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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • August 2014 • Vol. 9, No. 8

CURRENT PRACTICE Online system helps chemotherapy patients manage symptoms .............

Cardiac risks are high in childhood cancer survivors ..................................

HEMATOLOGIC DISEASE Kieron Dunleavy, MD: How I manage adults with Burkitt lymphoma .... 14 Clinical Conundrums .......

Chicago—Patients with KRAS wildtype metastatic colorectal cancer (mCRC) receiving first-line treatment with a chemotherapy backbone plus bevacizumab or cetuximab survived for a median of 29 months, the longest median survival time reported in a major trial of these severely ill patients. Importantly, survival times were the same, whether patients received the anti–vascular endothelial growth factor bevacizumab (Avastin, Genentech) or the anti–epidermal growth factor receptor (EGFR) cetuximab (Erbitux, Bristol-Myers Squibb), or whether they received FOLFOX or FOLFIRI, see HIGHER BAR, R page 18

SOLID TUMORS Immunotherapy for lung cancer: promising, but combined strategies will likely be needed ..............

IMAGES in ONCOLOGY

Higher Bar Set for Trials in Advanced Colorectal Cancer

INSIDE

EDITORIAL BOARD COMMENTARY

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Regulations Cause Serious Ethical Issue In Ca Trial Design Calls into question ‘control arms’ of drug approval trials

his is unfortunately not the first time I have raised the major ethical issue addressed in this column. Regardless of the apparent lack of attention by the clinMaurie ical oncology research Markman, MD community to the matter highlighted in the following paragraphs, a response is required. We begin with a consideration of the Nuremberg Code, arguably the single most important document ever written see ETHICAL ISSUE, E page 5

Dividing breast cancer cell; exemestane with ovarian suppression emerging as new standard for treating premenopausal breast cancer; story on page 20.

What’s an Oncologist’s Role In Containing Health Costs? Chicago—In an era when the rising cost of cancer care has been called a crisis, do oncologists have a duty to society as well as to their patients? In a session during the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), clinicians discussed this ethical dilemma. According to Beverly Moy, MD, MPH, the clinical director of the Breast Oncology Program at Massachusetts General Hospital, in Boston, the professional norm is that the foremost responsibility of oncologists is to do what is best for their patients. But, she said, this norm is eroding under the pressure of escalating costs. Those cost pressures are tremendous. In 2009, the National Institutes of Health estimated overall annual costs of cancer care at $216.6 billion. Data from WellPoint Inc., the largest managed health care company in the Blue Cross Blue Shield Association, show that drugs and technology are the main drivers of those costs (Table). “In 2013, six of the eight drugs approved for cancer therapy were around $10,000 per month, and in 2014, nine of the 12 anticancer therapies approved were or exceeded $10,000 in cost,” Dr. Moy said. “More alarmingly, most of those drugs failed to show a prolongation of survival in clinical trials. For the ones that did, the benefit was modest, ranging from 10 days to a few months.” see VALUE, E page 11

SPECIAL ASCO 2014 COVERAGE Growth Factors Often Given to Low-Risk Patients, Despite Guidelines .......................................................................................................

Panobinostat Shines in PANORAMA-1 Trial ....................................................

Checkpoint Inhibitors for Metastatic Renal Cell Carcinoma ...................

In the research of advanced cancers

What if inhibiting the PD-1 helped restore immune

The PD-1 checkpoint pathway plays a key, distinct role in modulating the immune system1-3 Antigen-presenting cell

Normal State Antigens

Active T cells

Apoptosis-inducing proteins Tumor

In a normal state, the immune system recognizes tumors and can mount an active antitumor response4,5 • Tumors release antigens that are collected by circulating antigen-presenting cells6 • Antigen-presenting cells activate T cells that proliferate and migrate to the tumor. T cells then release apoptosis-inducing proteins, which attack tumor cells6,7

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity 1-3,8 Tumor Immune Evasion

Antigen-presenting cell

Antigens Inactive T cells

Active T cells

PD-L1 ligand

Tumor cell

PD-1 receptor

Inhibited T cell

Tumor PD-L2 ligand

PD-1 receptor

Through tumor immune evasion, tumors can convert active T cells to inactive T cells through the PD-1 checkpoint pathway to inhibit normal immune response1-3,8 • In some cancers, tumor cells express PD-L1 and/or PD-L2. Either of these ligands can bind to the PD-1 receptors on T cells to exploit the immune checkpoint pathway1-3,8,9 • Binding of the PD-1 receptor on T cells to either PD-L1 or PD-L2 ligands on tumor cells can inhibit activated T cells, suppressing T-cell attack and negatively regulating immune response1-3,8,9

checkpoint pathway response to tumor cells? Bristol-Myers Squibb is researching ways of inhibiting the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands, allowing the immune system to restore T-cell attack on tumor cells, which may play a role in helping the body fight cancer 3,10 Active T cell

X Apoptosis-inducing proteins

PD-L2 ligand

PD-L1 ligand

PD-1 receptor

Tumor

The PD-1 immune checkpoint pathway: an innovative target for cancer research • By exploiting the PD-1 immune checkpoint pathway, cancer cells can evade the normal immune response and continue to proliferate1-3,8 • Understanding the PD-1 pathway has the potential to change the way we approach certain cancers

Learn more at www.pd1pathway.com • Experience the PD-1 checkpoint pathway through an immersive video • Hear a leading oncologist answer questions about the PD-1 checkpoint pathway • Learn more about how Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology

PD-1=programmed death 1; PD-L1=PD-1 ligand 1; PD-L2=PD-1 ligand 2. References: 1. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 2. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 3. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 5. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 7. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735-747. 8. Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

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

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

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Oncology Nursing

Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Betty Ferrell, RN, PhD

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

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Harry Erba, MD, PhD University of Alabama Birmingham, AL

Pharmacy Shaji Kumar, 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

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

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

Memorial Sloan-Kettering Cancer Center New York, NY

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

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 in providing the best possible care for their patients.

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

Steven D. Passik, PhD

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Albert Einstein College of Medicine New York, NY

Medical Oncologist New York, NY

Edward S. Kim, MD

Richard J. Gralla, MD

Susan K. Seo, MD

Cancer Treatment Centers of America Zion, Illinois

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

Infection Control

Syed A. Abutalib, MD

Steven Vogl, MD Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

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

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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

Hematologic Malignancies Breast Cancer

Bioethics

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

Russell K. Portenoy, MD Beth Israel Medical 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, in their area of specialty, 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., and review the articles before they go to print. 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. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD COMMENTARY

ETHICAL ISSUE continued from page 1

on the subject of the rights of individuals (either patients or normal volunteers) asked to become “research subjects” in human clinical investigations.1 The Code is mentioned here, not because there is any suggestion that the ethical concerns to be discussed relate to the abuses that resulted in its composition more than 60 years ago, but rather because of the purity of its profound and essential statements delineating the requirements that need to be fulfilled for any clinical research involving human subjects to be considered ethical. Two particular and highly relevant points made in this landmark statement are noted here: 1. “The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.” 2. “The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.” The specific context of the current ethical concern relates to the apparently rather rigid regulatory “rules” for the conduct of Phase III randomized trials designed for an antineoplastic agent to be granted “approval” to be marketed in the United States. One of the requirements appears to be that the “control arm” (for comparison to the

investigational agent seeking approval) must be an “exact copy” of a regimen previously approved by the regulatory agency for this purpose (dose, schedule, method of administration, etc.), even when that particular method of drug administration or dose is no longer employed in routine clinical practice. Consider the use of pegylated liposomal doxorubicin (PLD) as a control arm for trials examining a novel antineoplastic agent in recurrent or platinum-resistant ovarian cancer, such as the ongoing trial presented at the recent annual meeting of the American Society of Clinical Oncology.2 The original approval of PLD in this setting was for the drug delivered at a dose of 50 mg/ m2 on an every-4-week schedule.3 It was quickly recognized that this dose, unfortunately, resulted in an unacceptable degree of serious symptomatic side effects (eg, stomatitis, mucositis, and hand–foot syndrome). The gynecologic cancer clinical research community went to considerable efforts to reduce the severity of these side effects, while maintaining the recognized efficacy of the agent to provide meaningful palliative benefit in this difficult clinical setting.3 These efforts resulted in the essentially universal decision to deliver PLD at a lower dose, 40 mg/m2 in most circumstances,3,4 which substantially reduced the risk for grade 3 side effects while preserving efficacy.3 Therefore, the questions to be asked

