October 2014 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • October 2014 • Vol. 9, No. 10

INSIDE CURRENT PRACTICE New pathway paving way for first U.S. biosimilar ......... 5 HEMATOLOGIC DISEASE Jane Winter, MD: How I manage advanced Hodgkin lymphoma, Part 1 .................. 10 SOLID TUMORS Report from ESMO: Afatinib tops erlotinib for PFS as second-line therapy for squamous cell lung cancer.......................... 15

n the past three years, six drugs have been approved for melanoma, including immunotherapies, BRAF inhibitors and a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor (Table 1, page 13). Programmed death receptor-1 (PD-1) inhibitors are the newest agents to jump into the mix, with the recent FDA approval of pembrolizumab, which was granted an indication for patients who do not respond to ipilimumab or a BRAF inhibitor. Approval of another PD-1 inhibitor, nivolumab, is thought to be just around the corner. see MELANOMA, page 13

by the

IMAGES in ONCOLOGY

PD-1 Blocker Class Will Shake Up Melanoma Treatment

Breast cancer cells. For strategies to streamline breast cancer care, see story on page 19.

numbers

Trial participation rates low for late-stage lung and CRC patients See story on page 7.

More Donor Grafts Means Transplants Can Play Larger Role

EDITORIAL BOARD COMMENTARY

For Optimal Cancer Care, Consider the Nontraditional

Experts encourage early HLA matching to maximize success 74.3%

25.7%

7.6% Did not discuss clinical trial Discussed clinical trial Participated in clinical trial

ematopoietic cell transplantation (HCT) should be considered for essentially every patient with a hematologic malignancy, according to a large and growing body of data collected by the National Marrow Donor Program (NMDP). According to those leading the NMDP, work-up for a possible HCT should begin at the earliest point in care. “The time to think of transplant and to conduct HLA typing is at the time of diagnosis,” according to Dennis Confer, MD, the chief medical officer of the NMDP, in Minneapolis. Routine workup in blood cancers is recommended see DONOR GRAFTS, S page 8

Psychosocial support and other such factors increasingly found to affect cancer outcomes

n the early days of the modern oncologic era, essentially the sole focus of clinical investigation was on favorably impacting overall survival by the effective surgical removal of the cancer, killing the malignancy with radiation, and/or destroying what could not be eliminated locally or regionally by delivering cytotoxic antineoplastic therapy (or, in certain cases, hormone-based treatments). Over the years, the concept of multimodality treatments has evolved and they have become the Maurie standard of care in many settings, both improving survival and reducing Markman, MD the unwanted side effects of specific treatments (eg, limb-sparing surgery with external beam radiation for extremity sarcomas). Additionally, cancer researchers have an ever-increasing awareness of the negative effect on quality of life of both the short-term (eg, emesis, mucositis, diarrhea, etc) see NONTRADITIONAL, page 4

Implementation of Immunotherapy in the Management of Melanoma The Society for Immunotherapy of Cancer Consensus Statement See insert after page 20.

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This international symposium aims to achieve a balance of clinical, translational, and basic research, providing a forum for interaction, communication, and education for a broad spectrum of researchers, health professionals, and those with a special interest in breast cancer.

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CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD, PhD University of California San Diego, CA

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Oncology Nursing

Hematologic Malignancies Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Texas, MD Anderson Cancer Center Houston, TX

University of Alabama Birmingham, AL

Pharmacy Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Mayo Clinic Rochester, MN

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Mitchell Cancer Institute Mobile, AL The Pritchard Group, Rockville, MD

Matt Brow

University of Colorado Cancer Center Denver, CO

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Genitourinary y Cancer Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Sara S. Kim, PharmD

Richard Stone, MD

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Policy and Management

Cindy O’Bryant, PharmD

Edward Chu, MD University of Pittsburgh Cancer Institute Pittsburgh, PA

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

Steven Vogl, MD

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists providing the best possible care for their patients.

Medical Oncologist New York, NY

Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings, such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members also are consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc.

Lung g and Head and Neck Cancers Edward S. Kim, MD

Steven D. Passik, PhD

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Lung g Cancer,, Emesis Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. How I Manage articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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EDITORIAL BOARD COMMENTARY

NONTRADITIONAL continued from page 1

and longer-term (eg, peripheral neuropathy, congestive heart failure) side effects of our therapeutic armamentarium. Avoiding or minimizing these toxicities has become an important component of both cancer care and research, made all the more important by the recognition that in many situations, advanced, metastatic, or recurrent cancers are very serious, but more chronic, conditions that need to be effectively managed in time spans measured in years rather than only weeks or months. The importance of age and relevant comorbidities (eg, heart disease, medication-dependent diabetes, etc) in cancer management paradigms also has generated increased interest in the cancer research community, including the recognition that elderly patients and individuals with serious comorbid conditions often are excluded from drug registration trials. Unfortunately, this makes it quite difficult to know how to optimally employ a given strategy in a patient over the age of 70 or 75 years or one suffering from one of these common illnesses. Less discussed, until relatively recently, is the influence of behavioral factors, and psychosocial, emotional, or family support in optimizing clinical outcomes. The

powerful influence of these factors is evident in multiple health-related domains. For example, a study examined the effect of the death of a partner on the incidence of acute cardiovascular episodes within a geographically based population (United Kingdom primary care database).1 The investigators found a doubling of such sudden illnesses (fatal or non-fatal myocardial infarction or stroke) among those who had experienced the death of a partner within the past 30 days compared with matched individuals within the population who did not experience this lifechanging event. In the cancer domain, a populationbased study looking at the influence of partner support on cancer outcomes provided provocative insight into the effect of this factor on survival.2 Investigators examined publicly reported data from the SEER (Surveillance, Epidemiology, and End Results) program involving more than 1 million patients diagnosed with a number of different cancers from 2004 through 2008, and they found that married cancer patients experienced a lower risk for cancer-related death (hazard ratio, 0.80; P<0.001) than their unmarried counterparts.2 This finding also was evident for the individual tumor types included in the analysis. Of interest, in this population-based analysis, men were found to benefit from the status of being married more

than women ((P<0.001). Finally, and perhaps most provocatively, the investigators noted that for certain cancers, the survival benefits associated with being married were greater than the observed improvement associated with cytotoxic antineoplastic drug administration. These data emphasize the major clinical relevance of the psychological, emotional, and physical support (eg, getting a patient to scheduled appointments for treatment) provided by a spouse, a significant other, or close family members. In addition, the importance of considering strategies to optimize the influence of such support cannot be overstated. The general topic of the nocebo effect, the nonspecific impact of negative behavioral factors on clinical outcomes, also has gained increased prominence in the medical literature.3 The potential for a “positive attitude” toward a medical intervention to enhance the opportunity for a favorable result has been demonstrated in a number of settings. The potential role of the entire health care or oncology team in this effort, particularly in avoiding an excessive focus on the negative aspects of a given situation, cannot be overstated. As we understand more about the effects of these nontraditional clinical factors on outcomes, it is hoped that oncologists will be open to new and novel ideas designed to assist their

Maurie Markman, MD President Medicine and Science Cancer Treatment Centers of America Philadelphia, Pennsylvania

patients in achieving and maintaining both a positive attitude and a personally involved approach to the management of their health.

References 1. Carey IM, Shah SM, DeWilde SD, et al. Increased risk of acute cardiovascular events after partner bereavement: a matched cohort study. JAMA Intern Med. 2014;174(4):598-605, PMID: 24566983. 2. Aizer AA, Chen MH, McCarthy EP, et al. Marital status and survival in patients with cancer. J Clin Oncol. 2013;31(31):3869-3876, PMID: 24062405. 3. Bingel U. Avoiding nocebo effects to optimize treatment outcome. JAMA. 2014;312(7):693-694, PMID: 25003609.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Sarah Tilyou at

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McMahon Publishing is a 42-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2014 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

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New Biosimilar Pathway Paves Way for U.S. Approvals W

ith the recent announcement that the FDA has accepted its first biologics license application (BLA) for a biosimilar version of filgrastim, many stakeholders are wondering how the drug will affect formulary decision making and drug costs. Sandoz’s BLA for filgrastim (granulocyte colony-stimulating factor [G-CSF]) will be the test case for the FDA’s new biosimilar approval pathway, giving the U.S. market access to these products.

Rigorous Approval Pathway The pathway to U.S. approval of biosimilars will be stringent and will require highly sophisticated and sensitive analytical data to compare the biosimilar product with the reference version. The purpose of these stringent requirements is to ensure that newly approved biosimilars will perform as well as the reference product. One of the reasons that it has taken so long to develop a biosimilar approval pathway is the complexity of replicating these products. Since these novel biological agents are not exact copies of the original or reference products, they present more of a challenge to evaluate their safety and efficacy than would generic medications. “Biologics need to be manufactured in living organisms. This manufacturing process results in differences among batches, also called ‘batch-tobatch variability,’” explained Carlos Sattler, MD, the vice president of U.S. clinical development and medical affairs at Sandoz Inc. This variability is normal for all biologic products. In fact, these slight dissimilarities from batch to batch, and even molecule to molecule, are a normal principle in biotechnology, Dr. Sattler noted. That variability was the crux of the FDA’s delay in finalizing its process for reviewing and approving these challenging compounds. How would biosimilar manufacturers recreate the reference molecule in a manner that would ensure safety and efficacy, and how would the FDA evaluate such a product without having access to comparable

clinical trial data? Manufacturers of branded biologicals and some health care providers said it could not be done, but experience outside the United States has shown that such doubts were unfounded. Indeed, the European Medicines Agency, the regulatory body in the European Union, already has approved at least 20 biosimilars. Congress’ passage of the Affordable Care Act (ACA) dramatically changed the discussion of biosimilars in the United States, paving the way for approval. Non-biologic products, including generic drugs, are regulated under the

that is seeking biosimilar marketing approval must submit a BLA with scientific data demonstrating, among other things, that the biological product: • Is similar to a reference product; • Has the same mechanism of action, condition of use, route of administration, dosage form and strength as the reference product; and • Is manufactured, processed, packed or held in a facility that meets standards designed to ensure that the biological product continues to be safe, pure and potent. “In addition to demonstrating bio-

The pathway to U.S. approval of biosimilars will be stringent and will require highly sophisticated and sensitive analytical data to compare the biosimilar product with the reference version. Federal Food, Drug, and Cosmetic Act (FD&C Act), which provides a clear pathway for approval to ensure that the generic drug is as safe and effective as the already approved branded drug. For approval, generic drugs must have the same active ingredients, previously approved conditions of use, dosage form, strength, route of administration and labeling as the reference drug. (In some cases, the labeling can differ.) “The generic must also be bioequivalent to the brand-name drug,” explained Leah Christl, PhD, the associate director for therapeutic biologics at the FDA Office of New Drugs. In contrast, the development of biosimilar products is done under the auspices of the Public Health Service Act (PHS Act). “Until the passage of the [ACA] in March 2010, the PHS Act did not have similar provisions to the FD&C Act that allow licensure of biological products based on comparison to already licensed biological products,” Dr. Christl said. Now, she explained, because that abbreviated licensure pathway has been designated, the FDA is now able to accept applications, According to Dr. Christl, a manufacturer

similarity, a manufacturer must show that the proposed interchangeable biological product is expected to produce the same clinical result as the reference product in any given patient,” Dr. Christl said. Additionally, when a product will be administered more than once to an individual, the manufacturers also must demonstrate that the risk for adverse events from alternating or switching between the reference product and the biosimilar will be similar to the risk of using the reference product without such a regimen alteration, she explained. In addition to state-of-the-art, highly sophisticated, powerful and sensitive analytical technologies and assays that are used to compare the biosimilar with the originator biologic and establish structural and functional comparability, biosimilars are also tested in actual clinical trials to confirm comparability between the products, Dr. Sattler said. The purpose of these stringent requirements is to assure regulatory agencies, health care providers, insurers and patients that the safety and

efficacy of these new products will be similar to the reference product.

An Eye Toward Costs Insurers and benefits managers are anxious to see a reduction in the cost of these expensive products, but the savings will not be as high as for generic drugs, according to industry analysts. In fact, prices for biosimilars are likely to be only about 10% to 30% lower than for reference products. Rob Adamson, PharmD, the vice president of clinical pharmacy services at Barnabas Health in West Orange, N.J., said that still could add up to a significant savings because the cost of the original biologics is so high. “Thirty percent of a lot of money is a lot of money,” he said. However, Dr. Adamson cautioned, “People are enamored of the idea that biosimilars will be lower in price, but we also have to look for guarantees of supply.” To accept the discount price, one may have to forgo an established relationship. “You move away from the branded product because this new one is cheaper, and then it is not available. Now, you have to go back to the branded product and end up paying full price. So, now this is costing you money, rather than saving you money.” The cost of the branded product may come down to remain competitive, Dr. Adamson pointed out. There has been some historical precedent for this, particularly in the oncology market. The future for biosimilars in the United States can also be glimpsed by looking at overseas experience with the compounds, where Sandoz, for example, has been marketing its biosimilar version of filgrastim, Zarzio, since 2009. Dr. Sattler said the product “has been marketed in more than 40 countries outside the U.S., generating nearly 6 million patient-exposure days of experience,” making it “the No. 1 prescribed daily G-CSF.” —Marie Rosenthal None of the sources reported any relevant financial relationships.

