

When a person gets a cancer diagnosis, the tendency is to immediately think it’s a death warrant.

— ­ Rich Longtin

Taking Control My years as a recovering addict taught me the power of taking control of my life. After my diagnosis, I searched the Internet for a month, looking for information about my cancer and its standard treatment. I didn’t want to feel afraid of my diagnosis and thought educating myself about the disease was the best way to tamp down that fear and figure out how to fight this enemy. I quickly discovered, however, that there are many unscrupulous people out there who are looking to sell you a cancer “cure” if you have the money to pay for it. The thought was enticing at first, but I quickly turned to the standard of care for my cancer.

Still, I had to go through several oncologists before I found the one I was most comfortable with.

I was given injections of leupro© Peter C. Vey/The New Yorker Collection/www.cartoonbank.com

I think that when a person gets a cancer diagnosis, the tendency is to immediately think it’s a death warrant.

I didn’t necessarily think that because of my background in recovery—I’ve seen that miracles happen every day.

But a lot of guys don’t have that experience, and they become very negative.

You have to keep a positive attitude.

That’s why it’s so important for doctors to explain the prognosis right away and what the patient can expect as he goes through treatment.

A cancer patient needs to have complete control of his thought processes and cannot accept defeat. Prior to getting cancer I was in excellent shape, so after my diagnosis, to get through the treatment, I went on a lot of walks to keep up my physical stamina and practiced meditation to build up my mental stamina. While I was getting radiation therapy, I would visualize the cancer cells with little T-shirts (with a big C on the front) and would imagine the radiation beam systematically killing those cells. I also used meditation to build up my immune system, to fight the cancer and overcome the treatment side effects.

After my first dose of hormone therapy, Arlene and I took that Hawaiian vacation. Now, 2 years later, I’m cancer-free and back to work, and we’re planning our next vacation.

■

Rich Longtin, 70, is a sales associate at the Seascape Beach Resort on Monterey Bay in Aptos, California.

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6 They may provide higher tumor selectivity, enhancing the cell-killing potential of monoclonal antibodies and improving tolerability.2,7,10

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852. 10. Ducry L, Stump B. Antibody窶電rug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.

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