are as follows: 1. What is the possible ethical justification for employing a particular dose of PLD (50 mg/m2) in this and other clinical trials, when this dose is recognized to result in the risk for excessive harm and is not employed in routine clinical practice? 2. What are patients who are asked to participate in this trial told regarding the dose for the control arm? Are they informed that they would not receive this more toxic dose if they elected to decline trial participation? 3. What has the institutional review board (IRB) been told about the decision to use this dose of PLD (50 mg/m2) in this trial, rather than the lower dose used routinely off-study? Does the consent form clearly state that this more toxic dose is only being used because of “regulatory requirements”? What is the responsibility of an IRB to research subjects in this setting regarding granting approval for the study to proceed, despite the requirements of the drug regulatory agency? 4. Why do investigators agree to participate in such studies if they would not use the dose of PLD (50 mg/m2) outside the confines of a regulatorymandated trial? And the final question is: 5. Does the drug regulatory agency (FDA) have an obligation to respond to such questions or are they simply permitted to make their own rules?

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

References 1. Shuster E. Fifty years later: the significance of the Nuremberg Code. N Engl J Med. 1997;337(20):1436-1440. 2. Coleman RL, Monk BJ, del Carmen MG, et al. A phase 3 study of trabectedin plus pegylated liposomal doxorubicin versus PLD for treatment of advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2014;32:(5 suppl): abstract TPS5612. 3. Markman M. Serious ethical dilemma of single-agent pegylated liposomal doxorubicin employed as a control arm in ovarian cancer chemotherapy trials. J Clin Oncol. 2010;28(19):e319-e320. 4. Ko EM, Lippmann Q, Caron WP, et al. Clinical risk factors of PEGylated liposomal doxorubicin induced palmar plantar erythrodysesthesia in recurrent ovarian cancer patients. Gynecol Oncol. 2013;131(3):683-688.

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

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Despite Guidelines...

Growth Factors Often Given to Low-Risk Patients Chicago—Community oncologists appear to be overusing growth factors, according to a review of 1,700 orders for growth factors made over a 10-month period. Of the 1,700 orders, 40% were given for low-risk patients, who should not routinely receive growth factors according to current guidelines, including those issued by the American Society of Clinical Oncology (ASCO). Of the remaining, 50% went to intermediate-risk patients for whom guidelines sud selectively. “The current ASCO policy recommends growth factors if the risk of febrile neutropenia exceeds 20%, but only 10% of the requests for growth factors we reviewed were administered to patients on these high-risk regimens,” said investigator William J. Hrushesky, MD, the chief scientific officer at Oncology Analytics Inc., in Plantation, Fla. It is likely that many of the prescriptions in the intermediate-risk group were justified by additional risk factors, such as the presence of infection, a prior history of febrile neutropenia or concomitant radiotherapy, but some overuse in this group also is probable, said Dr. Hrushesky, presenting these data at ASCO’s 2014 annual meeting (abstract 9654). “Even in the intermediate-risk patients, the data suggest these agents are being used freely when the guidelines would support a more selective approach,” he said. He noted that overuse does not just

raise issues of cost. Bone pain, an adverse effect that affects as many as 50% of those taking a growth factor, is a significant potential contributor to decreased quality of life over the course of cancer therapy. The data on growth factors were col-

According to Dr. Hrushesky, the goal is not to deny use of growth factors to those who might benefit, but rather to raise awareness that these products have financial and quality-of-life costs so they should be used selectively.

‘The bigger mistake is not giving growth factors too often; [it is] failing to prescribe them when they are clearly indicated.’ —James Armitage, MD lected from approximately 2,800 community oncology practices that submit patient care data to Oncology Analytics, a company that assesses use of drugs and services in the context of guidelines and level 1 evidence. When reviewing an order for a growth factor for patients taking chemotherapy associated with a less than 10% risk for febrile neutropenia, Oncology Analytics issues a referenced communication to the prescribing physician outlining current guidelines. For patients taking chemotherapy associated with an intermediate risk, Oncology Analytics evaluates the patient records for additional factors that might justify the growth factor prescription. If none is identified, the physician is contacted to determine the reason for the prescription. If there is support for the prescription, no further steps are taken. If not, physicians are again supplied with guidelines.

“Over the 10 months, 12% of the orders for growth factors were withdrawn,” Dr. Hrushesky reported. This represented a $2.1 million reduction in costs. However, cost is not necessarily the key issue, he emphasized. In addition to the risk for bone pain, which can be severe in up to 25% of patients, and rare toxicities, such as splenic rupture, there is the inconvenience to the patient who must return for periodic injections. “By restricting growth factors to those most likely to benefit, we can improve the experience of patients who do not want to take any more medicine than they need,” Dr. Hrushesky said. “The guidelines for growth factor use make sense.” Asked to comment about the potential overuse of growth factors, James Armitage, MD, a professor in the Division of Hematology/Oncology at the University of Nebraska Medical Center, in Omaha, agreed that there is a potential for

overuse in low-risk patients, but he cautioned that clinicians need to be concerned about both overuse and underuse. “The bigger mistake is not giving growth factors too often; [it is] failing to prescribe them when they are clearly indicated,” Dr. Armitage said. “Growth factors are expensive but rarely dangerous. The problem is that they can cause substantial bone pain. While all patients should be warned of this risk, it may be particularly severe in young patients,” a group less likely to require growth factors, particularly if they are receiving low-risk regimens. “Some clinicians give growth factors to every patient 60 years old or older. It is better to select therapy on the basis of both regimen and the health status of the patient, but there is some subjectivity to this decision,” Dr. Armitage explained. For example, he does not typically prescribe growth factors to patients taking R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), but he makes an exception for frail patients. “Like many things in medicine, there is no one answer,” Dr. Armitage advised. “There is a risk of overusing these agents, but clinicians need to be concerned about both too much and too little.” —Ted Bosworth Dr. Armitage reported no relevant financial conflicts of interest.

Online System Helps Patients Control Symptom Severity W

ith the aid of a Web-based assessment tool, patients undergoing chemotherapy can rein in the severity of their symptoms and stress, according to a study by investigators at Harvard Medical School and the University of Washington. “If we can give [patients] support in the comfort of their own homes—or on their cell phones—without requiring a trip to the clinic, we can actually reduce symptom distress,” said investigator Donna Berry, PhD, RN, an associate professor in the Department of Medicine at Harvard Medical School, in Boston. In a randomized clinical trial, the ESRA-C (Electronic Self-Report Assessment—Cancer) II, Dr. Berry and her colleagues enrolled 752 patients with more than 15 types of cancer. Dr. Berry said they tried to cast a wide net so that they would be able “to generalize this to all patients with cancer going through therapy.” Participants in the intervention group

(n=374) were free to use the ESRA-C software to evaluate their symptoms at home or in a clinical setting, as well as during each of three or four clinician assessments, over a period of up to eight weeks. The control group (n=378) did not have access to the program but received three or four assessments. In a comparison between the two groups, the investigators calculated that access to the ESRA-C program was associated with an average Symptom Distress Scale (SDS-15) score that was 1.21 points lower in the intervention group than the control arm ( =0.02). “It’s not that we were able to (P simply lower the [symptom distress of the] intervention group and the control group stayed the same,” Dr. Berry said. “The control group got worse,” with an average change of 1.27 points, indicating increased distress from baseline. A change in the SDS-15 score by one or two points, Dr. Berry said, is equal to the

difference between giving a major symptom (such as fatigue or pain intensity) a mild rating compared with a moderate or severe rating. This study is an “excellent example of testing a large sample in the community,” to show how patients can benefit from a symptom reporting system, said Xin Shelley Wang, MD, MPH, a professor in the Department of Symptom Research at the University of Texas MD Anderson Cancer Center, in Houston. The program was most effective for participants aged 50 years or older, who

scored, on average, 1.93 points lower on the SDS-15 compared with the control group (95% confidence interval, –3.16 to –0.70; P=0.002). No significant change was detected as a result of the intervention among participants younger than age 50 (P ( =0.40). Dr. Berry postulated that younger patients, in general, are more familiar with accessing information from the Internet. “That’s a big assumption,” she said, but patients older than age 50 might “need the structure that this program was able to give them.” The ESRA-C program was designed to help patients determine the appropriate course of action given certain symptoms. “Patients are often at home when they’re having problems,” Dr. Berry said, and they may not know if their symptoms are serious enough to merit a call to their doctors. “More often than not, they don’t call.” When the program detects that a see ONLINE SYSTEM, M page 17