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In Geriatric Patients…

Factors Predicting Early Death Can Guide Treatment Chicago—Some of the factors that predict early death in geriatric cancer patients appear to be modifiable, judging from the results of a French study of more than 500 patients. “In addition to frailty, there are several predictive factors of mortality we believe may be useful for guiding therapeutic decisions,” reported investigator Rabia Boulahssass, MD, a staff geriatrician at the Centre Hospitalier Universitaire, in Nice, France. Presenting the findings at the 2014 annual meeting of the American Society of Clinical Oncology, Dr. Boulahssass emphasized that the study was observational not interventional, but she said that it still has lessons for clinical care. Dr. Boulahssass and her coinvestigators evaluated 547 patients using a geriatric comprehensive assessment and then followed them for 100 days, collecting data on a broad range of variables, including frailty with the Balducci criteria, comorbidities with the Charlson score, nutrition status with the Mini Nutrition Assessment (MNA), gait speed and quality of life (QoL)

‘More research is needed to determine whether modifying these risk factors in older adults with cancer improves outcomes.’ —Grant R. Williams, MD (abstract 9511). The mean age of the study population was 82 years. Within 100 days of the assessment, 22% of the patients had died. In univariate analyses, the factors associated with a higher likelihood of mortality included slower gait speed (HR, 4.2; P=0.001), male gender (hazard ratio [HR], 1.45; P=0.03), loss of autonomy in ADL (HR=2.6; P=0.0001) and instrumental ADL (HR=2.8; P=0.0001), metastatic cancers (HR, 2.1; P=0.001), poor nutritional status (MNA ≤23.5) (HR, 13.4; P=0.001), as well as poor QoL, comorbidities (Charlson >6) (HR, 2.2; P=0.13 ) and increased frailty (Balducci score 3) (HR, 20; P=0.003). Although some of the predictors of mortality on univariate analysis were not modifiable, such as male gender and advanced cancer, there were several potentially modifiable predictors,

including nutritional status, impaired ADL and impaired QoL. Additionally, two of the three factors that emerged as independent predictors of mortality at 100 days in an adjusted regression model were potentially modifiable: poor nutrition status with an MNA ≤23.5 (HR, 2.3; P=0.04) and slow gait speed (HR, 1.9; P=0.03). This study provides evidence that predictive factors for early death can be identified in geriatric patients. Moreover, Dr. Boulahssass suggested that a comprehensive assessment might isolate modifiable risk factors that provide an opportunity for intervention. “It is necessary to screen for potential deficiencies in a geriatric population in order to introduce interventions, such as a care plan for nutrition or physiotherapy, that will reverse some of these adverse risk factors,” Dr. Boulahssass

said. She indicated that the treatments for most of these modifiable risk factors are well tolerated and have the potential to improve QoL, even if the effect on the duration of survival is modest. Asked for a comment about this direction of research, Grant R. Williams, MD, who is performing a joint fellowship in geriatrics and oncology at the University of North Carolina at Chapel Hill, suggested that it is logical to consider specific risk factors for poor outcomes in geriatric patients with cancer, but evidence for benefit from treatment in this population is incomplete. “Geriatric assessment has been shown to be feasible in various oncology settings and is able to identify modifiable risk factors that have interventions with proven benefits in older adults without cancer,” Dr. Williams noted. However, “more research is needed to determine whether modifying these risk factors in older adults with cancer improves outcomes.” —Ted Bosworth Drs. Boulahssass and Williams reported no relevant financial relationships.

Medicaid Payment Tied to Timing of Breast Cancer Surgery Chicago—In states where surgeons receive lower Medicaid reimbursements for breast cancer surgery, Medicaid patients have longer wait times for breast-conserving surgery and outpatient mastectomies, according to a study by researchers from RTI International, in Research Triangle Park, N.C. The researchers conducted the study because there is a large variability in Medicaid policies. As long as states meet certain requirements set by the federal government, they have the flexibility to determine which patients are eligible for Medicaid and how much physicians will be reimbursed for services. Previous studies have shown that Medicaid patients are more likely to receive some medical services, such as cancer screenings, in states that have higher Medicaid reimbursements. To find out how payment policies affect the receipt of breast cancer surgery, the investigators analyzed data from women between the ages of 18 and 64 who were enrolled in fee-for-service Medicaid for at least four months between 2006 and 2008, in 46 states or Washington, D.C. The study, which was presented at the 2014 annual meeting of the American Society of Clinical Oncology, focused on breast cancer patients who had at least

‘Requiring recertification annually rather than a shorter [time period] may lead to more stability of care.’ —Michael Halpern, MD, PhD

two claims with diagnostic codes on different dates before a claim for mastectomy or breast-conserving surgery. The study included 3,272 women who received breast-conserving surgery; 2,156 who received an outpatient mastectomy; and 2,114 who received an inpatient mastectomy. In states with lower reimbursements, patients were more likely to experience longer wait times for breast-conserving surgery (r= –0.32; P<0.05) and outpatient mastectomy (r= –0.41; P<0.005). There was no statistically significant association between timing for inpatient mastectomy and reimbursement. According to Michael Halpern, MD, PhD, a senior fellow with RTI

International, who presented the study, one explanation for the finding is that surgeons who accept Medicaid patients have busier caseloads and greater waiting periods. When Medicaid reimburses doctors at higher rates, more doctors may be willing to take on Medicaid patients, which will reduce overall waiting times. The study also found that beneficiaries in states with Medicaid eligibility recertification every 12 months had a shorter time to all three types of breast cancer surgery than states that required recertification more frequently. “We think there are substantial policy implications for this,” said Dr. Halpern. “Increasing Medicaid reimbursement may increase the number of surgeons

who accept Medicaid patients, and consequentially decrease time from diagnosis to surgery. Requiring recertification annually rather than a shorter [time period] may lead to more stability of care.” According to Dr. Halpern, given that the Affordable Care Act will substantially expand Medicaid, state policymakers need to consider approaches to improve access to high-quality cancer care for this underserved population. Sandra Wong, MD, MS, an associate professor of surgery, at the University of Michigan Health System, in Ann Arbor, said the research was important. “This study clearly demonstrates that Medicaid reimbursement levels seem to be tied to delays in surgical treatment and, as a result, probably downstream impact on patient outcomes whether that be morbidity or mortality,” she said. Dr. Wong pointed out that the study provided no information on the provider perspective on systems issues. “It is ... important to look at/compare how other payor systems/levels of reimbursement impact time to treatment,” she said. She said policies are needed to eliminate barriers across patients for receipt of care in breast cancer and other cancers. —Kate O’Rourke

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Trial Participation Low in Lung and Colorectal Cancers Chicagoâ&#x20AC;&#x201D;Only about 25% of patients receiving chemotherapy for advanced lung or colorectal cancer participate in a discussion about the option of entering a clinical trial, according to a survey of a large sample of patients. Of those who have that discussion, less than 30% enroll. Low rates of participation in clinical trials have been reported before, but data from a survey presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 6509) suggest that clinicians may carry much of the responsibility. The data were presented by Kenneth L. Kehl, MD, now an oncology fellow at the University of Texas MD Anderson Cancer Center, in Houston, who initiated this work under the direction of Nancy Keating, MD, an associate professor of health care policy at Harvard Medical School, in Boston. According to the data, the vast majority of patients depend on clinicians to hear about trials. Specifically, more than 90% of those who decided to participate in a clinical trial first heard of the opportunity from a health care provider. Notably, that participation was much greater among patients who characterized decision making in their cancer care as shared or patient-controlled, rather than physician-controlled. The survey was conducted through the Cancer Care Outcomes Research and Surveillance (CanCORS) consortium, which has assembled a nationally representative population at participating

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centers across the United States. Of the 7,887 patients with lung and colorectal cancer who were asked if they participated in a discussion of clinical trials, only 1,114 (14.1%) responded affirmatively. Among the 2,173 patients treated with chemotherapy for stage III or IV disease, the proportion rose to 25.7%, of which less than one-third enrolled. A multivariate analysis found that a college education and an income greater than $60,000 nearly doubled the

is that clinicians need to take the lead in introducing the option of a clinical trial when the limitations of standard therapies are well known. Dr. Kehl emphasized the â&#x20AC;&#x153;underlying reality that before a patient enrolls in a clinical trial, he or she must first learn about the possibility.â&#x20AC;? â&#x20AC;&#x201D;Ted Bosworth Drs. Kehl and Keating reported no relevant financial relationships.

CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ÂŽ November 5-7, 2014, New York City The Greenspan Meeting XXXII

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likelihood of having a discussion about trial participation. A significant inverse relationship existed between the likelihood of participating in a discussion about a trial and increasing age, and participation in such discussions was significantly lower among minority ethnic groups as well. Despite these differences, once the discussion occurred, none of these factors affected participation in trials. The main implication of this study

Past as prelude: Further Dilemmas in Hormonal Treatment of Early Breast Cancer /PSNBO 8PMNBSL .%

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CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

DONOR GRAFTS continued from page 1

because HCT often is considered the best treatment option, provided a graft is available and the procedure can be tolerated, according to Dr. Confer, who added that good outcomes achieved with unrelated donor grafts and reducedintensity conditioning regimens have largely eliminated restrictions on HCT based on age alone.

Good Outcomes Even With Less Optimal Matches The criteria for an optimal HCT donor graft, which is high-resolution matching of HLA gene loci for HLA-A, HLA-B, HLA-C and HLA-DRB1, have not changed, but the definition of a suitable match has. Extensive data have been presented in the past year, including several large studies presented at the annual meeting of the American Society of Hematology (ASH), showing that outcomes are acceptable with 7/8 allele matches for unrelated donor blood and 4/6 allele matches for umbilical cord blood (UCB). Even if outcomes are inferior to those of an optimally matched graft, outcomes are better than those anticipated in the absence of HCT. In one study of patients with acute myeloid leukemia (AML) who were older than 50 years and who received an unrelated donor HCT between 2005 and 2010, 441 patients received grafts with 8/8 alleles matched, 94 received grafts with 7/8 alleles matched and 205 received UCB with as few as 4/6 alleles matched (ASH 2013; abstract 302). The rates of leukemia-free survival at three years were significantly higher for all

‘We once thought the more chemotherapy the better. Now, I think the limitations of chemotherapy are better appreciated. We realize that the grafts themselves offer a significant antileukemic effect, and the opportunity to control disease with transplant may be best when it is offered promptly.’ —Dennis Confer, MD three strategies than would be expected in the absence of HCT but did not differ significantly among the groups. “For the older population with AML, allo-transplantation in first complete remission can provide extended leukemiafree survival for 30% to 43% of patients using any of these graft sources,” reported Daniel J. Weisdorf, MD, the director of the University of Minnesota’s Adult

Blood and Marrow Transplant Program, in Minneapolis. Although Dr. Weisdorf acknowledged that survival rates were numerically higher with 8/8 allele donor matches and that they are “preferred” for unrelated donor grafts, he emphasized that substantial rates of response can be achieved with all three HCT strategies in a population once considered contraindicated for HCT due to age.

100 90

Likelihood of Match, %

80 70 60

“The rapid availability of UCB provides effective therapy for older patients with expected short-term remissions, such as in patients where ongoing consolidation therapy has not been effective in limiting risk of relapse,” said Dr. Weisdorf, who also works in the NMDP’s affiliated Center for International Blood and Marrow Transplant Research (CIBMTR). Similar conclusions were drawn from a study in which the same mix of HCT strategies was evaluated in 1,593 patients with Hodgkin or non-Hodgkin lymphoma who were as old as 75 years. Like the AML study, this analysis was conducted under the NMDP’s CIBMTR program (ASH 2013; abstract 161). Again, all three HCT strategies extended survival beyond that expected without HCT, regardless of age. This study prompted the lead author, Veronika Bachanova, MD, PhD, an assistant professor in the Division of Hematology, Oncology, and Transplantation, at the University of Minnesota, Minneapolis, to conclude that HCT is viable in most lymphoma patients and so should be considered routinely. The data from these two studies, which are consistent with those found in other studies, suggest that 30% to 40% of patients with common hematologic malignancies, regardless of age, can expect extended survival with HCT, Dr. Confer said. He added that this might even be an underestimate because of protocols that have improved since the data collection for these studies. In contrast, he said that the efficacy of other options, such as chemotherapy, is measured “in the single digits.” Most eligible patients should opt for HCT if the treatment is offered to them, according to Dr. Confer. “In patients with several coexisting chronic conditions that lower performance status, [HCT] may not be suitable, but age, by itself, is no longer a selection criterion. One important limitation to [HCT] right now is that clinicians are not thinking about it soon enough,” Dr. Confer suggested.

More and More Patients Can Find Donor Graft

40 30 20 10 Eu W id ro h dl pe ite e a N Ea n . A st fr er ic n/ a A A n m fr er ic ic an an A f ric C en B an tr la al ck A S m o er ut ic h/ an C ar B ib la be c an k C hi ne se Ko re an So ut h A si an Ja pa ne se Fi lip i So no ut he A a si st V a ie tn n am Pa ci H ese fic a w Is ai la ia nd n er / M e xi C Hi ca en sp n tr an al ic A S m o er ut ic h/ a C Hi n ar sp ib a N b n at ea ic i A ve n m N er or C en N ic th an tr ati al ve A S m o er ut ic h/ an C ar N i bb ati N at ea ve iv n e A la sk an

Race/Ethnic Group of Patient

Figure. Likelihood of finding an 8/8 HLA match from an unrelated adult donor. Based on Gragert et al. N Engl J Med. 2014;371(4):339-348.