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Cardiac Risks Are High in Childhood Ca Survivors Chicago—One in four survivors of childhood cancer will develop coronary artery disease (CAD) and/or cardiomyopathy by age 50, according to a report presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). In one of the most comprehensive studies to look at cardiac outcomes in adult survivors of childhood cancer, a substantial proportion of survivors who were exposed to cardiotoxic therapy had cardiac disease by age 50 (abstract 10025). “This is actually a very frightening outcome in survivors,” said Cindy Schwartz, MD, MPH, a professor of pediatrics at the University of Texas MD Anderson Cancer Center, in Houston, during a presentation on new research addressing such late cardiopulmonary toxicities in childhood cancer. In one study, Daniel A. Mulrooney, MD, and his colleagues at St. Jude Children’s Research Hospital, in Memphis, Tenn., studied 1,831 survivors of childhood cancers who were at least 10 years out from their radiation and/or anthracycline therapy. On average, the survivors were diagnosed at 8.3 years of age and were 32 years old at the time of the study. Unlike most studies of adult survivors, which rely on patients’ self-reported cardiac conditions, in the St. Jude study, the investigators performed clinical tests to detect cardiomyopathy, CAD, and valve and conduction abnormalities. Survivors also completed a walk test and health status assessment using the SF-36 physical component score. Dr. Mulrooney and his colleagues found cardiomyopathy in 6.7% of the patients, CAD in 7.1%, valve disorders in 52%, conduction abnormalities in 11% and diastolic dysfunction in 12%; 8% of the survivors had more than one cardiac condition. Survivors who had exposure to anthracycline doses greater than 250 mg/m2 had substantially increased risk for cardiomyopathy (relative risk [RR], 4.1), valve disorders (RR, 1.4) and conduction abnormalities (RR, 2.0) compared with survivors not exposed to anthracyclines. Those who had received radiation to the heart had higher rates of CAD (RR, 3.5), valve disorders (RR, 1.3) and conduction abnormalities (RR, 1.5) than those whose hearts were not exposed to radiation therapy. Although little is known about how to protect patients from these

complications, Dr. Schwartz said some “very encouraging” new evidence suggests that exercise may help protect survivors from some cardiovascular events. Lee Jones, MD, of Memorial Sloan-Kettering Cancer Center, in New York City and his colleagues from six cancer centers across North America looked at the effects of exercise in survivors of childhood Hodgkin lymphoma. Dr. Jones and his colleagues studied 1,187 survivors who were a median age of 31.2 years and free of cardiovascular events at baseline (abstract 10023). They followed the participants for a median of 11.9 years, completing questionnaires addressing their exercise habits and cardiovascular health, and used Poisson regression analyses to estimate the association between exercise and major cardiovascular events, adjusting for age, smoking, baseline health conditions and cancer treatment. The analysis showed that the more exercise patients did per week, the less likely they were to develop cardiovascular problems. Survivors who performed 0 METS per week (a measure of hours of metabolic equivalent tasks) had a 12.2% cumulative incidence of any cardiovascular event at 10 years compared with a 5.2% cumulative incidence for those who achieved the national exercise guideline of at least 9 METS per week. Adherence to national exercise guidelines was associated with a 51% reduction in the risk for any cardiovascular event, the investigators reported. “Vigorous exercise reduces the incidence of cardiovascular events in a dosedependent manner, beyond cardiovascular risk profile and treatment exposure in adult survivors of childhood Hodgkin lymphoma,” according to Dr. Jones. But it’s a bit of a chicken-versus-egg argument, Dr. Schwartz said. “Does the exercise promote health or does health promote exercise? I think we know that healthy people are much more likely to exercise than unhealthy people. But do we only get our choice of one? Or we can have both? Can we have healthy people who exercise but also promote health in those other patients by promoting exercise for them?” It’s difficult to put together the studies that could answer that question, she said. Patients would have to comply with interventions such as better diets and exercise, report their compliance honestly and undergo follow-up for decades.

‘Vigorous exercise reduces the incidence of cardiovascular events in a dose-dependent manner, beyond cardiovascular risk profile and treatment exposure in adult survivors of childhood Hodgkin lymphoma.’ —Lee Jones, MD

Even if those studies are never completed, there are steps that patients should take, said Dr. Schwartz. Studies show that many survivors of childhood cancer do not follow the basics of preventive cardiac care. She called on health care providers to stress to patients the need to maintain a healthy weight and refrain from smoking. Another possible prevention strategy buoyed by new research is dexrazoxane (Zinecard, Pfizer). In the past several years, this free radical scavenger has been shown in multiple trials to reduce incidence of heart failure in cancer patients. In a 2010 randomized study of 205 children with acute lymphocytic leukemia, dexrazoxane mitigated some left ventricular dysfunction associated with doxorubicin administration ((Lancet Oncol 2010;11[10]:950-961). But many doctors were concerned about dexrazoxane after reports of acute myeloid leukemia and myelodysplastic syndrome in children receiving the agent in combination with other drugs

associated with secondary leukemias ((J Clin Oncoll 2007;25[5]:493-500). A study presented at ASCO suggests that dexrazoxane does not drive up the risks for mortality or relapse among pediatric leukemia and lymphoma patients. Investigators analyzed data collected in three trials that randomized pediatric patients to treatment with or without dexrazoxane. The cohort included 537 children with T-cell acute lymphoblastic leukemia/lymphoma, 215 with advancedstage Hodgkin lymphoma and 255 with low/intermediate Hodgkin lymphoma. Dexrazoxane did not affect overall mortality or relapse at 10 years. “I think this is very encouraging,” said Dr. Schwartz, who was one of the study investigators. An ongoing prospective study is focused on whether dexrazoxane reduces cardiotoxicity. —Christina Frangou None of the sources reported any relevant financial conflicts of interest.

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NOW

IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As ﬁrst-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with ﬂuoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. mCRC = metastatic colorectal cancer; OS = overall survival.

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

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. • In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix ® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. • Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS mCRC

• In an interim analysis of an open-label, multicenter, randomized clinical

• Because many drugs are excreted into human milk and because of the

trial in the ﬁrst-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the ﬁrst 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. • Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. • Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. • In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inﬂammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aﬂibercept) prescribing information, sanoﬁ-aventis. Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc.

Visit www.vectibix.com

Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic g Toxicity: y Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].] INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRASS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing Information]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRASS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRASS mutational status in colorectal tumors and confirm the absence of a KRASS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRASS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic g Toxicityy [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS W Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)].] Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with KRAS-Mutant S mCRC Determination of KRASS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibixx®. Vectibixx® is indicated only for the treatment of patients with KRASS wild-type mCRC. Vectibixx® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use[see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information].] In Study 3, 221 patients with KRAS-mutant S mCRC tumors receiving Vectibixx® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRASS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix ® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant S mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]

• Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix ® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reﬂect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRASS mCRC. py Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reﬂect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1) Study 1

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inﬂammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin ﬁssures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Vectibix® Plus Best Supportive Care (N = 229) Any Grade Grade 3-4 n (%) n (%)

Best Supportive Care (N = 234) Any Grade n (%)

Grade 3-4 n (%)

13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

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

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inﬂammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

116 (36) 96 (30) 68 (21) 26 (8)

14 (4) 21 (7) 32 (10) 8 (2)

85 (26) 26 (8) 42 (13) 10 (3)

46 (14)

30 (9)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10) 30 (9)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1) 4 (1)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%) 24 (7)

1 (< 1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1) 9 (3)

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting highaffinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore ® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.

2 (< 1) 1 (< 1)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

SYSTEM ORGAN CLASS Preferred Term SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin ﬁssures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

6 (2) 1 (< 1) 15 (5) 5 (2)

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. v20 05/14

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

VALUE continued from page 1

Bedside Rationing Not the Answer Are practicing oncologists, as prescribers, responsible for some of the cost containment that needs to be done? Daniel Sulmasy, MD, PhD, the associate director of University of Chicago Medicine’s MacLean Center for Clinical Medical Ethics, said it is clear that something needs to be done to rein in health care spending, but cost control should not be done at the bedside. “Oncologists have social duties and a vital role to play in controlling the costs of care. What I object to vigorously is the notion that this is best accomplished at the bedside, by directing individual oncologists to decide whether or how to treat an individual patient based on considerations of cost,” he said. “Population medicine cannot be practiced at the bedside.” Dr. Sulmasy said rationing of health care at the individual level is morally problematic for a number of reasons. It threatens the integrity of medicine and undermines the trust of patients who will wonder, for example, whether a scan is not being done because it wouldn’t help or because a doctor is being rewarded for not ordering it. In the absence of transparent and universally applicable rules, rationing also is unfair and unlikely to achieve the goals of those who advocate for it. “Not giving pertuzumab [Perjeta, Genentech] to Susie is extraordinarily unlikely to

Table. Breakdown of Cancer Therapy Costs

Expenses

Portion of Cancer Care Costs, %

Chemotherapy

Hospitalization

Surgery

Radiation oncology

Other outpatient

Diagnostic imaging

Pharmacy

Physician visits

‘Overuse of resources on low-value care is one of many situations where individually rational decisions can lead to collectively inferior outcomes.’ —Reshma Jagsi, MD, DPhil help unwed teenager mothers on the South Side of Chicago get better prenatal care,” said Dr. Sulmasy. He said the clinician’s role in cost containment is to strive for two goals: therapeutic parsimony, only using as much treatment is as needed, and diagnostic elegance, only using truly necessary tests. Cost savings may be a side effect of these two practices, but the aim is still the best interest of the patient.

Oncologists Need To Be Stewards of Resources But Reshma Jagsi, MD, DPhil, an associate professor of radiation oncology and a research investigator at the University of Michigan Health System’s Center for Bioethics and Social Sciences in Medicine, in Ann Arbor, said that physicians have obligations to society as well as to their individual patients

—Daniel Sulmasy, MD, PhD

Source: Wellpoint, Inc.

because of the way they are trained. “Our specialized knowledge and skills are the direct product of publicly funded graduate medical education and hands-on education from a general public that allows trainees to participate in patient care,” she said. If oncologists are not responsible stewards of resources, the unsustainable pattern of health care spending growth will crowd out other resources that are important to population health, she argued. Rationing has to happen on some level. Although not advocating bedside rationing, she said that physicians owe it to society to engage the public in deliberation to develop priorities and professional norms that ensure that resources are allocated in a way that helps society overall.

Dr. Jagsi said that there are examples of wasteful practices that physicians must help identify and eliminate. For example, large randomized trials have established the noninferiority of shorter courses of hypofractionated radiotherapy to the whole breast compared with conventional courses using smaller daily doses for patients with breast cancer, yet overall use of this costsaving approach remains low, at 14% (ASCO 2014, abstract 6522). ASCO has published two “top 5” lists of opportunities to improve the quality and value of cancer care. The lists suggest eliminating various treatments and tests, such as multidrug therapy for metastatic breast cancer (except when needed for rapid symptom relief ). “There is a lot of low-hanging fruit out there, before we have to go after the true tragic choices,” said Dr.

‘Not giving pertuzumab to Susie is extraordinarily unlikely to help unwed teenager mothers on the South Side of Chicago get better prenatal care.’

Jagsi. Harder cases, in which benefit is unlikely, costs are high, and a patient wishes to “try” a treatment, put the physician’s obligations to a patient and society in conflict. Dr. Jagsi pointed to proton therapy in prostate cancer as an example. For patients with prostate cancer, proton therapy costs twice as much as intensity-modulated radiation therapy with photons (Medicare reimbursement $32,400 vs. $18,600), but there is little evidence that it is better. Participating in clinical trials to assess which patients derive meaningful benefits from new treatments or technologies is one way physicians can help fulfill their duty to society. “It is absolutely

our responsibility to lead the development of a robust evidence base for the assessment of value. Overuse of resources on low-value care is one of many situations where individually rational decisions can lead to collectively inferior outcomes,” said Dr. Jagsi. If physicians focus exclusively on their duty to individual patients, they fail to uphold the full scope of their professional duties, Dr. Jagsi said. Referring to the economic phenomenon of common pool resources being susceptible to overuse when individual and group interests are in conflict, Dr. Jagsi concluded, “Physician leadership to encourage public deliberation over priorities and value in health care is essential to avoid a ‘tragedy of the commons.’ —Kate O’Rourke Drs. Moy, Sulmasy and Jagsi reported no relevant financial conflicts of interest.

Survey Gauges Oncologists’ Communication About Care Costs CHICAGO—As a follow-up to a 2008 national survey of 1,400 medical Table. Comparison of oncologists that assessed how risResponses From 2008 and ing cancer treatment costs influ2013 Surveys of Oncologists ence clinical practice, investigators resurveyed 850 of these oncologists 2008, % 2013, % P Value between June and August 2013; 136 Out-of84 70 <0.01 (16%) responded, and the results pocket costs were presented at the 2014 annual influence my meeting of the American Society of decisions on Clinical Oncology (abstract 6554). treatment Although only 4% of the responI feel well 42 65 <0.01 dents agreed that the government prepared should play a role in determining the to interpret value of a cancer therapy (Table), cost-effec53% thought that governmenttiveness imposed price controls for cancer The govern21 4 <0.01 drugs were needed. Roughly 90% ment should felt it was important to discuss outdecide of-pocket costs with patients. “good value” The survey also evaluated oncolfor drugs ogists’ perceptions of cancer therPhysicians 60 67 0.11 apy costs under the Affordable Care should Act (ACA) over the next five years decide and found that 61% thought out-of“good value” for drugs pocket costs would have a larger effect on treatment decisions; 73% said the ACA would require them to increase communication about costs; and 62% said health care system costs would have a larger effect on treatment decisions. —K.O.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Panobinostat Shines in PANORAMA-1 Trial Chicago—Adding panobinostat to a commonly used two-drug therapy in patients with relapsed or relapsed and refractory multiple myeloma improves progression-free survival (PFS) by approximately four months, according to the Phase III PANORAMA-1 trial. Preclinical studies showed that panobinostat (Novartis), an oral pan-deacetylase inhibitor, is synergistic with bortezomib (Velcade, Millennium) and dexamethasone. In PANORAMA (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma)-1, presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 8510), investigators randomized 768 patients with relapsed/refractory multiple myeloma to dexamethasone plus bortezomib, with either panobinostat or placebo (Table 1). The patients previously had received one to three lines of therapy. Noting that the primary end point of the trial was met, presenter Paul G. Richardson, MD, the director of clinical research at Dana-Farber Cancer Institute’s Jerome Lipper Multiple Myeloma Center, and the RJ Corman Professor of Medicine at Harvard Medical School, in Boston, reported that patients receiving the panobinostat combination had a clinically relevant increase in median PFS of 3.9 months (12.0 vs. 8.1 months; hazard ratio, 0.63; P<0.0001). The improved outcome was seen in all patients, regardless of race, sex, age, clinical staging, cytogenetic risk group and previous treatment history. In an interim analysis, there was no difference in overall survival, but the data are immature. The complete and near-complete response rates were nearly doubled in

Table 1. Study Schema of PANORAMA-1

768 patients with relapsed/ refractory multiple myeloma randomized 1:1

Treatment Phase I Assessment Eight 21-d Cycles For Phase II

Treatment Phase II Four 42-d Cycles

Panobinostat + bortezomib + dexamethasone

If clinical benefit identified, patient proceeds to Phase II

Placebo + bortezomib + dexamethasone

PANORAMA, Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients W t Relapsed With e apsed Multiple u t p e Myeloma ye eo a