One obstacle has been a lack of graft availability, but this is a rapidly diminishing problem. According to recently published NMDP data, 80% of patients in the United States can now find a suitable donor graft (Gragert et al. N Engl J Med 2014;371[4]:339348, PMID: 25054717). This number is reached by including both 7/8 allele matched grafts and UCB, but the proportion of patients able to obtain an 8/8 allele donor graft match also is increasing. Among whites with European ancestry, 75% can expect to find an 8/8 allele donor graft, according to an NMDP model used to calculate

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

Clinical Conundrums Hematology and bone marrow transplant review Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Primum non nocere. (First, do no harm.)

2. True or False? The central event

of the graft-versus-host reaction is the activation of donor T cells by host antigen-presenting cells (APCs) in allogeneic transplantation (allo-HCT).

3. True QUESTIONS

1. True or False? Data from the

or False? Bortezomib (Velcade, Millennium) can be a therapeutic option for patients with extensive and steroid-refractory chronic GVHD (cGVHD).

4. According to recently published

b. Dexamethasone, rituximab, and cyclophosphamide (DRC) remains a front-line therapy option. c. Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is no longer considered a first-line option. d. Bendamustine (Treanda, Cephalon)rituximab is a primary treatment option, especially for patients with high tumor bulk. e. Bortezomib-rituximab combinations are not considered a front-line option. f. Fludarabine-based combinations are not recommended for primary therapy but remain an option for patients with relapsed/refractory disease with adequate performance status.

True or False? Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a genetically heterogeneous disease with widely disparate outcomes following standard therapy.

Swedish Lymphoma Registry do not show favorable outcomes with up-front autologous hematopoietic cell transplantation (auto-HCT) in patients with peripheral T-cell lymphoma (PTCL), especially when etoposide was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial therapy.

International Workshops on Waldenström macroglobulinemia-7 (IWWM-7) consensus, all of the following are true except: a. Rituximab (Rituxan, Genentech)based regimens remain a recommended primary therapy for most patients with WM.

matched related donor (MRD) peripheral blood HCT, the combination of tacrolimus and sirolimus is an acceptable alternative to tacrolimus and methotrexate.

access (Figure). Although these numbers are lower for other populations (less than 50% for those with Asian or Middle Eastern ancestry and 19% among African-Americans), these numbers are growing, increasing the probability of identifying an 8/8 HLAmatched donor. According to the published report, the registry is growing at a rate of about 9% per year, which increases the likelihood of an 8/8 allele matched donor graft by between 4% and 7% annually. By 2017, more than 5 million donors will be added to the nearly 10 million current donors and

the pool of nearly 200,000 UCBs. HLA typing and searching for a match in the NMDP database at the time of cancer diagnosis is recommended in anticipation of a potential HCT because it starts the process and avoids delays if HCT is performed. According to Dr. Confer, “there is no charge for the initial search, so it makes no sense to delay.” In fact, the NMDP can evaluate its database of potential matches “in a matter of seconds.” The emphasis on immediate HLA typing in hematologic malignancies is a major shift in practice and underscores

the central role increasingly played by HCT in cancer control. “We once thought the more chemotherapy the better. Now, I think the limitations of chemotherapy are better appreciated. We realize that the grafts themselves offer a significant antileukemic effect, and the opportunity to control disease with transplant may be best when it is offered promptly,” Dr. Confer explained. This message is starting to spread. Dr. Confer reported that the growth of unrelated donor grafts has been increasing steadily at about 6% to 8%

6. True or False? In the setting of

7. True or False? The use of young

(<30 years), male, noninherited maternal antigen (NIMA)-mismatched donors results in the best survival after HLA haplotype–mismatched related donor transplants.

8. True or False? Steven P. Treon,

MD, PhD, at Dana-Farber Cancer Institute, in Boston, Massachusetts, and his colleagues reported the results of carfilzomib (Kyprolis, Onyx) combined with rituximab and dexamethasone as a new effective, neuropathy-sparing alternative treatment regimen for patients with symptomatic WM requiring proteasome inhibitor–based therapy who were naive to bortezomib and rituximab.

9. True or False? The transplantation

program with lenalidomide (Revlimid, Celgene), bortezomib, and dexamethasone (RVD) induction and consolidation followed by 1 year of lenalidomide maintenance resulted in poor response in patients with newly diagnosed multiple myeloma (MM).

10.

True or False? In patients with primary myelofibrosis (PMF), additional sex combs-like 1 (ASXL1) mutation has been shown to carry a favorable prognosis. see CONUNDRUMS, S page 12

annually for some time, but the most rapid growth for unrelated donor grafts has been among patients over age 50 years, with solid growth also seen among patients older than 65 years. With HCT, Dr. Confer said, “we are able to salvage patients who are otherwise unsalvageable, and this is getting easier with more tolerable conditioning regimens and improvements in supportive care.” —Ted Bosworth Drs. Confer, Weisdorf and Bachanova reported no relevant financial relationships.

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

How I Manage ...

How I Manage Advanced (Stage III/IV) Hodgkin Lymphoma in Adults, Part 1 W

Jane N. Winter, MD Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

Is Escalated BEACOPP Superior to ABVD in Advanced Hodgkin Lymphoma? ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) remains the standard of care for the treatment of HL in North America. First developed as a second-line regimen for patients who failed MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), the first effective multiagent program for HL, ABVD proved at least as effective as MOPP and its derivatives, including MOPP/ABV hybrid, with fewer adverse effects.1,2 In an attempt to improve outcomes by intensifying therapy, the German Hodgkin Study Group (GHSG) developed an escalated version of BEACOPP (escBEACOPP), a MOPP-like regimen that incorporates bleomycin, etoposide, doxorubicin, and cyclophosphamide in addition to procarbazine and prednisone but eliminates mechlorethamine, the component in MOPP of greatest concern with regard to immediate and long-term toxicities. Results from HD9, a Phase III randomized trial comparing 8 cycles of escalated BEACOPP, 8 cycles of standard-dose

ith cure rates for Hodgkin lymphoma (HL) now exceeding the 80% mark, much of the attention has shifted from the achievement of durable remissions to reductions in long-term complications of treatment, especially secondary malignancies and cardiovascular disease. The eradication of HL in all patients, however, must remain the primary goal as we work to reduce late effects. The median age of patients with HL is in the prime of life, so both improvements in disease control and reductions in treatment-related mortality over the long term will impact overall survival (OS). Today’s challenge is to maximize cure rates and minimize secondary effects while also preserving an excellent quality of life.

BEACOPP, and 8 alternating cycles of COPP and ABVD, all with consolidative radiotherapy for bulky or residual disease, demonstrated the superiority of the most intensive arm (escBEACOPP), now with 10 years of follow-up.3 Disease control was better with escBEACOPP, and the estimated 10-year OS for patients treated with this intensified approach was 86% compared with 80% for standard-dose BEACOPP and 75% for alternating COPP and ABVD ( =0.0005). Despite the reported (P advantages of this intensive regimen, the higher rates of acute hematologic toxicity, infection, infertility, and secondary myelodysplasia and AML in the escBEACOPP arm as well as skepticism regarding its overall effectiveness and the choice of comparator (COPP-ABVD) have kept North American physicians from adopting this regimen. Two randomized trials comparing escBEACOPP with ABVD have not shown an OS advantage of the more intensive approach, likely, at least in part, related to acceptable remission rates achieved with salvage autologous transplantation (autoHCT) in the ABVD arms.

What Attempts Have Been Made To Reduce Escalated BEACOPP–Associated Toxicity? The GHSG has investigated several approaches to reducing toxicity of the escBEACOPP regimen.3 De-escalation to standard-dose BEACOPP after 4 cycles of escBEACOPP did not significantly reduce acute toxicity, and it appeared likely that disease control was compromised among patients not receiving consolidative radiotherapy for apparent residual disease. When compared with 8 cycles of ABVD in separate randomized trials for low- and high-risk patients, this “de-escalated” BEACOPP approach did not improve the event-free survival or OS end points compared with ABVD. A third trial that included planned salvage therapy also did not show long-term benefit compared with ABVD. Reducing the number of escBEACOPP cycles from 8 to 6, however, reduced hematologic toxicity as well as secondary malignancies, resulting in improved clinical outcomes (both freedom from treatment

failure and OS). A reduction in the percentage of patients receiving consolidative radiotherapy also has occurred over successive GHSG protocols, which likely will result in a reduction in secondary malignancies following escBEACOPP. Additionally, age and performance status have been shown to be risk factors for escBEACOPP-related mortality, which helps identify patients requiring special attention or for whom escBEACOPP should be avoided. Identifying patients most likely to benefit from the more intensive regimen is the current challenge. Interim positron emission tomography (PET)/ computed tomography (CT) (iPET2) after 2 cycles of ABVD is being investigated as a strategy for selecting patients at high risk for treatment failure for transition to alternative therapies. Whether this approach will be as effective as up-front treatment with escBEACOPP, especially for high-risk patients (Tables 1 and 2), is unknown. At least for now, ABVD remains the standard of care in North America. Clinical trials evaluating the addition of new agents to conventional ABVD, including brentuximab vedotin, are underway4,5 in hopes of improving outcomes without introducing more intensive therapies.

If ABVD, Then How Many Cycles? Although treatment with 6 cycles of ABVD has never been directly compared with the traditional 8-cycle program, clinical trials and practice have transitioned to the more abbreviated course without compromising efficacy. Achievement of a complete remission following 4 cycles of treatment was the basis for reducing the

Table 1. Prognostic Score for Advanced HL Patients with advanced disease are risk stratified using the IPS, which includes the following risk factors (for each factor present, the patient receives 1 point):

AT A GLANCE • ABVD remains the standard of care for the treatment of HL in North America. • Two randomized trials comparing escBEACOPP to ABVD have not shown an OS advantage over the more intensive approach. • No more than 6 cycles of ABVD or escBEACOPP are recommended for the treatment of advanced-stage HL today.

• Albumin <4 g/dL • Hemoglobin <10.5 g/dL • Male • Age ≥45 y • Stage IV disease • Leukocytosis: WBC count >15,000/mm3 • Lymphopenia: lymphocyte count <8% of WBC count and/or absolute lymphocyte count <600 cells/mm3 HL, Hodgkin lymphoma; IPS, International Prognostic Score; WBC, white blood cell Adapted dapted from o N Engl g J Med. ed 1998;339(21):1506-1514. 998;339( ) 506 5

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

Table 2. 5-y OS in Patients With Advanced HL, Based on IPS Score

5-y OS, %

IPS 0-1

IPS ≥2

IPS ≥3

IPS ≥4

IPS, International Prognostic Score; OS, overall survival Adapted from N Engl J Med. 1998;339(21):1506-1514. 998;339( ) 506 5

total number of cycles from 8 to 6 in the Phase III trial comparing ABVD with escBEACOPP conducted by the Italian cooperative groups, in which 48% of patients received only 6 cycles.6 Similarly, other trials including the US Intergroup trial comparing ABVD with Stanford V, also permitted 6 cycles of ABVD according to CT-based response criteria after 4 cycles.7 Despite the reduction in numbers of cycles, outcomes with ABVD appear to have improved over time, as shown by the estimated 10-year OS of 87% for patients treated with 6 cycles of ABVD on the HD9601 trial.8 It is possible that the integration of an early fluorodeoxyglucose-PET into our management of patients with HL will facilitate further reductions in therapy. At the present time, the National Comprehensive Cancer Network guidelines recommend no more than 6 cycles of ABVD for any patient with HL.

References 1. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an Intergroup Trial. J Clin Oncol. 2003;21(4):607-614, PMID: 12586796. 2. Bruce A. Peterson and Canellos GP, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992; 327(21):1478-1484, PMID: 1383821. 3. Eichenauer DA, Thielen I, Haverkamp H, et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Coming Soon How I Manage Relapsed and Refractory Multiple Myeloma by Mohamad Mothy, MD, PhD University of Nantes, France

patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2014;123(11):1658-1664, PMID: 24478403. 4. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348-1356, PMID: 24239220. 5. Clinicaltrials.gov. Phase 3 Frontline therapy trial in patients with advanced classical Hodgkin lymphoma. http://clinicaltrials.gov/ct2/show/ NCT01712490?term=C25003&rank=1. Accessed September 18, 2014. 6. Federico M, Luminari S, Iannitto E. ABVD compared with BEACOPP compared with

CED for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009;27(5):805-811, PMID: 19124807. 7.

Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advancedstage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31:684-691, PMID: 23182987.

8. Chisesi T, Bellei M, Luminari S, et al. Longterm follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin’s

lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol. 2011;29(32):4227-4233, PMID: 21990405.

Look for Part 2 of this series, in which Dr. Winter will answer the following questions: • What is the role of consolidation radiation therapy in advanced-stage HL patients treated with ABVD? • What is the role of interim FDG-PET scanning? • Can treatment be personalized based on age and prognostic factors?

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CMEZone.com

HEMATOLOGIC DISEASE

CONUNDRUMS

CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

bortezomib. Blood. 2014;124(10):1677-1688, PMID: 25009225.

oropharyngeal mucositis compared with tacrolimus and methotrexate.

Herrera AF, Kim HT, Bindra B, et al. A Phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014; doi: 10.1016/j. bbmt.2014.06.040. [Epub ahead of print], PMID: 25017765.

Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124(8):1372-1377, PMID: 24982504.

nations may also be considered a primary option for patients with specific highrisk features (ie, hyperviscosity) and in younger patients for whom avoidance of alkylator therapy is preferred to prevent hampering hematopoietic cell collection. See also question 8.

jing, China, and colleagues suggest an algorithm for the selection of the best donor in HLA haplotype–mismatched transplantation of T-replete granulocyte-colony stimulating factor–mobilized bone marrow and peripheral blood hematopoietic cells. Younger donors (<30 years) had a lower incidence of acute GVHD than older donors (>30 years), and younger male donors had lower treatment-related mortality (TRM) and better survival than older or female donors. Another factor with respect to the development of acute GVHD was the noninherited NIMA and noninherited paternal antigen (NIPA) disparity, and transplantation from NIMA-mismatched siblings showed a lower incidence of acute GVHD compared with NIPA-mismatched sibling donors or paternal and maternal donors, although the NIMA or NIPA mismatch had no influence on TRM, chronic GVHD, relapse, or survival. These results should be interpreted with caution due to differences in preparative and post-transplant immunosuppressive therapies employed in the Chinese and US transplant groups.

continued from page 9

ANSWERS

1. False.

In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding ALK+ ALCL), upfront auto-HCT was associated with a superior overall survival (OS) (HR, 0.58; P=0.004) and progression-free survival (PFS) (HR, 0.56; P=0.002) compared with patients treated without auto-HCT. The addition of etoposide to CHOP resulted in superior PFS in patients aged 60 years or younger (HR, 0.49; P=0.008). This study is based on the entire Swedish population, covers a 10-year period, and reportedly is the largest population-based material reported on PTCL. Ellin F, Landström J, Jerkeman M, et al. Realworld data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood. 2014;124(10):1570-1577, PMID: 25006130.

2. True. High-dose chemoradiother-

apy prior to allo-HCT eliminates most, but not all, hematopoietic APCs. The APCs that remain, however, are activated and elicit inflammatory responses from the T cells in the donor graft, eventually resulting in graft-versushost disease (GVHD). Ferrara J. Cellular therapy of the host to prevent GVHD. Blood. 2014;124(11):1703-1704, PMID: 25214197.

3. True. This is being demonstrat-

ed in an ongoing single-institution, single-arm, pilot study of bortezomib in patients with steroid-dependent, -intolerant, or -refractory cGVHD at University of California, Davis Comprehensive Cancer Center (#NCT01672229). Interestingly, another recently published study in Biology of Blood and Marrow Transplant showed organ-specific complete response rates of 73% for skin; 53% for liver; 75% for gastrointestinal tract; and 33% for joint, muscle, or fascia involvement with bortezomib plus prednisone as front-line therapy (note: not steroid-refractory) for cGVHD. This was a single-arm Phase II trial. The combination was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. Pai CC, Chen M, Mirsoian A, et al. Treatment of chronic graft-versus-host disease with

True. Dr. Y Wang, at Peking Uni4. e. Bortezomib-rituximab combi- 7. versity Institute of Hematology, in Bei-

Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124(9):1404-1411, PMID: 25027391.

True. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCL cases, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCL cases. Five-year OS rates were 85% for patients with ALK-positive ALCL, 90% for those with DUSP22 -rearranged ALCL, 17% for those with TP63-rearranged ALCL, and 42% for cases lacking all 3 genetic markers (P<0.0001). Hazard ratios (HRs) for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P=7.10 × 10−5). Interestingly, DUSP22 -rearranged cases have favorable outcomes similar to those seen among cases with ALK-positive ALCL, whereas other genetic subtypes have inferior outcomes. DUSP22 rearrangement may serve as predictive biomarkers to help guide patient management. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473-1480, PMID: 24894770.

6. True. In an open-label, Phase III,

multicenter, randomized trial conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), there was no difference in the probability of day 114 grades 2-4 acute GVHDfree survival (67% vs 62%; P=0.38). However, the combination of tacrolimus and sirolimus is associated with more rapid engraftment and reduced

Handgretinger R. Haploidentical transplantation: the search for the best donor. Blood. 2014;124(6):827-828, PMID: 25104858. Wang Y, Chang YJ, Xu LP, et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124(6):843-850, PMID: 24916508.

True. Induction therapy consisted of IV carfilzomib 20 mg/m2 infused over 20 minutes in cycle 1 and 36 mg/m2 in cycles 2 to 6, with IV dexamethasone 20 mg given on days 1, 2, 8, and 9 and rituximab 375 mg/m2 on days 2 and 9 every 21 days for 6 cycles. Maintenance therapy followed 8 weeks later with IV carfilzomib 36 mg/m2 and IV dexamethasone 20 mg, on days 1 and 2, and rituximab 375 mg/m2 on day 2, every 8 weeks for 8 cycles. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström’s macroglobulinemia. Blood. 2014;124(4):503-510, PMID: 24859363.

9. False. The transplantation pro-

gram with RVD induction and consolidation followed by lenalidomide maintenance produced high-quality responses and showed favorable tolerability in patients with newly diagnosed MM. In this Phase II study, 31 symptomatic patients aged less than 65 years were enrolled to receive 3 RVD induction cycles followed by cyclophosphamide harvest and auto-HCT. Patients subsequently received 2 RVD consolidation cycles and 1 year of lenalidomide maintenance. Overall, 68% of patients achieved MRD negativity; none of these patients relapsed. This program is being evaluated in the ongoing IFM/ Dana-Farber Cancer Institute 2009 Phase III study. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014;32(25):2712-2717, PMID: 25024076.

10. False.

In this international study, 570 PMF patients were recruited for derivation (n=277) and validation (n=293) of a molecular prognostic model based on 2 mutations (CALR [favorable] and ASXL1 [unfavorable]). Survival was the longest in CALR+ASXL1− (median 10.4 years) and shortest in CALR ASXL1+ patients (median 2.3 years; HR, 5.9; 95% confidence interval [CI], 3.5-10.0). CALR+ASXL1+ and CALR–ASXL1− patients had similar survival and were grouped into an intermediate-risk category (median survival, 5.8 years; HR, 2.5; 95% CI, 1.5-4.0). The CALR/ASXL1 mutations–based prognostic model was DIPSS Plus– independent (P ( <0.0001) and effective in identifying low-/intermediate-1–risk patients with shorter (median 4 years) or longer (median 20 years) survival and high-/intermediate-2–risk patients with shorter (median 2.3 years) survival. According to the investigators, these observations are of immediate clinical relevance and warrant CALR and ASXL1 mutation determination in all patients with PMF and molecular revision of DIPSS Plus. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494-1500, PMID: 24496303.

SEND US YOUR NEWS Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.

Write to managing editor Sarah Tilyou at sm tilyou@mcmahonmed.com

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Table 1. Recently Approved Agents for Melanoma

MELANOMA continued from page 1

Stressing the efficacy of this new class of agents in an interview, Jeffrey Weber, MD, PhD, a melanoma expert from the Moffitt Cancer Center, in Tampa, Fla., said, “PD-1 blockers are great drugs.” Both nivolumab and pembrolizumab, he said, have impressive anti-melanoma activity, with low toxicity, high overall response rates and a long duration of response.

Pembrolizumab The FDA approved pembrolizumab (Keytruda, Merck) based on data from two trials. One trial included only patients who had failed prior treatment, but the other also included treatment-naive patients. In a study of 173 melanoma patients whose disease had progressed after prior therapy, 24% of individuals who received the recommended dose of the drug (2 mg/kg) experienced tumor shrinkage. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients, according to the FDA. A similar response rate was seen in patients who received a 10-mg/kg dose. The second trial tested seven different pembrolizumab dosing strategies in 411 patients with advanced melanoma. Antoni Ribas, MD, PhD, the director of the Tumor Immunology Program Area at the Jonsson Comprehensive Cancer Center, in Los Angeles, presented results from this trial at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA9000). The overall response rate (ORR) was 34% in the entire study cohort, 44% in treatment-naive patients, 40% in ipilimumab (Yervoy, Bristol-Myers Squibb [BMS])-naive patients and 28% in ipilimumab-treated patients. Responses were durable for both ipilimumab-naive and ipilimumab-treated

Drug Name

Drug Class

Year Approved

Immunotherapy

2011

Ipilimumab

Immunotherapy (anti–CTLA-4)

2011

Vemurafenib

BRAF F inhibitor

2011

Dabrafenib

BRAF F inhibitor

2013

Trametinib

MEK inhibitor

2013

Pembrolizumab

Immunotherapy (PD-1 blocker)

2014

Table 2. Dose Cohorts in CA209-004, Nivolumab Plus Ipilimumab Cohort No.

Nivolumab Dose, mg/kg

Ipilimumab Dose, mg/kg

Induction

Maintenance

Nivolumab q3wk × 8 doses + ipilimumab q3wk × 4 doses

Nivolumab + ipilimumab q12wk × 8 doses

Concurrent regimens

107 patients with advanced melanoma who received different doses of the anti–PD-1 agent nivolumab (abstract 9002). The OS was 48% at two years and 41% at three years. With a median of 22 months of follow-up, the median duration of response was 22.9 months. Additional end points were ORR, 32%; median OS, 17.3 months; and median PFS, 3.7 months. Grade 3/4 events occurred in 5% of the patients. The study was the first to assess threeyear OS in nivolumab-treated patients, according to the investigators, who included Mario Sznol, MD, a medical oncologist at Yale Cancer Center, in New Haven, Conn., as well as researchers from BMS.

Combination Therapy

0.3

Nivolumab 3 mg/kg q2wk (maximum 48 doses)

Sequenced regimens 6

Prior

patients, with 88% of responses persisting. The median progression-free survival (PFS) was 5.5 months, and the median overall survival (OS) at one year was 69%. Grade 3/4 events occurred in 12% of patients, with fatigue being the most common (2%). Treatment discontinuation due to adverse events (AEs) hovered around 5%, and there were no treatment-related deaths, according to the investigators, which included researchers from Merck. Steven O’Day, MD, the director of clinical research at the Los Angeles Skin

Nivolumab q2wk (maximum 48 doses)

Cancer Institute at the Beverly Hills Cancer Center, in California, is also impressed with the anti–PD-1 data. “Pembrolizumab results in long-lasting clinical responses in the majority of patients, and impressive overall survival with low toxicity. Importantly, it’s effective regardless of prior ipilimumab treatment. Anti–PD-1 as a single agent is a major breakthrough.”

Nivolumab In another study presented at the ASCO meeting, investigators reviewed data on

Researchers also are testing combining anti–PD-1 therapies with other drugs. At the ASCO meeting, Dr. Sznol presented data on several subsets of patients with advanced melanoma in the Phase I CA209-004 trial (abstract LBA9003). Patients in subdivided cohorts received either concurrent or sequential nivolumab plus ipilimumab (Table 2). In cohorts 1, 2, 2a and 3, the ORR was 42%, the complete response rate (CRR) was 17%, and the two-year OS was 79%. In cohort 8, the ORR was 43% and the CRR was 10%. Most patients who responded to treatment had a reduction in tumor volume that exceeded 80%. The majority of responses were ongoing and the median duration of response had not been reached. Mutant BRAF F or low/ absent PD-L1 tumor expression did not substantially affect activity. Rapid and deep responses were observed in very aggressive and large bulky disease, and most patients who discontinued therapy continued to have ongoing responses, according to the investigative team, see MELANOMA, page 14

Report From ESMO 2014 Congress

Studies Support MEK Inhibitor for BRAF-Positive Melanoma MADRID—Adding a MEK inhibitor to a BRAF inhibitor substantially improves outcome in patients with BRAF mutation–positive advanced melanoma, according to two large Phase III studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress. The results of the two studies, although using different types of BRAF and MEK inhibitors, were considered mutually reinforcing. In both studies, patients with metastatic cutaneous melanoma with a BRAF F V600 mutation were randomized to receive a BRAF inhibitor alone or a BRAF inhibitor with a MEK inhibitor. One demonstrated—and the other strongly suggested—a significant improvement in overall survival (OS). In a trial called coBRIM, the BRAF inhibitor vemurafenib (Zelboraf, Genentech) combined with the MEK inhibitor cobimetinib was compared with vemurafenib alone (abstract LBA5_PR). In the other trial, called COMBI-V, the combination of the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline [GSK]) plus the MEK inhibitor trametinib (Mekinist,

GSK) was compared with vemurafenib alone (abstract LBA4_PR). In coBRIM, the major finding was a 49% reduction in the risk for progression for the combination relative to the BRAF inhibitor alone, but the combination was also associated with a “promising” 35% reduction (P<0.05) in the risk for death, according to the presenting author, Grant McArthur, MD, PhD, the head of the Molecular Oncology Laboratory at Peter McCallum Cancer Centre, in Victoria, Australia. The survival benefit has not yet met the prespecified definition of significance. The COMBI-V trial, which has more mature data, was stopped at an interim analysis when the primary survival end point was reached. At that time, the risk for death was reduced by 31% (HR, 0.69; P=0.005) for the combination relative to the BRAF inhibitor alone, according to the principal investigator, Caroline Robert, MD, the head of the Dermatology Unit at Institute Gustave Roussy, in Paris. She and Dr.