Table 2. Selected Adverse Events in PANORAMA-1 Panobinostat + Bortezomib + Dexamethasone

Placebo + Bortezomib + Dexamethasone

Grade 3/4 diarrhea, %

25.5

8.0

Grade 3/4 asthenia/fatigue, %

23.9

11.9

Grade 3/4 hemorrhage, %

4.2

2.4

Grade 4 neutropenia, %

6.6

2.4

PANORAMA, Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma

patients who received panobinostat (27.6% vs. 15.7%; P=0.00006). However, patients receiving the additional drug had higher rates of adverse events, including diarrhea and asthenia/fatigue (Table 2). Almost all patients receiving panobinostat had thrombocytopenia, which was grade 3/4 in two-thirds of cases, but this was, for the most part, reversible. Side effects, generally, were manageable. The trial results confirm the efficacy of dexamethasone-bortezomib-pan-

obinostat seen in the PANORAMA-2 trial, a single-arm, multicenter Phase II trial, during which the three-drug combination induced a 35% response rate in heavily pretreated bortezomibrefractory patients with relapsed and refractory multiple myeloma (Blood ( 2013;122:2331-2337). “We believe that panobinostat constitutes a significant advance in this field, and especially for patients with relapsed and refractory multiple myeloma,” said

Dr. Richardson. He pointed out that panobinostat also has shown promise in other hematologic cancers, including myelofibrosis, suggesting a broader role for this class of agent. A Phase IB study presented at the ASCO meeting showed that the combination of ruxolitinib (Jakafi, Incyte) and panobinostat induced significant responses in patients with myelofibrosis (abstract 7022). Robert Z. Orlowski, MD, PhD, the Florence Maude Thomas Cancer Research Professor at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved with the study, applauded the fact that the regimen appeared to be equally effective in low- and high-risk patients. He said there were factors that could make the data seem more impressive, such as the fact that up to 44% of patients had received prior bortezomib and that patients who received the three-drug combination received less-intense doses of bortezomib and dexamethasone. He said, however, that there also were factors that could make the data look less impressive. For example, the patients in the study generally had a low burden of disease and many had received only one previous line of therapy. Toxicity, which decreases quality of life and increases use of health care resources, also was a concern. Overall, Dr. Orlowski concluded, “the data look very encouraging and [indicate the drug is] worthy of an FDA approval.” —Kate O’Rourke Dr. Richardson disclosed relationships with Celgene, Johnson & Johnson, Millennium and Novartis. Dr. Orlowski disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Celgene, Millennium and Onyx.

New Standard Proposed for Mantle Cell Lymphoma Chicago—Adding bortezomib to the backbone of front-line cytotoxic therapy for patients with mantle cell lymphoma (MCL) increased progression-free survival (PFS) by 10 months during a recent Phase III trial, supporting a shift for the agent from second- to first-line treatment in this population. This “could be considered a new standard of care for newly diagnosed patients with mantle cell lymphoma not considered for [bone marrow transplant],” said Franco Cavalli, MD, the director of oncology at the Oncology Institute of Southern Switzerland, in Bellinozona, presenting the results at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 8500). Currently, bortezomib (Velcade, Millennium) is approved for the treatment of relapsed MCL in combination

Table. Selected Outcomes in Lymphoma-302 R-CHOP

VR-CAP

CR + CRu, bone marrow, %

Median duration of response CR + CRu + PR, mo

15.1

36.5

Neutropenia, %

Thrombocytopenia, %

Leukopenia, %

Lymphopenia, %

CR,, complete p response; p ; CRu,, complete p response p unconfirmed;; PR,, partial p response p

with rituximab (Rituxan, Genentech), cyclophosphamide, doxorubicin and prednisone (VR-CAP), and the standard front-line therapy for newly diagnosed patients is R-CHOP (rituximab,

cyclophosphamide, doxorubicin, prednisone and vincristine). The Lymphoma-302 study was a randomized trial designed to compare the efficacy and safety of R-CHOP or

VR-CAP in newly diagnosed patients with stage II-IV MCL who were ineligible for bone marrow transplant. Patients in the study, all of whom had an Eastern Cooperative Oncology Group performance status of 0 to 2, were scheduled for six, 21-day cycles of therapy but could receive up to eight. With a median follow-up of 40 months, the median PFS by independent review was 14.4 months in patients receiving R-CHOP (n=165) and 24.7 months in patients receiving VR-CAP (n=133) (hazard ratio, 0.63; P<0.001). Roughly 20% of patients discontinued treatment because of adverse events (AEs). Overall survival (OS) data are not yet mature but hint at improved OS with VR-CAP, a 10% difference at four years (53.9% vs. 64.4%; P=0.173). see MANTLE CELL, page 17

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MODEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself. C L I N I C A L E X PE R T I SE

T R A N SPL A N TAT I O N

C L I N I C A L T R I A L S A N D R E SE A RC H

More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in speciﬁc malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology.

In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

t Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem cells for peripheral blood transplants t Four ICU beds integrated with Carolinas HealthCare System’s virtual ICU, which provides 24/7 oversight of all patients t Patient support, including familyfriendly patient rooms, an exercise room, a laundry room and lounge t Patient navigation

t First-in-man clinical trials testing novel therapies and treatment options t Access to high-quality care, and expertise from physicians who subspecialize in treating speciﬁc diseases t The ability to enroll patients in the newest, most promising trials, whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

How I Manage ...

How I Manage Adults With Burkitt Lymphoma B

Kieron Dunleavy, MD Clinical Director Lymphoid Malignancies Branch National Cancer Institute Bethesda, Maryland

When Do You Suspect BL? BL, first described in African children in 1956 by Irish surgeon Denis Burkitt, makes up approximately 30% of pediatric lymphomas; it has a peak onset between ages 10 and 14 years.1 It is much less commonly encountered in adults. Epidemiologic studies have recognized 3 variants of the disease with variable Epstein-Barr virus (EBV) expression: Endemic BL occurs in certain geographic regions such as equatorial Africa; sporadic BL may occur anywhere; and immunodeficiency-associated BL primarily is encountered in the setting of HIV

urkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that occurs across all age groups and is highly curable with intensive and toxic chemotherapy approaches. These approaches, however, are much less effective and more toxic in adults with and without HIV than in children. Recently, a low-intensity approach using infusional therapy has shown high efficacy and good tolerability in adults of all age groups and in patients with HIV. This approach is being tested in a multicenter National Cancer Institute (NCI) Intergroup study, which is discussed in detail in the following sections.

infection. Endemic BL is associated with EBV in nearly all cases, whereas the other variants are positive for EBV approximately 30% to 40% of the time. All variants are derived from a germinal center B cell, and the genetic hallmark of BL is a translocation between the MYC C oncogene on chromosome 14 and an immunoglobulin promoter.2 Different variants of BL are associated with distinct clinical presentations; for example, endemic BL classically presents with jaw disease, whereas the sporadic type usually is associated with ileocecal disease. One should suspect this diagnosis

AT A GLANCE • Burkitt lymphoma (BL) is a rare type of B-cell non-Hodgkin lymphoma that affects both children and adults. • There are 3 different variants of the disease: endemic, sporadic, and immunodeficiency-associated BL. • Although BL is highly curable with intensive chemotherapy, it is poorly tolerated in adults and immunocompromised patients and, therefore, these groups of patients have inferior outcomes compared with children with BL. • An NCI study evaluated a low-intensity approach using EPOCH-R therapy in adults with BL and demonstrated excellent efficacy and low toxicity. As a result of this, a confirmatory Intergroup study using this approach is ongoing. • A Burkitt Lymphoma Genome Sequencing Project (BLGSP) is being conducted by NCI to explore potential genetic changes that could lead to improved prevention, detection, and treatment of BL worldwide. • Recently, novel insights into the molecular biology of BL suggest that drug targeting of specific pathways is a rational strategy to explore in this disease.

in children or young adults who present with rapidly enlarging lymph nodes or masses (particularly in the abdomen) or who develop new-onset rapid renal failure from obstructive uropathy or spontaneous tumor lysis syndrome (TLS). BL is the most highly proliferative human cancer, so the onset of symptoms is typically very rapid, and advanced disease is common at the time of presentation and diagnosis. This type of lymphoma frequently involves the bone marrow, peripheral blood, and/or central nervous system (CNS). HIV-positive populations are at a significantly increased risk for developing BL compared with their HIVnegative counterparts (estimated to be a 1,000-fold elevated risk); therefore, BL should always be considered in the differential diagnosis of HIV-positive individuals presenting with the signs and symptoms of lymphoma.3 Therapy needs to be instituted as soon as the diagnosis is made, and particular attention should be paid to the risk for developing TLS, which may have begun spontaneously.