McArthur noted that the addition of a MEK inhibitor was generally well tolerated, leading to an increase in some side effects, such as pyrexia, but a reduction in others, particularly photosensitivity. Both studies confirm that MEK inhibition slows resistance to BRAF inhibitors. According to the invited ESMO discussant, Christian Blank, MD, PhD, the group leader in immunology at the Netherlands Cancer Institute, in Amsterdam, a combination of BRAF and MEK inhibitors “is becoming the new standard of care” in melanoma with a BRAF F V600 mutation, based on the consistency of these data. —Ted Bosworth Dr. McArthur reported financial relationships with Celgene, Millennium, Novartis and Pfizer. Dr. Robert reported financial relationships with Amgen, BMS, GSK, Merck, Novartis and Roche. Dr. Blank reported financial relationships with BMS, GSK, Merck, Novartis and Roche.

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New Marker for Colon Cancer Identified Chicago—EpHA2, a receptor tyrosine kinase (RTK), is an independent marker for poor prognosis in patients with early-stage colorectal cancer (CRC), researchers have found. If validated in further studies, the marker could be used to identify patients who are appropriate for more aggressive treatment, especially in stage II disease, where the role of adjuvant chemotherapy remains controversial. EpHA2, an erythropoietin-producing hepatocellular RTK, also has been shown to be overexpressed in cancers of the urinary tract, bladder and skin (Expert ( Opin Ther Targets 2011;15[1]:31-51, PMID: 21142802). High expression of the molecule in cancer cells is correlated with a poor prognosis, driven by recurrence due to enhanced metastasis. “This marker has been shown to be highly expressed in other cancers— breast, ovarian, prostate, glioblastoma and others—but this is the first comprehensive work that has been done in colorectal cancer in the context of a specific poor prognostic genotype ((KRAS and BRAF mutation),” said Sonali Dasgupta, MD, a clinical research fellow at Queen’s University Belfast School of Medicine, in the United Kingdom, who led the study. In the new study, presented at the recent annual meeting of the American Society of Clinical Oncology (abstract 3581), Dr. Dasgupta and her colleagues performed a series of experiments in colon cancer cell lines and tissue samples from 509 patients with CRC. They found that EpHA2 is overexpressed in both CRC cell lines and human tissues. High expression of EpHA2 mediated cell migration and invasion in cell lines

and correlated with vascular invasion in clinical samples. In a univariate analysis, high expression of EpHA2 predicted worse overall survival in patients with colon cancer (Table 1). In a multivariate analysis that took into account age, sex, tumor size, ethnic group and vascular invasion, EpHA2 was a strong independent prognostic marker in stage II CRC (Table 2). The researchers also demonstrated that soluble EFNA1-Fc ligand or EpHA2 RNA interference can be used to inhibit

expression of EpHA2—and possibly control this type of colon cancer. EpHA2 is a “very attractive target” for novel anticancer therapies, Dr. Dasgupta said. “Our study is the first to show that EpHA2 is an independent predictor of poor clinical outcome and a potential target in early-stage CRC,” Dr. Dasgupta said. “If you have a patient who has this marker highly expressed, they are likely to do much worse in terms of survival compared to persons who have low expression.” Such “patients are potential targets

MELANOMA

seen in any Phase I or Phase Ib trial of melanoma,” he said.

and nivolumab,” Dr. Weber said. “Each trial has an active-control arm (not placebo), so we are going to be waiting a little bit to see the results, but if those trials are positive, which I feel confident they both will be, the FDA will approve the anti–PD-1 drugs in the front-line [setting]. In the future, I would bet you good money that everybody is going to use PD-1 drugs first and ipilimumab later.” Vananh Trinh, PharmD, BCOP, a clinical pharmacy specialist at the University of Texas MD Anderson Cancer Center, in Houston, also expects the Phase III front-line trials of anti–PD-1 therapies to be positive. She “absolutely” sees pembrolizumab and other anti–PD-1 therapies being used as first-line therapy in the future. The concurrent nivolumab and ipilimumab data presented at ASCO were “remarkable,” she said, and are being confirmed in the Checkmate 067 trial. “A Phase I/II trial of pembrolizumab in combination with

continued from page 13

which included researchers from BMS. The rate of grade 3/4 AEs was roughly 60%. Dr. Sznol downplayed this high rate, pointing out that the most common grade 3/4 events were increased lipase and amylase, and laboratory abnormalities, which were easily reversible. Onefourth of patients discontinued therapy due to treatment-related AEs, he noted. “The vast majority of adverse events were managed fairly easily with standard algorithms that were initially developed for ipilimumab-related adverse events,” Dr. Sznol said. There was one drug-related death from multi-organ failure in cohort 8. Dr. Sznol pointed out that the KaplanMeier estimate of median survival was 40 months in the 53 patients in cohorts 1, 2, 2a and 3 (not calculated for cohort 8). “This is the highest number that I have

Table 1. Univariate Analysis of EpHA2 Expression And OS in CRCa Stage

EpHA2

Hazard Ratio

P Value

Stage II

Low

0.00613

High

1.9703

Low

High

1.597

Stage II/III

0.00376

Using Cox proportional hazard ratio.

CRC, colorectal cancer; OS, OS S, overall survival

Table 2. Multivariate Analysis of EpHA2 Expression And OS in CRCa Stage

EpHA2

Hazard Ratio

P Value

Stage II

Low

0.0376

High

1.681

Low

High

1.549

Stage II/III

0.00755

Using Cox proportional hazard ratio. A backward selection method using Akaike’s information criterion was used to determine a refined multivariate model.

CRC, colorectal cancer; OS, OS S, overall survival

Future of PD-1 Treatment Although pembrolizumab was approved in the second-line setting, melanoma experts believe that the PD-1 blockers have a bright future in the first-line setting. “With pembrolizumab, patients have a 25% to 35% response rate,” Dr. Weber said. “If you are a BRAF wild-type patient, the maximum [response rate] with ipilimumab is 15% to 20%.” He pointed out that the FDA and the European Medicines Agency will only approve a drug in a setting that is supported by data, and so far, Merck has only submitted secondline data. This, however, will change. “There is an ongoing pembrolizumab versus ipilimumab trial in treatmentnaive patients. There is a first-line nivolumab trial: ipilimumab versus nivolumab versus combo ipilimumab

for either intensive surveillance or more treatment,” Dr. Dasgupta added. “This can come in many forms: intense chemotherapy, early chemotherapy, chemotherapy in combination with EpHA2 treatment or even EpHA2-targeted treatment in isolation. However, prospective randomized clinical trials are needed to prove or disprove the individual merit of each option. Right now, we have soluble ligand to target EpHA2, but we are also looking at monoclonal antibodies that could target EpHA2.” Nilo Azad, MD, a medical oncologist at the Johns Hopkins Kimmel Cancer Center, in Baltimore, said, “The data look interesting, but it is a small group of patients and it will be hard to know where this will end up going.” Dr. Azad pointed out that there have been many markers that have been identified as being prognostic in colon cancer. Large prognostic panels for stage II/III colon cancer, such as Oncotype DX and ColoPrint, are available commercially. However, these tests are not widely used because it is unclear what to do for patients who are identified as having a poor prognosis. “If you get a result that a patient is at high risk for recurrence, you don’t know what to do with that,” Dr. Azad said. “Does that mean if you give that patient chemotherapy that they will do better? Or, do they just have bad biology, so you are not going to be able to change [the prognosis]?” —Kate O’Rourke Drs. Dasgupta and Azad reported no relevant financial relationships.

peg-IFN [pegylated interferon] or with ipilimumab in patients with advanced melanoma has just started enrollment,” Dr. Trinh said. “A Phase I/II trial of pembrolizumab with dabrafenib [Tafinlar, GlaxoSmithKline] and trametinib [Mekinist, GSK] is also enrolling patients.” —Kate O’Rourke Dr. Ribas reported relationships with Amgen, Compugen, DaiichiSankyo, Genentech/Roche, GSK, Merck, Novartis and Pierre Fabre. Dr. Sznol reported relationships with Amphivena, Anaeropharma, BeiGene, BMS, Genentech/Roche, Immune Design, KyowaKirin, Lion Biotechnologies, MediImmune, Merus, NektasequentialeoStem, Seattle Genetics and Symphogen. Dr. O’Day reported financial relationships with BMS, Delcath, Merck and Novartis. Dr. Weber reported relationships with BMS, Genentech/Roche, GSK and Merck. Dr. Trinh reported no relevant financial relationships.

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LUX-Lung 3 and LUX-Lung 6 Studies:

EGFR R Mutation Type Dictates OS Benefit With Afatinib Chicago—In metastatic non-small cell lung cancer (NSCLC), an overall survival (OS) benefit from first-line afatinib appears to be specific to the type of epidermal growth factor receptor (EGFR ( ) mutation. In an analysis of two large multicenter trials that previously associated this tyrosine kinase inhibitor (TKI) with a progressionfree survival (PFS) advantage over chemotherapy, afatinib was found to significantly improve OS in those with the EGFR mutation in exon del 19, but not in those with the L858R mutation. In addition to generating new information about the role of afatinib (Gilotrif, Boehringer Ingelheim) in the treatment of metastatic NSCLC, these data suggest that the type of EGFR mutation defines “distinct populations that should be studied separately in the future,” said James Chih-Hsin Yang, MD, PhD, a professor in the Graduate Institute of Oncology at National Taiwan University, in Taipei. They also suggest that afatinib should be considered the standard of care for first-line treatment of patients with del 19 EGFR mutation–positive NSCLC. The trial data were drawn from the LUX-Lung 3 and LUX-Lung 6 studies, which compared afatinib with chemotherapy in patients with EGFR mutation–positive, previously untreated, metastatic NSCLC. LUX- Lung 3 was a global trial in which afatinib was compared with cisplatin plus pemetrexed ((J Clin Oncol 2013;31:3327-3334, PMID: 23816960), and LUX-Lung 6 enrolled patients in Asian

countries and compared afatinib with cisplatin plus gemcitabine ((Lancet Oncol 2014;15:213-222, PMID: 24439929). Both produced highly significant reductions in the hazard ratio (HR) of PFS. Neither of the studies had sufficient power to test whether afatinib had an OS advantage over chemotherapy. In this new analysis, presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 8004), the data for the two most common EGFR mutations (del 19 or L858R) were combined from the two trials and analyzed separately. Of the patients enrolled in the study, approximately 50% had the del 19 mutation and 40% had the L858R mutation. When the data were combined, afatinib improved median OS by about three months (27.3 vs. 24.3 months), an advantage that reached significance (HR, 0.81; P=0.0374). However, the

effect was not evenly distributed. In those with the del 19 mutation, median OS increased by nearly one year (31.7 vs. 20.7 months; HR, 0.59; P=0.0001). In contrast, OS was not improved in the L858R mutation group (HR, 1.25; P=0.16). A series of analyses looking for confounding factors, such as the effective relative crossover rates in different countries participating in the study, did not alter the major findings. “With the positive results of two independently performed studies, we can conclude with a very high level of confidence that first-line afatinib significantly improves OS relative to chemotherapy in NSCLC patients with the del 19 EGFR mutation,” Dr. Yang said. More study is needed to evaluate the role of afatinib in patients with L858R mutations, but Dr. Yang suggested that this TKI remains “an option” based on the previously published PFS benefit.

These data may encourage a reorientation in regard to future studies of how treatment affects patients with specific EGFR mutations, said Howard Jack West, MD, the director of the Thoracic Oncology Program at Swedish Medical Center, in Seattle. Invited by ASCO to comment on these data, Dr. West said that “it has been general practice to pool cancers with these mutations,” although evidence that they may behave differently has been reported since 2005. Dr. West said he is not yet convinced that afatinib is necessarily more active for del 19 or any other EGFR mutation relative to other EGFR TKIs because no other large data set has looked at OS stratified by mutation subtype. “That said, the OS benefit for del 19 cancers is quite impressive and robust” in this analysis, he noted. Overall, more data are needed to compare EGFR TKIs with one another rather than chemotherapy, with which they have been compared to date. According to Dr. West, chemotherapy is no longer the relevant comparator. He expressed great interest in the ongoing LUX-Lung 7 trial, which will compare EGFR TKIs. He believes both the relative efficacy and tolerability may yet determine which of these agents is first-line. —Ted Bosworth Dr. Yang reported financial relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Clivus, Genentech, InnoPharma, Lilly, Merck Serono, Novartis, Pfizer, Roche and Takeda. Dr. West reported no relevant financial relationships.