How Do You Risk-Stratify Newly Diagnosed Patients With BL? Although early treatment strategies for BL were modeled on acute lymphoblastic leukemia (ALL) treatment regimens and incorporated induction, consolidation, and maintenance phases, later recognition that tumor volume was an important prognostic factor led to the use of riskadaptive approaches and a reduction in treatment for patients with low-burden disease. Over the years, physicians treating pediatric and adult patients have variably defined risk groups in BL. The precise definition of what low-risk disease is has varied between cooperative groups. However, low-risk patients generally have

been considered to be those with earlystage disease (I or II) without any adverse risk factors, and high-risk patients are those with advanced-stage disease or early-stage disease with adverse clinical characteristics, such as a high lactate dehydrogenase (LDH) level or a high (Eastern Cooperative Oncology Group [ECOG] or Karnofsky) performance status.4-6 In the ongoing NCI Intergroup prospective study in adult patients with BL, patients are stratified as follows: Low-risk patients must have a normal LDH, an ECOG performance status of 0 to 1, an Ann Arbor stage of I or II, and a maximal tumor mass size less than 7 cm. All other patients are considered high-risk.

What Is the Best Front-Line Therapy for Patients With BL? The choice of front-line therapy remains controversial in adults with BL; the optimal front-line therapy has not yet been defined. If one goes back to the early history of BL therapeutics, the recognition of biologic overlap between BL and B-cell ALL led to the widespread use of intensive, multiagent leukemia regimens for the disease. It was accepted early on that because of its very short doubling time, BL required intensive short-cycle chemotherapy approaches. Risk-stratified approaches were introduced for lowrisk patients, but these constitute a very small proportion of BL patients. Although intensive approaches are reasonably tolerated in children, albeit with significant morbidity and long hospitalizations, this is definitely not the case for most adults and patients with immunodeficiency. In adults with or without HIV, attempts have been made to lower treatment intensity, with the goal of reducing toxicity and improving tolerability; this has not resulted in better outcomes.7-9 Thus, although approaches such as CODOX-M-IVAC (cyclophosphamide, vincristine, doxorubicin-methotrexate-ifosfamide, etoposide, and cytarabine) or modified [LMB] lymphoma malign B pediatric protocols can be considered for young adults, they are not optimal for other groups in whom toxicity is unacceptably high, necessitating alternative effective and less toxic approaches. Our group at the National Institutes of Health investigated a low-intensity approach in patients with BL.10 We tested treatment consisting of infused EPOCHR (etoposide, prednisone, vincristine,

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Table. Ongoing Trials in Patients With BL Trial

Details

NCT01092182

A Phase II study of dose-adjusted EPOCH ± rituximab in adults with untreated Burkitt lymphoma, c-MYC-positive diffuse large B-cell lymphoma, and plasmablastic lymphoma. Contact information: dunleavk@mail.nih.gov

Burkitt Lymphoma Genome Sequencing Project (BLGSP)

BLGSP project manager contact information: nicholas.griner@nih.gov

cyclophosphamide, doxorubicin, and rituximab) in adults with BL and demonstrated a similarly good outcome to that of intensive short-duration regimens in pediatric populations. A subset of patients who were HIV-positive did as well as their HIV-negative counterparts, despite fewer cycles of therapy and cumulative drug doses. Treatment tolerability was excellent in all age groups, with low rates of febrile neutropenia, hematologic toxicities, and TLS compared with intensive approaches. Based on these results, the NCI Intergroup is conducting a multicenter study of risk-stratified dose-adjusted (DA)-EPOCH-R therapy in adults with BL. Remarkably, this regimen does not contain systemic methotrexate and cytarabine, which are associated with high toxicity. Although systemic methotrexate and cytarabine historically have been considered essential for disease control in BL, the good results with EPOCH-R therapy question their necessity. Another study using the regimen in children with aggressive B-cell lymphomas, including BL, is ongoing.

Should All Patients With BL Receive Prophylactic Intrathecal Chemotherapy? Because the risk for CNS disease is relatively high in BL, intensive regimens typically have incorporated intrathecal (IT) prophylaxis for all patients. Whether or not this is always necessary has not been well studied. At this point, all patients should receive prophylaxis, but this remains an area of investigation, specifically in the low-risk BL patient population. In my opinion, all high-risk patients should receive it based on their risk for CNS relapse, and there is controversy about its necessity in low-risk BL patients. Indeed, one pediatric study— FAB/LMB 96—evaluated the use of abbreviated (lower-intensity) chemotherapy without IT prophylaxis in low-risk pediatric B-cell non-Hodgkin lymphomas (including BL) patients with resected localized disease.11 The omission of IT treatment was associated with an excellent outcome, a 4-year event-free survival (EFS) of 98.3%. Based on this, we omitted prophylactic IT therapy in low-risk patients in the ongoing NCI Intergroup study (Figure); nevertheless, IT prophylaxis should not be omitted in low-risk BL patients outside of a clinical trial.

The Role of PET Scanning in BL There is limited experience investigating the role of fluorodeoxyglucosepositron emission tomography (FDGPET) scanning in BL, and the studies that have evaluated its role to date have been retrospective.12,13 As is the case with other aggressive B-cell lymphomas, BL lesions have high PET avidity, but the clinical utility of this imaging modality in BL is unknown.12 It may be useful as an adjunct to computed tomography staging at initial diagnosis, and early interim PET scanning may identify a population of chemoresistant patients with a poor prognosis who could benefit from alternative therapies. Additionally, FDG-PET may identify a patient population that should not receive limited therapy. The ongoing NCI Intergroup study is prospectively evaluating the role of FDG-PET—both at initial diagnosis and following 2 cycles of treatment—to determine if it is feasible to give limited immunochemotherapy in lowrisk patients.

Future Prospects There are many exciting ongoing developments and future prospects in the field of BL (Table). We await the results of the NCI Intergroup and other studies to 1) validate the use of lower-intensity and less-toxic approaches that maintain high cure rates and 2) determine the role of interim PET scanning. The NCI is performing a Burkitt Lymphoma Genome Sequencing Project (BLGSP) that evaluates samples from all subtypes of the disease, with the aim of exploring potential genetic changes that could lead to improved prevention, detection, and treatment of BL worldwide. The molecular data retrieved from this project ultimately will be made available to the global research community. Participation of patients and community oncologists in these 2 and other well-designed clinical trials is pivotal to advance our understanding of this disease. Recent genomic sequencing studies have identified critical genetic events that cooperate with MYC to increase tumor proliferation and growth through the phosphatidylinositide 3 (PI3)-kinase pathway and cyclin-dependent kinases (CDKs).14 These insights are potentially important therapeutically and suggest that drug targeting of pathways such as PI3 kinase are rational strategies to investigate in BL.

Figure. Risk-adapted therapy in BL—ongoing NCI Intergroup study.a a

NCT01092182/CTSU 9177

BL, Burkitt lymphoma; CT, computed tomography; CTSU, Clinical Trials Support Unit; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FDG, fluorodeoxyglucose; IT, intrathecal; LDH, lactate dehydrogenase; MTX, methotrexate; NCI, National Cancer Institute; PET, positron-emission tomography

References 1. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg. g 1958;46(197):218-223, PMID: 13628987. 2. Taub R, Moulding C, Battey J, et al. Activation and somatic mutation of the translocated c-myc gene in burkitt lymphoma cells. Cell. 1984;36(2):339-348, PMID: 6319017. 3. Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood. 2012;119(14):3245-3255, PMID: 22337719. 4. Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002;13(8):1264-1274, PMID: 12181251. 5. Divine M, Casassus P, Koscielny S, et al. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005;16(12):1928-1935, PMID: 16284057. 6. Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14(3):925-934, PMID: 8622041. 7.