Report From ESMO 2014 Congress

Lux-Lung 8: Slight Edge to Afatinib Over Erlotinib for PFS in Lung SCC MADRID—In a head-to-head comparison of tyrosine kinase inhibitors (TKIs) for relapsed squamous cell carcinoma (SCC) of the lung, afatinib demonstrated an incremental benefit over erlotinib for the primary outcome of progression-free survival (PFS). Disease control rates in this Phase III multicenter trial were also significantly greater with afatinib than erlotinib, which is widely regarded as a standard for secondline therapy in advanced lung SCC. The improvement in PFS was characterized as “encouraging” by the principal investigator, Glen D. Ross, MD, the director of Clinical and Translational Research at Ottawa Hospital Cancer Centre, in Canada. However, in presenting these results at the European Society for Medical Oncology (ESMO) 2014 Congress (abstract 1222O), Dr. Ross suggested that a better idea of the relative role of these therapies would be obtained if afatinib (Gilotrif, Boehringer Ingelheim) also showed an advantage for overall survival (OS), a secondary trial end point to be evaluated with longer follow-up. In this study, called LUX-Lung 8, 795 patients with stage IIIB/IV SCC of the lung who had relapsed following an initial platinum-based regimen were

randomized to 40 mg per day of afatinib (uptitrated to 50 mg per day at the second cycle if well tolerated) or 150 mg per day of erlotinib (Tarceva, Genentech). The primary analysis presented in Madrid was based on 414 PFS events established by RECIST 1.1 criteria in the first 669 patients randomized. The median PFS was 2.4 months for afatinib and 1.9 months for erlotinib, which produced a hazard ratio (HR) of 0.82 (P=0.043) in favor of afatinib. By investigator review, the PFS advantage increased modestly but gained in statistical power (2.7 vs. 1.9 months; HR, 0.78; P=0.005). The suggestion that afatinib is more active than erlotinib in the relapsed setting was reinforced by a statistically significant greater rate of disease control (45.7% vs. 38.8%; P=0.02) as well as numerically but not significantly greater objective response rates (4.8% vs. 3.0%) in patients receiving afatinib. Rates of grade 3 or higher diarrhea (9.7% vs. 2.4%) and stomatitis (3.3% vs. 0%) were greater with afatinib, whereas grade 3 or higher rash (9% vs. 5.5%) was more common with erlotinib. Although Dr. Ross characterized the tolerability of

these agents as “comparable,” Stefan Zimmerman, MD, a medical oncologist at HFR-Fribourg Hospital, in Fribourg, Switzerland, disagreed. In an interview with Clinical Oncology News, Dr. Zimmerman said that he considered the toxicity associated with afatinib to be more burdensome and not necessarily worth the two-week median gain in PFS observed in this trial. He said he sees afatinib as an option for second-line therapy in relapsed SCC but not necessarily as a better choice than erlotinib. “The clinical value of erlotinib in the second-line setting was established in a trial that randomized patients who were ineligible for chemotherapy,” Dr. Zimmerman said. “In this trial, patients were not necessarily ineligible for second-line chemotherapy, so I am not sure that we are seeing greater benefit for afatinib in the population for which the advantage of erlotinib was initially demonstrated.” —Ted Bosworth Dr. Ross reported a financial relationship with Boehringer Ingelheim, the sponsor of this trial. Dr. Zimmerman reported no relevant financial relationships.

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Study Bolsters Obesity’s Link to Poor Breast Ca Survival Chicago—Obesity is associated with substantially increased mortality among women diagnosed with estrogen receptor (ER)-positive early breast cancer before menopause, according to data assembled from 80,000 patients presented at the 2014 annual meeting of the American Society of Clinical Oncology. The data showed little to no association between obesity and any other type of breast cancer, including ER-positive tumors diagnosed after menopause, in contrast to the results of an earlier meta-analysis published in April in Annals of Oncology. The effect of obesity on pre- rather than postmenopausal breast cancer patients was “the opposite of what we expected” but was highly significant, said investigator Hongchao Pan, PhD, who presented the study at the meeting (abstract 503). Dr. Pan, a senior researcher in the Clinical Trials Service Unit at the University of Oxford, in the United Kingdom, reported that the result was consistent across cancer grade, nodal status and HER2 receptor status. The data were obtained from 70 clinical trials in early breast cancer that had detailed information about patient characteristics, including body mass index (BMI), menopause status, hormone receptor status and outcomes over extended follow-up. A Cox regression analysis was performed to evaluate the associations. For the 20,000 premenopausal women with ER-positive breast cancer, the 10-year mortality among those who were obese—defined as a BMI of 30 kg/m2 or greater—was 21.5%, which represented an absolute increase of 5% over the 16.6%

Breast Cancer Mortality Rate Ratio

2.00

1.50 RR, 1.34 for obese (B BMI ≥30) vss normal weight (BMI 20-25)

1.25

1.00

BMI

<20

1,913

20-25

10,189

25-30

5,983

30-35

2,348

35+

1,286

0 5 0.75 15

BMI, kg/m2

Figure. Premenopausal ER+ breast cancer mortality by y BM MI. I BMI, body mass index; ER+, estrogen receptor–positive; RR, relative risk

‘Excess body fatness leads to poorer survival in women with breast cancer. This is supported by plausible biological mechanisms, including tumor proliferation, increased cell survival and angiogenesis.’ —Doris Chan mortality among those who were not obese. This translated into a relative risk (RR) for death of 1.34 (95% confidence interval [CI], 1.22-1.47; P<0.00001; Figure). The RR for death rose steadily in a stepwise fashion for increasing BMIs stratified as less than 20, 20-25, 25-30, 30-35 and more than 35. In the postmenopausal women with ER-positive breast cancer, the RR for death of 1.06 was not statistically

significant, and there was no change in risk for death for obese compared with non-obese women who had ER-negative breast cancer, regardless of menopausal status. When the analysis was restricted to ER-positive breast cancer patients aged between 44 and 54 years, the RR for death was 1.34 among premenopausal patients and 1.08 among postmenopausal patients, regardless of age; this finding reinforced menopausal

status, not age, as the discriminator for the association between obesity and risk for death. It was noted that tumors were somewhat smaller in normal-weight women at the time of diagnosis than in obese women, but the effect of obesity persisted after adjusting for this variable. There was no heterogeneity when looking at the overall effect of obesity on mortality when patients were grouped

Weight Gain Common After Breast Cancer Diagnosis CHICAGO—Within a year of a diagnosis of breast cancer, nearly half of patients gain significant body weight, according to data from a prospective cohort study. By the end of two years, the proportion grows to more than 60%. This finding confirms anecdotal reports and raises concern in the context of evidence that increased weight may adversely affect prognosis. The factors involved in weight gain after a diagnosis of breast cancer may be complex, according to data presented by a team of investigators from the hematology/oncology program at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, in Chicago. At the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 1543), they reported that certain types of breast cancer and certain genetic polymorphisms were associated with an increased likelihood of weight gain.

In this study, 120 women were recruited at Northwestern and evaluated at the time of diagnosis and then every six months for body mass index (BMI), nutritional status and exercise levels. In addition, patients were genotyped for single nucleotide polymorphisms (SNPs) in the FTO gene, which had been previously shown by two of the authors of this study, Virginia G. Kaklamani, MD, and Maureen Sadim, to be related to both breast cancer and obesity (Kaklamani et al. BMC Med Genet 2011;12:52, PMID: 21489227). At the end of 12 months, 45.3% of patients had a significant increase in BMI, and this rose to 60.9% at the end of 24 months, according to Dr. Kaklamani, an associate professor in the Division of Hematology/Oncology. Although neither chemotherapy nor endocrine therapy was associated with weight gain

after controlling for age, race, baseline BMI, nutritional status and exercise levels, patients with progesterone receptor–positive breast cancer were significantly more likely than other breast cancer subtypes to experience significant weight gain. Moreover, two SNPs—rs9939609 and rs1477196—were associated with increased likelihood of weight gain. Several studies have associated obesity with adverse outcomes in breast cancer, including a new study at the 2014 ASCO annual meeting in premenopausal women (see related story), but it is unclear whether weight gain after diagnosis also adversely affects outcome and if prevention of weight gain can provide a protective effect. Data from this study suggest that the pathologies of obesity and breast cancer may share a common mechanism, piquing interest in understanding whether weight control is a meaningful goal in the management of patients with breast cancer. —T.B.

Dr. Kaklamani and Ms. Sadim reported no relevant financial relationships.

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ASCO Targets Link Between Obesity and Ca in New Initiative

n its first policy statement on the connection between obesity and cancer, the American Society of Clinical Oncology (ASCO) called for increased education, research and advocacy to reduce the epidemic, both as a leading cause of cancer and as a hurdle in the care of patients with cancer. The society outlined four priorities, including increased education and awareness about links between obesity and cancer, development of new physician tools and resources, intensified and coordinated research, and policy changes to increase access to obesity screening, diagnosis and treatment. In addition to the recommendations, the release

by different variables, such as breast conservation or type of chemotherapy. This is not the first study to associate obesity with increased mortality among breast cancer patients, but it is one of the largest and provides compelling evidence that the risk is greatest for premenopausal women with ER-positive disease, implicating ovarian activity in this association. Despite this, not all the evidence suggests that the risk is confined to premenopausal women. In the meta-analysis, recently published in Annals of Oncology (Chan et al. 2014 April 27. [Epub ahead of print]), the RR for breast cancer death in the presence of obesity before diagnosis was 1.50 (95% CI, 1.13-2.00) in premenopausal women and 1.34 (95% CI, 1.21-1.48) in postmenopausal women. These data do not necessarily contradict the data from Pan et al, according to Doris Chan, the study’s first author, who is completing a PhD in the Department of Epidemiology and Biostatistics at the Imperial College’s School of Public Health, in London. Unlike the pooled analysis conducted by Pan et al, which used data from women participating in clinical trials, the metaanalysis led by Ms. Chan also included observational studies. Patients participating in trials “could be younger, better educated and healthier,” speculated Ms. Chan, who noted that the association between obesity and higher mortality in the study by Pan et al also was positive in postmenopausal women, even if it was not statistically significant. She suggested that more data are needed from population-based studies that “are more applicable to a wider range of breast cancer survivors.” Indeed, Ms. Chan indicated that these two studies may have more similarities than differences. “Both studies highlighted evidence that excess body fatness leads to poorer survival in women with breast cancer,” she said. “This is supported by plausible biological mechanisms, including tumor proliferation, increased cell survival and angiogenesis.” —Ted Bosworth Drs. Pan and Ms. Chan reported no relevant financial relationships.

emphasizes that obesity is projected to soon overtake tobacco as the leading preventable cause of cancer in the United States. “With nearly three in four Americans obese or overweight, obesity has become a tremendous public health challenge that also impacts cancer care and prevention today,” ASCO immediate past president Clifford A. Hudis, MD, FACP, said in a statement. “We can’t allow obesity to undo decades of progress in prevention, early diagnosis and treatment of cancer.” Supporting ASCO’s stance, studies related to breast cancer and colorectal cancer have

strengthened the association between obesity and cancer and increased mortality. The related story on this page describes a recent study that underscores the connection of obesity to lower survival among premenopausal women. Additionally, data presented at the annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research showed that young Swedish men who were obese or had blood markers indicating high levels of inflammation were 2.37 times more likely to develop colorectal cancer later in life than those who were normal weight as adolescents (see http://bit.ly/1CEmIjv). —Paul Bufano

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Preserving Fertility in Women With Breast Cancer Chicago—Adding goserelin to standard chemotherapy preserves fertility in women with early-stage, hormone receptor– negative breast cancer, according to data from POEMS (Prevention of Early Menopause Study) presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract LBA505). “For the 25% or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment,” said POEMS investigator Halle Moore, MD, a staff physician in the Department of Solid Tumor Oncology at Cleveland Clinic’s Taussig Cancer Institute. “This is the first demonstration of improved fertility prospects and more successful pregnancies when goserelin was used.” Previous randomized trials that have investigated the prevention of ovarian cycling during chemotherapy with hormone-suppressing drugs have yielded mixed results. Most have used the return of menses as the primary end point, and few studies have evaluated pregnancy outcomes. The Phase III POEMS enrolled women younger than age 50 with operable stage I, II and IIIA estrogen and progesterone receptor–negative breast cancers. Women who were going to receive an adjuvant or a neoadjuvant regimen containing cyclophosphamide were stratified by age and chemotherapy regimen and randomized to receive goserelin (Zoladex, AstraZeneca) (n=126) or not (n=131). Patients were ineligible if they were taking estrogen, progesterone, selective estrogen receptor modulators

or aromatase inhibitors. In the experimental arm, patients received goserelin 3.6 mg subcutaneously every four weeks, starting at least one week before the first chemotherapy dose. Hormone suppression was continued for the duration of chemotherapy, and the last dose was administered within two weeks of the final chemotherapy dose. Compared with those not receiving goserelin, women receiving it had less ovarian failure, as measured by elevated follicle-stimulating hormone and less amenorrhea at two years (8% vs. 22%; odds ratio [OR], 0.30; P=0.04). Women in the goserelin arm also had lower rates of ovarian dysfunction and higher rates of pregnancy (Table). Grade II to IV endocrine toxicities, including hot flashes, mood changes, vaginal dryness and headache, were more common in patients receiving goserelin (48% vs. 24%; P=0.0006). There was no statistically significant difference in the number of grade III/IV endocrine toxicities, and there was only one grade IV toxicity, a thromboembolic event that occurred in a patient receiving goserelin. The two arms had a similar number of total miscarriages, elective terminations and delivery complications. An exploratory analysis, adjusted for age, regimen and stage, showed that women in the goserelin arm had better four-year disease-free survival (89% vs. 78%; P=0.04) and overall survival (92% vs. 82%; P=0.05) than those not taking goserelin. Dr. Moore said the survival findings are “intriguing” and provide reassurance to patients that the