Corazzelli G, Frigeri F, Russo F, et al. RDCODOX-M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and ‘unclassifiable’ highly aggressive B-cell lymphoma. Br J Haematol. 2012;156(2):234-244, PMID: 22098541.

8. Montoto S, Wilson J, Shaw K, et al. Excellent immunological recovery following CODOX-M/IVAC, an effective intensive chemotherapy for HIV-associated Burkitt’s lymphoma. AIDS. 2010;24(6):851-856, PMID: 20124971. 9. Mead GM, Barrans SL, Qian W, et al. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI / LY10 trial). Blood. 2008;112(6):2248-2260, PMID: 18612102.

10. Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt’s lymphoma. N Engl J Med. 2013;369(20):1915-1925, PMID: 24224624. 11. Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell nonHodgkin’s lymphoma: results of the FAB/ LMB 96 international study. Br J Haematol. 2008;141(6):840-847, PMID: 18371107. 12. Carrillo-Cruz E, Marin-Oyaga VA, Rodriguez MS, et al. Role of 18f-Fdg-Pet/Ct in the management of Burkitt lymphoma. Eur J Haematol. 2014. Epub 2014/02/12, PMID: 24520874. 13. Zeng W, Lechowicz MJ, Winton E, et al. Spectrum of FDG PET/CT findings in Burkitt lymphoma. Clin Nucl Med. 2009;34(6):355-358, PMID: 19487844. 14. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490(7418):116-120, PMID: 22885699.

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

Coming Soon How I Manage Survivorship Issues After Allogeneic HCT by Tarah J. Ballinger, MD, and Bipin N. Savani, MD Vanderbilt University

HEMATOLOGIC DISEASE

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Clinical Conundrums Hematology Highlights from ASCO—Part II Prepared by

QUESTIONS

4. True or False? CLL: Mutations

in Bruton’s tyrosine kinase (BTK) and/or phospholipase C gg2 ( PLCgg2) may result in failure of ibrutinib therapy in CLL.

5. True or False? AML: Crenolanib is

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

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

immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody in patients with CML.

Karyopharm) has the potential to induce remissions in heavily pretreated patients with AML.

2. True or False? Chronic lympho-

cytic leukemia (CLL): Oral therapy with ABT-199 has no activity in patients with relapsed and refractory CLL harboring del(17p).

an FLT3 tyrosine kinase inhibitor (TKI) that has clinical activity in heavily pretreated patients with both FLT3 D835 and compound FLT3 ITD/D835 mutant AML clones.

of phosphoinositide 3-kinase (PI3K)δ,γγ isoforms by IPI-145, an oral PI3K-δ,γ inhibitor, has unique therapeutic potential in hematologic malignancies.

7. True or False? AML: A randomized

1. True or False? Acute myeloid leuke- 3. True or False? Chronic myeloid mia (AML): Oral therapy with the investigational agent KPT-330 (Selinexor,

leukemia (CML): Dasatinib may have synergy with nivolumab, a fully human

ANSWERS

patients (pts) with previously treated chronic myeloid leukemia (CML). J Clin Oncol. 2014; 32(5 suppl): abstract TPS7119.

favorable safety profile in a broad range of hematologic malignancies in an ongoing Phase I trial (IPI-145-02). Based on these data, the DUO Phase III trial (IPI-145-07; NCT02004522) has been initiated to evaluate the efficacy and safety of IPI-145 compared with those of ofatumumab in patients with relapsed or refractory CLL or small lymphocytic lymphoma.

ible XPO1 inhibitor that forces the nuclear retention and activation of more than 10 tumor suppressor proteins, including NPM1c, reduces cMYC and BCLx and induces AML cell death while sparing normal hematopoietic cells. A randomized study of KPT-330 versus available agents in chemotherapy-ineligible relapsed AML is being initiated (NCT01607892). Yee KW, Savona M, Sorensen M, et al. A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with relapsed/refractory acute myeloid leukemia (AML). J Clin Oncol.l 2014;32(5 suppl): abstract 7032.

2. False. ABT-199 induces a high rate

of response in patients with relapsed and refractory CLL, including those with del(17p) and fludarabine-refractory disease (NCT01328626). Seymour JF, Matthew Davids S, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high completeresponse rate and durable disease control. J Clin Oncol.l 2014;32(5 suppl): abstract 7015.

True. The combination of dasatinib and nivolumab will assess safety, tolerability and preliminary efficacy in previously treated patients with CML in chronic or accelerated phases. The study is anticipated to be completed in August 2018 (NCT02011945). Porkka K, Mauro MJ, Lipton JH, et al. An openlabel, phase 1b, dose-escalation study (CA180-373) of dasatinib plus nivolumab, an investigational anti-programmed cell death 1 (PD-1) antibody, in

4. False. The BTK inhibitor ibrutinib

is very effective in CLL, with progression-free survival of 76% at 26 months for patients with relapsed CLL. A singlecenter experience (The Ohio State University Comprehensive Cancer Center, Columbus) that included 267 patients with CLL was reported, describing a mechanism of resistance in patients taking ibrutinib. This was accomplished by using Torrent deep sequencing on peripheral blood at baseline and relapse.

Flinn I, Jäger U, Offner F, et al. DUO: a phase 3 trial of the PI3K-δ,γγ inhibitor IPI-145 versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. J Clin Oncol. 2014;32(5 suppl): abstract TPS7122.

than conventional “7+3” induction therapy in patients older than 60 years and those with poor-risk features. The results are promising and a Phase III is comparing FLAM with 7+3.

5. True. Crenolanib is also the first

Zeidner JF, Foster MC, Blackford A, et al. Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML). J Clin Oncol.l 2014;32(5 suppl): abstract 7002.

Collins R, Kantarjian HM, Levis MJ, et al. Clinical activity of crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML). J Clin Oncol. 2014; 32(5 suppl): abstract 7027.

6. True. PI3K-δ,γ isoforms are pref-

erentially expressed in leukocytes and are central to the growth and survival of certain B- and T-cell malignancies. IPI-145 has shown clinical activity and a

ic leukemia (ALL): Therapy with a combination of inotuzumab ozogamicin (IO) and low-intensity mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction and cytarabine at 0.5 g/m2 ×4 doses) is not feasible due to increased toxicity in older adults with ALL.

is an orally active inhibitor of the FLT3 receptor tyrosine kinase with substantial activity in AML.

10. True or False? AML: In a Phase

II trial, cladribine with low-dose cytarabine alternating with decitabine was an effective, well-tolerated ambulatory regimen for adults older than 60 years with AML.

patients (pts) and as salvage therapy for adult with R/R acute lymphoblastic leukemia (ALL). J Clin Oncol.l 2014; 32(5 suppl); abstract 7019.

9. True. The ability of quizartinib to

lower the blast count in a high percentage of patients and bridge these patients to a potentially curative hematopoietic stem cell transplant, with an acceptable safety profile, represents an important clinical benefit from quizartinib. Levis MJ, Martinelli G, Perl AE, et al. The benefit of treatment with quizartinib and subsequent bridging to HSCT for FLT3-ITD(+) patients with AML. J Clin Oncol.l 2014;32(5 suppl): abstract 7093.

7. True. FLAM appears to be more active 10. True. Fifty-nine AML patients

Woyach JA, Ruppert AS, Lozanski G, et al. Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: a single-center experience of 267 patients. J Clin Oncol.l 2014;32(5 suppl): abstract 7010.

agent to demonstrate clinical activity in patients refractory to other FLT3 TKIs via the major clinical resistance mechanism. Trials of crenolanib are being initiated in patients with AML who are newly diagnosed or are at first relapse (NCT01522469, NCT01657682).