‘This is the first demonstration of improved fertility prospects and more successful pregnancies when goserelin was used.’ —Halle Moore, MD

goserelin-containing regimen is safe. Sharon Giordano, MD, MPH, an

‘Because of the missing data and low accrual on this study … I don’t think we can consider these results definitive, [but] … I would be comfortable offering this option to my young patients with estrogen receptor–negative breast cancer who desire future fertility or prevention of premature menopause.’ —Sharon Giordano, MD, MPH

Table. Outcomes in Patients Treated With and Without Goserelin in POEMS Outcome Measure

Standard Chemotherapy, %

Standard Chemotherapy + Goserelin, %

Odds Ratio

Adjusted P Value

Elevated FSH and amenorrhea at 2 y

0.30

0.04

Elevated FSH orr amenorrhea at 2 y

0.29

0.006

Ovarian dysfunction at 2 y

0.35

0.03

Patients with pregnancy

2.45

0.03

Patients delivering or ongoing pregnancy

2.45

0.04

Patients with ≥1 delivery

2.51

0.05

internist at the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, in Houston, who was not involved with POEMS, pointed out that the study was hampered by a small sample size and missing end point data for 38% of participants. “Because of the missing data and low accrual on this study, some uncertainty remains on this topic, and I don’t think we can consider these results definitive,” she said. “Having said that … I would be comfortable offering this option to my young patients with estrogen receptor–negative breast cancer who desire future fertility or prevention of premature menopause.” A recent meta-analysis of nine studies involving 765 patients also supports these data. It identified a significant reduction in the risk for premature ovarian failure in breast cancer patients receiving gonadotropin-releasing hormone analogs (OR, 0.43; 95% confidence interval, 0.22-0.84; P=0.013) (Cancer Treat Rev 2014;40[5]:675-683, PMID: 24360817). —Kate O’Rourke

FSH, follicle-stimulating hormone

Drs. Moore and Giordano reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • OCTOBER 2014 • CLINICALONCOLOGY.COM

Streamlining Early Breast Cancer Care Expert lists procedures to avoid because they do not add value

n an era when health care resources are limited, clinicians are under increasing pressure to avoid therapies that provide marginal or no benefit. At the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), Monica Morrow, MD, the chief of the breast surgery service at Memorial Sloan-Kettering Cancer Center, in New York City, identified five procedures that should be avoided in the treatment of early breast cancer because they do not add value. “Value” is defined as a fair return in goods, services or money for something exchanged. “In the context of health care, return should be in overall survival [OS], disease-free survival [DFS], local control or quality of life, to balance the cost of treatment, not only economic cost but toxicity,” Dr. Morrow said.

Table. Use of MRI and Contralateral Breast Cancer Detection Incidence of Contralateral Breast Cancer, %

Study

Patients Undergoing MRI, %

l 2004;14(10):1725-1731, PMID: 15248080

346

3.4

1.7

<0.001

J Clin Oncoll 2008;26(3):386-391, PMID: 18202414

756

0.39

Radiology 2013;267(1):57-66, PMID: 23329656

3,094

3.8

0.5

1.4

0.02

J Surg Oncoll 2013;107(8):815-821, PMID: 23505028

615

5.7

2.2

1.3

0.51

Follow-up, y

MRI

No MRI

P Value

MRI, magnetic resonance imaging

The List

Magnetic resonance imaging (MRI) for staging

The arguments for using MRI for local staging include improved selection of patients for breast-conserving surgery (BCS), improved definition of tumor extent, synchronous identification of contralateral cancer and decreased local recurrence. According to Dr. Morrow, however, these arguments aren’t supported by data. A recent meta-analysis involving 3,112 patients revealed that patients who undergo MRI before surgery and those who do not have the same rate of reexcision and unexpected conversion to mastectomy ((Ann Surgg 2013;257[2]:249255, PMID: 23187751). MRI significantly increased mastectomy rates (1.5 to threefold) without improving outcomes. Additionally, studies showing that MRI improves the detection of contralateral cancer are inconclusive, and even when there is a benefit, it is slight (Table).

Contralateral prophylactic mastectomy

There is no evidence that contralateral prophylactic mastectomy improves survival for the average woman with breast cancer, but there are costs. “We know if you have twice as much surgery, it doubles your risk of surgical complications,” Dr. Morrow said.

Routine re-excision of margins

A year ago, the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) held a consensus conference to review the evidence for routine re-excision of close margins in patients who undergo BCS.

These groups commissioned a meta-analysis of 33 studies involving 28,162 patients with stage I/II breast cancer and a minimum mean/median follow-up of four years. There was no statistically significant difference between local recurrence and threshold margin distances of 1, 2 or 5 mm ((Ann Surg Oncoll 2014;21[3]:717-730, PMID: 24473640). According to the consensus statement, endorsed by SSO, ASTRO, ASCO and the American Society of Breast Surgeons, negative margins (no ink on tumor) optimize local control; wider margins do not significantly improve local control, and the routine practice of obtaining margins more widely clear than no tumor on ink is not indicated. Pointing to the 26,550 re-excisions performed annually for close margins, Dr. Morrow said the potential impact of this guideline adoption is a minimum savings of $30 million annually using Medicare data ((Ann Surg Oncol 2014;21[5]:1512-1514, PMID: 24577813).

23-01 demonstrated that there was no difference in local, regional or distant recurrences based on performing ALND for micrometastases ((Lancet Oncol 2013;14[4]:297-305, PMID: 23491275). Similar results were seen in patients with macrometastases undergoing BCS and receiving whole-breast irradiation and systemic therapy ((JAMA 2011;305[6]:569-575, PMID: 21304082). The American College of Surgeons Oncology Group Z0011 trial showed a nodal recurrence rate of less than 1% and no difference in DFS or OS for patients randomized to the group not undergoing ALND; additionally, these women had significantly fewer side effects than those having ALND.

The Cancer and Leukemia Group B-9343 study demonstrated that adjuvant radiation therapy after BCS and tamoxifen in women age 70 years and older with early-stage breast cancer had no effect on OS, DFS or breast preservation ((J Clin Oncoll 2013;31[19]:2382-2387, PMID: 23690420).

Routine axillary lymph node dissection (ALND) for one to two positive sentinel nodes

The 10-year follow-up of the National Surgical Adjuvant Breast and Bowel Project B32 trial showed that the presence of micrometastases had no effect on DFS and OS in node-negative invasive breast cancer (abstract 1000; ASCO 2013 annual meeting). The International Breast Cancer Study Group trial

Radiation after BCS in women older than age 70 years with estrogen receptor (ER)-positive, early-stage breast cancer

Expert Reaction Gary Lyman, MD, MPH, a medical oncologist specializing in breast cancer

at the University of Washington and the Fred Hutchinson Cancer Research Center, and a co-director of the Hutchinson Institute for Cancer Outcomes Research, in Seattle, applauded the list. “I agree with all five of these in general, with the understanding that every generalization has exceptions, and it still behooves the oncologist to use their best judgment when applying any of these recommendations,” Dr. Lyman said. For example, every oncologist has been in the situation where an MRI identified other unsuspected lesions, but MRI has a high false-positive rate, is very expensive, and has not been shown to be useful on a routine basis. Despite these drawbacks, there may be specific cases for which, based on an examination or a complicated history, MRI may be useful and warranted. The one recommendation that Dr. Lyman said he would challenge “a bit” was radiation in elderly patients. He does not like using age per se as a criterion. “It is not so much about chronological age as physiological age and life expectancy,” he said. A frail, elderly woman with multiple comorbidities may be a good candidate to skip radiation, but radiation may be reasonable for an active 75-year-old who may live into her 90s. —Kate O’Rourke Drs. Morrow and Lyman reported no relevant financial relationships.

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REPORT Implementation of Immunotherapy In the Management of Melanoma The Society for Immunotherapy of Cancer Consensus Statement

he incidence of melanoma Addressing the Gap Faculty has increased significantly In Clinical Practice since the 1970s,1 and the numHoward L. Kaufman, MD, FACS ber of cases continues to rise.1,2 Because melanoma is the fifth Chief Surgical Officer most common type of cancer,3,10 In the United States, experts estimate that 76,100 patients will oncologists in many communities Associate Director for Clinical Sciences be diagnosed with melanoma may not see it as frequently as Rutgers Cancer Institute of New Jersey in 2014 and 9,710 will die from other cancers. Therefore, these Professor, Department of Surgery the disease.3 Among skin canclinicians may lack an experiential Rutgers, The State University of New Jersey basis for making the decision to cers, melanoma accounts for New Brunswick, New Jersey use immunotherapy and for only 2% of cases making it a rare selecting appropriate patients for form3 ; however, it accounts for treatment. Additionally, clinicians may be unfamiliar with the majority of skin cancer deaths. Early detection is critsome of the recently approved immunotherapies, and uncerical and treatment is often successful; however, diagnotain on how to sequence immunotherapy and manage its sis after disease progression has a poor prognosis.4 The adverse effects (AEs). The Society for Immunotherapy of American Joint Committee on Cancer Melanoma Staging Cancer (SITC) guidelines address the concern that a number Database (AJCC) has shown that, for stage IIIA, B, and C of practicing oncologists may not be entirely familiar with the disease 5-year disease, 5 year survival is 78%, 78% 59%, 59% and 40%, 40% respecrespec use of immunotherapy in melanoma. tively.4 One-year survival in stage IV disease ranges from 62% to 33% depending on the increasing severity of metThe SITC guidelines were developed to provide pracastatic (M) substage—M1a, b, or c.4 ticing oncologists an evidence-based consensus statement on immunotherapy for melanoma. The objective of Prior to 2011, systemic therapy for melanoma includthe SITC guidelines is to enhance clinicians’ understanded high-dose interferon-α2b for adjuvant therapy with ing of immunotherapy within the context of chemotherapy chemotherapy (dacarbazine) and high-dose interleukin-2 and BRAF-targeted therapies. In this regard, SITC guide(IL-2) used in advanced disease.5 Over the last 3 years, lines enrich the treatment recommendations for melanoma the therapeutic armamentarium has expanded with the provided by the National Comprehensive Cancer Network, approvals of pegylated interferon-α2b for adjuvant treatwhich list but do not sequence treatment options.11 ment5,6 and, in metastatic disease, molecularly targeted therapy with BRAF and MEK inhibitors,7 as well as novel Algorithms in the SITC guidelines delineate sequencing 5 iimmunotherapy th using i ipilimumab, i ili b an anti-CTLA4 ti CTLA4 monoand d iindicate di t when h to t stop t iimmunotherapy. th A kkey feature f t 8,9 clonal antibody, and pembrolizumab, a PD-1 inhibitor. of sequencing is the important differentiation of optimal

Supported by

REPORT settings for the use of BRAF inhibitors versus immunotherapy.5 Finally, the publication of the guidelines will facilitate the adoption of novel immune-checkpoint inhibitors, such as the PD-1 inhibitor class of therapy. With the ongoing development of novel therapies,5 it is undeniable that when to use immunotherapy will become more complicated as novel agents are introduced. The development of the consensus statement will help to stabilize practice treatment patterns and provide clinicians with a resource for core treatment approaches into which they can incorporate new therapies without starting from scratch when treatments are approved. Clinicians also can anticipate guideline updates5 that identify appropriate candidates for new immunotherapies and delineate where novel agents fit in the guidelines.

The breadth and level of evidence for algorithm recommendations vary, and these differences are noted in the guidelines. For example, whereas evidence for the use of immunotherapy is fairly limited in stage II melanoma, there is more robust evidence for immunotherapy in stage IV.5 Prior to initiating any treatment pathway, the SITC guidelines recommend a review of patient and tumor data by the multidisciplinary care team, determination of tumor stage, and careful assessment of all features of the patient’s disease.5 In general, the melanoma guidelines focused on disease stage and included recommendations based on evidence from the peer-reviewed literature and supplemented with suggestions from the consensus panel where clear evidence-based data were lacking. The following reviews the basic recommendations.

Immunotherapy for Melanoma

Stage II Immunotherapy

Experts have known for over a century that the immune system plays a significant role in cancer, leading to the development of immunotherapy.12 Several features distinguish immunotherapy from other forms of anticancer treatment, including its durable response of 10 to 15 years—in a subset of patients both in metastatic melanoma and in metastatic renal cell carcinoma.5,13,14 IL-2 has produced multi-year durable responses in metastatic melanoma. Using pooled data from 8 trials, Atkins and colleagues15 found that IL-2 produced a median duration of response of at least 59 months and follow-up for survivors exceeded 7 years. In 2014, a retrospective, community-based analysis of 314 patients treated for metastatic melanoma with IL-2 found a 3-year overall survival (OS) of 31%.16 Ipilimumab, a more recent addition to the treatment armamentarium, has also shown durable responses in long-term follow-up data.17 In a pivotal Phase III trial of 676 patients with metastatic melanoma, 2-year survival with ipilimumab was about 23.5%.8 Long-term follow-up of 177 patients from 3 trials reported 5-year OS rates of 13% to 25%, depending on the trial14; in clinical trials, ipilimumab was given with glycoprotein 100 peptide vaccine or with IL-2. Combined therapy may have affected the outcome.14 Among 14 of 15 complete responders to ipilimumab across the 3 trials, survival was ongoing from 54 to 99 months.14 Results with both IL-2 and ipilimumab show a durable response, but also indicate that this favorable outcome occurs only in a subset of patients.5,8,14-16 Immunotherapy works more slowly than other therapies and the delayed kinetics of response makes clinical monitoring of patients more challenging.5,16,18,19 Moreover, with immunotherapy, tumors can flare in the short term, as the immunologic attack begins.19 Immunotherapy also has a different adverse event profile, including autoimmune effects,20 some of which can be severe, lifethreatening, and long-lasting (eg, autoimmune colitis,8 pulmonary toxicity,16 neurocortical toxicity,16 and immune-mediated adrenal insufficiency8 ), and some of which interfere with a patient’s quality of life (eg, depression,21 fatigue,8,21 diarrhea,8,21 hypothyroidism,8,21 and immune-mediated skin conditions8 ). Despite these AEs, clinical management of the autoimmune events appears possible by using corticosteroids, and when necessary, more potent immunosuppressive agents.

This algorithm divides treatment pathways on the basis of predicted risk.5 For patients considered low-risk, observation is recommended. High-risk patients—defined as those with tumors larger than 4 mm in diameter, ulcerated tumors, or a tumor mitotic rate of at least 1 per mm2—may be enrolled in a clinical trial or treated with interferon-α2b; interferon therapy should be terminated after 1 year or if poorly tolerated.5 Candidates for treatment with interferon-α2b should have a good performance status without a history of major depression, mental illness, or autoimmune disease. The consensus panel does not advocate for pegylated interferon-α2b in patients with high-risk, stage II melanoma.5

SITC Recommendations for Immunotherapy At the core of the SITC guidelines are evidence-based algorithms for immunotherapy in melanoma stages II through IV.5 Considerations have been made based on patient selection, toxicity management, and treatment sequencing and cessation.5

Stage III Immunotherapy Prior to initiating treatment in this group of patients, a diagnostic evaluation and tumor staging should include serum lactate dehydrogenase (LDH) testing, imaging studies (eg, whole body imaging/computed tomography [CT] of the chest, abdomen, and pelvis and magnetic resonance imaging [MRI] of the brain), and review of pathologic features and performance status.5 Treatment is dependent on the basis of nodal (N) status, determined by sentinel lymph node biopsy or lymph node dissection: N1a versus N1b/N2-3.5 For patients with N1a nodal status, the guidelines recommend 4 treatment options: (a) clinical trial; (b) pegylated interferon-α2b (terminated after 5 years or if poorly tolerated); (c) interferon-α2b (terminated after 1 year or if poorly tolerated); or (d) observation.5 Although evidence is insufficient to rank these 4 treatments, panel opinion offers some additional guidance. A minority of the panel members (14.3%) considers pegylated interferon-α2b for N1a disease, or in ulcerated lesions, whereas the majority of the panel recommends 1 year of interferon-α2b for stage III patients regardless of nodal status.5 For patients with N1b/N2-3, the panel recommends interferon-α2b (terminated after 1 year or if poorly tolerated) or enrollment in a clinical trial.5 Of the consensus panel, 72.7% recommend that patients with macroscopic nodal disease receive 1 year of interferon-α2b.5

Stage IV Immunotherapy For patients with stage IV (metastatic) melanoma, surgery should be considered first when tumors can be resected.5 Treatment selection in stage IV is determined by performance status, central nervous system (CNS) disease status, and BRAF/ KIT T mutation status individualized with patient involvement.5 The Figure outlines an algorithm on treatment sequencing

REPORT

Diagnostic Workup

pathways.5 Treatment in stage IV does not have a time-specific termination point. Rather, it should continue until maximum response, confirmed progression, or poor tolerability occurs.5 For patients whose tumors harbor a BRAF F mutation, those with poor performance status and/or active CNS disease, the guidelines recommend first-line treatment with molecularly targeted therapy using BRAF and/or MEK inhibitors (ie, vemurafenib, dabrafenib or trametinib).5 Ipilimumab and chemotherapy (eg, dacarbazine 6 ) is considered second-line therapy, whereas IL-2 and enrollment in clinical trials is considered third-line therapy.5 Despite the presence of a BRAF F mutation, immunotherapy with IL-2 is recommended as first-line therapy for BRAF-positive F patients with good performance status and no active CNS disease, whereas ipilimumab is considered a second-line option.5 BRAF inhibition is reserved for a third-line choice with clinical trial enrollment and chemotherapy as fourth- and fifth-line choices, respectively.5 For these patients, a good performance

Staging confirmed including pathology, imaging, serum LDH and mutation analysis of tumour Evaluation for metastasectomy Special attention to the presence of CNS disease

Patient Selection

Surgical candidate

Treatment Recommendations

status indicates the potential for a durable response with IL-2 or ipilimumab.5 Patients with wild-type BRAF F tumors with poor performance status and/or untreated CNS disease may receive ipilimumab first-line, chemotherapy second-line, and clinical trial enrollment as third-line therapy.5 The rationale for this recommendation is that ipilimumab demonstrated activity against CNS metastases in a Phase II trial.22 This patient group often requires highly individualized management with surgery and/or radiation therapy to control CNS metastases prior to systemic therapy consideration.5 In contrast, patients whose tumors are BRAF-negative F with good performance status and treated (or no) CNS disease may receive IL-2 first followed by ipilimumab, a clinical trial, or chemotherapy as second-, third-, and fourth-line recommendations, respectively.5 The panel considered both forms of immunotherapy—IL-2 and ipilimumab—as good choices for this patient group, but recommended IL-2 first because there are no data on the safety of IL-2 after ipilimumab.5

Yes

Proceed with surgery

No BRAF+ Poor PS CNS disease

BRAFGood PS

1st Vemurafenib, dabrafenib, or trametinib 2nd IL-2 3rd Ipilimumab 4th Chemotherapy 5th Clinical trial

Treatment Cessation

Good PS Treated CNS disease

KIT+ Poor PS Untreated CNS disease

1st IL-2 2nd Ipilimumab 3rd Clinical trial 4th Chemotherapy

1st IL-2 2nd Ipilimumab 3rd Vemurafenib, dabrafenib or trametinib 4th Clinical trial 5th Chemotherapy

1st Clinical trial 2nd IL-2 3rd Ipilimumab 4th Chemotherapy

1st Ipilimumab 2nd Chemotherapy 3rd Clinical trial

Treatment until response, progression or unacceptable adverse effects

Figure. Stage IV melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. This algorithm represents consensus sequencing suggestions by the panel. BRAF+, F positive for actionable BRAF mutations; BRAF–, F negative for actionable BRAF mutations; CNS, central nervous system; IL, interleukin; KIT+, T positive for actionable KIT T mutations; LDH, lactate dehydrogenase; PS, performance status Reprinted with permission. Kaufman HL, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10(10):588-598.

REPORT

Considerations for Radiation and Surgical Intervention The consensus process revealed several interesting trends. Some experts championed the view that resection or radiation therapy need to be considered more frequently in patients with metastatic disease.5 This view was based on data supporting a benefit for metastasectomy,23-26 and it may be considered first line in stage IV disease if complete resection of metastatic disease is possible.5 Surgery also may be indicated in some patients who attain partial or stable disease after immunotherapy, and the guidelines suggest that patients with an incomplete response to treatment be re-evaluated for surgical options after completing systemic therapy.5,27 The rationale for these approaches is that radiation or surgery plus immunotherapy may have synergistic or additive effects. A limited body of literature supports this view. For example, a Phase I trial indicated that stereotactic body radiation followed by IL-2 produced a higher than expected response rate.28 Surgical metastasectomy of residual disease after IL-2 can sometimes produce durable, progression-free survival.27 Various sequences of surgery/radiation plus immunotherapy might be effective strategies to eliminate as much disease as possible and maintain suppression.

Individualization of Treatment The consensus panel emphasized the importance of individualization of therapy according to the patient’s performance status and therapeutic goals, tumor characteristics, and availability of treatment options. CNS metastasis also complicates immunotherapy and militates against its use for similar reasons.5 PD-1 inhibitors represent a new form of immunotherapy and provide additional opportunity to adapt treatment. Further interest in combination immunotherapy is a high priority for the field, and the consensus panel may consider recommendations for high-priority combinations. This is supported by a Phase I trial that investigated the efficacy of combining nivolumab and ipilimumab in patients with advanced melanoma; 2-agent concurrent immunotherapy in this study produced an objective response in 53% of patients versus 20% of patients in a 2-agent sequenced group.29

Conclusion The SITC guidelines provide practicing oncologists with a uniform set of recommendations for the use of immunotherapy in stages II, III, and IV melanoma. These recommendations enable clinicians to identify appropriate patients for immunotherapy and make an evidence-based choice of intervention that depends on the patient profile. The guidelines are iterative, and will be updated in the near future to include recommendations based on new clinical evidence—particularly evidence on the use of PD-1 inhibitors and other emerging immunotherapy agents and combinations.

References 1. National Cancer Institute. Cancer Trends Progress Report—2011/2012 Update. http://progressreport.cancer.gov/index.asp. Accessed September 29, 2014. 2. Jemal A, Saraiya M, Patel P, et al. J Am Acad Dermatol. 2011;65(5 suppl 1): S17-S25.e1-13. 3. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. 4. Balch CM, Gershenwald JE, Soong S-J, et al. J Clin Oncol. 2009;27(36): 6199-6206. 5. Kaufman HJ, Kirkwood JM, Hodi FS. Nat Rev Clin Oncol. 2013;10(10): 588-598. 6. Eggermont AM, Suciu S, Santinami M, et al. Lancet. 2008;372(9633): 117-126. 7. Chapman PB, Hauschild A, Robert C, et al. N Engl J Med. 2011;364(26): 2507-2516. 8. Hodi FS, O’Day SJ, McDermott DF, et al. N Engl J Med. 2010;363(8): 711-723. 9. Robert C, Ribas A, Wolchok JD, et al. Lancet. 2014 [Epub ahead of print]. 10. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Accessed September 24, 2014. 11. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma, V4, 2014. http://www.nccn.org. Accessed September 29, 2014. 12. Goldman B, DeFrancesco L. Nat Biotechnol. 2009;27(2):129-139. 13. Atkins MB, Kunkel L, Sznol M, et al. Cancer J Sci Am. 2000;6(suppl 1): S11-S14. 14. Prieto PA, Yang JC, Sherry RM, et al. Clin Cancer Res. 2012;18(7):20392047. 15. Atkins MB, Lotze MT, Dutcher JP, et al. J Clin Oncol. 1999;17(7):2105-2116. 16. Payne R, Glenn L, Hoen H. et al. J Immunother Cancer. r 2014;13(2):1-10. 17. Lebbe C, Weber JS, Maio M, et al. Ann Oncol. 2014 [Epub ahead of print]. 18. Hoos A, Eggermont AM, Janetzki S, et al. J Natl Cancer Inst. 2010;102(18): 1388-1397. 19. Pennock GK, Wakefield W, Wolchok JD. Am J Clin Oncol. 2012;35(6): 606-611. 20. Chianese-Bullock KA, Woodson EM, Tao H, et al. J Immunother. 2005;8(4): 412-419. 21. Eton O, Rosenblum MG, Legha SS, et al. Cancer. 2002;95(1):127-134. 22. Margolin K, Ernstoff MS, Hamid O, et al. Lancet Oncol. 2012;13(5):459-465. 23. Schuhan C, Muley T, Dienemann H, et al. Thorac Cardiovasc Surg. 2011; 59(3):158-162. 24. Wasif N, Bagaria SP, Ray P, et al. J Surg Oncol.l 2011;104(2):111-115. 25. Chua TC, Scolyer RA, Kennedy CW, et al. Ann Surg Oncol. 2012;19(6): 1774-1781. 26. Howard JH. Ann Surg Oncol. 2012;19(8):2547-2555. 27. Lee DS, White DE, Hurst R, Rosenberg SA, Yang JC. Cancer J Sci Am. 1998;4(2):86-93. 28. Seung SK, Curti BD, Crittenden M, et al. Sci Transl Med. 2012;4(137): 137ra74. 29. Wolchok JD, Kluger H, Callahan MK, et al. N Engl J Med. 2013;369(2): 122-133.

Disclosure: Dr. Kaufman reported that he is a consultant for Amgen, EMD Serono, Prometheus, and Sanofi. He also serves on advisory boards for Alkermes, Merck, and Nodality. He also received research funding from Amgen, Bristol-Meyers Squibb, and EMD Serono. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Prometheus, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

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The guidelines recommend that, for all KIT-positive T patients with stage IV disease, a clinical trial is the first choice. Second-, third-, and fourth-line therapies are IL-2, ipilimumab, or chemotherapy, respectively. The presence of KIT T mutation is a special circumstance that warrants highly individualized treatment planning since there are KIT inhibitors in clinical development; therefore, a clinical trial is the first choice, followed by IL-2, ipilimumab, or chemotherapy.5 The SITC identified and tackled several unique issues relevant to the treatment of melanoma. These included recommendations for imaging during and after immunotherapy, laboratory monitoring during immunotherapy, management of depression in patients treated with interferon-α2b, and the termination of immunotherapy.5 These recommendations include panel consensus on routine monitoring of thyroid function, blood counts, liver enzymes, metabolic panels, and LDH; a goal of these assessments is to augment monitoring for the AEs of immunotherapy, particularly autoimmune and immune-related effects.5