8. True or False? Acute lymphocyt-

6. True or False? CLL: Inhibition 9. True or False? AML: Quizartinib

multicenter Phase II trial of timedsequential therapy with FLAM (flavopiridol [alvocidib], cytarabine and mitoxantrone) resulted in significantly higher

1. True. KPT-330 is a slowly revers-

complete response (CR) rates without increased toxicity compared with conventional “7+3” induction therapy for adults with newly diagnosed AML.

8. False. The combination of IO with

low-intensity mini-hyper-CVD is safe and shows very encouraging results (overall response rate [ORR], 95%) in the front-line setting in older adults with ALL and as a salvage approach (ORR, 75%). According to the investigators, these results appear to be better than those achieved with chemotherapy-only approach and may become the new standard of care. Jabbour E, O’Brien SM, Jain N, et al. Inotuzumab ozogamicin (IO) in combination with low-intensity chemotherapy as front-line therapy for older

have been enrolled (NCT01515527) with a median age of 69 years (range, 49-85), including 28 patients (47%) age 70 or older. Of the 55 patients evaluable for response, there were 32 CRs (58%), three CRs with platelet counts less than 100,000/mcL (5%) and two partial responses (4%), for an ORR of 67%. With a median follow-up of more than four months, median overall survival and median CR duration have not been reached. The one-year overall survival estimate is 55%. The regimen was very well tolerated, with 0% four-week mortality. There were no treatment-related grade 3/4 nonheme adverse events (AEs). Most common nonheme AEs were elevated bilirubin, constipation, nausea/vomiting, mucositis, diarrhea and rash. Kadia TM, Cortes JE, Borthakur G, et al. Phase II trial of cladribine and low-dose AraC alternating with decitabine in older patients with AML. J Clin Oncol.l 2014;32(5 suppl): abstract 7031.

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

MANTLE CELL continued from page 12

AEs were similar, for the most part, except for higher rates of neutropenia, thrombocytopenia, leukopenia and lymphopenia in the VR-CAP arm (Table). Although patients receiving VR-CAP had higher rates of grade 3 or higher thrombocytopenia (57% vs. 6%), bleeding events were similar because of wider use of platelet transfusions in the experimental arm. Dr. Cavalli said that patients in the study received IV bortezomib and that perhaps subcutaneous dosing of the drug could decrease AEs. Michael Williams, MD, ScM, the chief of the Hematology/Oncology Division at the University of Virginia Cancer Center,

in Charlottesville, who was not involved with the study, agreed, saying it would be interesting to determine whether subcutaneous or weekly dosing of bortezomib could ameliorate some of the side effects. He was impressed with the results, and pondered whether they could be further improved by adding maintenance therapy. The European MCL Network study showed that maintenance with rituximab following R-CHOP induction improved outcomes ((New Engl J Med 2012;367:520-521). He noted that it is unknown how the addition of bortezomib would stack up against the addition

of a newer agent, such as lenalidomide (Revlimid, Celgene) or ibrutinib (Imbruvica, Pharmacyclics). Dr. Williams pointed out that many novel agents are being tested in frontline therapy of MCL and some may allow avoidance of traditional cytotoxic therapy altogether. In a Phase II study of patients with newly diagnosed MCL presented at the American Society of Hematology 2013 annual meeting (abstract 247), lenalidomide plus rituximab yielded an 80% overall response rate and 12-month PFS of 93.2%, with a median follow-up of 16 months.

“About a decade ago, there were few options for patients with mantle cell,” said Dr. Williams. “Now, it turns out that this disease is really a great model system for testing many targeted therapies,” such as inhibitors of mammalian target of rapamycin (mTOR), PI3K, Bruton tyrosine kinase and histone deacetylase. —Kate O’Rourke Dr. Cavalli reported no relevant financial relationships. Dr. Williams disclosed relationships with numerous companies including a consultancy/advisory role and research funding from Millennium.

CURRENT PRACTICE

ONLINE SYSTEM continued from page 6

patient has reported high levels of pain or another severe symptom, it prompts the patient to contact his or her physician. If, on the other hand, a patient’s symptoms are not as severe, the program provides self-care information. It will suggest that a patient drink plenty of water, for example, if he or she reports having mild diarrhea. This system could also “provide good information to post-therapy patients,” Dr. Wang said, such as patients receiving concurrent chemoradiation therapy who may not have scheduled follow-up visits in the peak of symptom burden. Patients finished with chemotherapy may still experience persistent symptoms, but a symptom-monitoring program could help with the transition. Cancer associations and foundations may offer online systems that track symptoms, but some of these symptom trackers may require up to grade 12 reading skills, Dr. Berry said. The ESRA-C was designed with a sixthgrade reading level in mind. “We’ve gone to great lengths to make it usable by people who’ve never touched a computer.” To make the program more accessible, Dr. Berry envisions that future plans could include installing iPads in waiting rooms. “A few years ago, there would have been a bigger barrier” for patient adoption, Dr. Wang said. “But now, even if you don’t have a computer, you can use an iPhone or smartphone, or an iPad,” she added, predicting that technology such as this will have a “bigger and bigger impact every day in oncology care.” —Ben Guarino Drs. Berry and Wang reported no relevant financial conflicts of interest.

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results from the long-awaited Phase III CALGB/SWOG 80405 trial showed. “What this tells us is that either FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, 5-fluorouracil and oxaliplatin] with either bevacizumab or cetuximab are perfectly reasonable options,” said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco. The results, presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract LBA3) as well as at the European Society for Medical Oncology (ESMO) 16th World Congress on Gastrointestinal Cancer, were achieved across a broad

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

clinical trials network, suggesting that the results apply in a variety of practice settings, Dr. Venook said. They show that “patients with KRAS wildtype colorectal cancer have choices,” he said. “First-line therapy should reflect the patient’s preference or concern for potential side effects.” The study, which began in 2004 after the two biologics were approved in this setting, included 1,420 patients with mCRC assigned to chemotherapy with FOLFOX (73.4%) or FOLFIRI (26.6%), given at the choice of the investigator, and then randomly assigned to also receive cetuximab (400 mg/m2 loading dose then 250 mg/m2 once a week), bevacizumab (5 mg/kg twice a week) or both. The combination arm was later discontinued. Once KRAS mutation testing became available, the study was amended to

‘There may be some temptation to top-line this as a negative trial [because] the two arms are the same. But the really important thing is that this sets an entirely new high standard and a new high bar for clinical trials in advanced CRC.’ —Clifford A. Hudis, MD

Model Questions Cost-Effectiveness Of Avastin for mCRC CHICAGO—The addition of bevacizumab to chemotherapy as a first- or secondline treatment for metastatic colorectal cancer is not cost-effective, according to an analysis presented at ASCO. However, new data from the SWOG/CALGB 80405 trial showing improved survival with bevacizumab could change that. The incremental cost-effectiveness ratio (ICER) for bevacizumab (Avastin, Genentech) as a first-line treatment was assessed at $240,814 for each qualityadjusted life-year (QALY), based on a Markov model. The rate was even higher when bevacizumab was included as part of a second-line therapy, at $363,066. That puts bevacizumab far beyond the typical cutoff for what is considered a cost-effective therapy. Typically, policymakers are willing to pay $100,000 to $150,000 per QALY. Anything beyond that is not considered cost-effective, said the investigators, led by Daniel A. Goldstein, MD, a hematology and medical oncology fellow at Emory University, in Atlanta. Dr. Goldstein said bevacizumab could become cost-effective if an effective biomarker were found to select patients most likely to benefit. “However, so far, this search has been elusive.” A spokesperson for Genentech said the company is examining a broad range of different types of biomarkers across more than five cancer types to identify a way to predict which patients may benefit most from bevacizumab treatments. “We are committed to determining if some patients derive a great benefit from Avastin,” said Holli Dickson, Genentech’s senior manager of corporate relations. Sandra Wong, MD, an assistant professor of surgical oncology at the University of Michigan, Ann Arbor, and a member of ASCO’s comparative effectiveness research task force, noted that based on the costs used in the analysis (in 2013 U.S. dollars), “there is no cost-effectiveness in what we’re seeing here.” However, Dr. Wong told Clinical Oncology News that recent data from SWOG/CALGB 80405 showing median survival of more than 29 months could affect the ICER for bevacizumab (see story). The improved survival could lead to higher QALYs for patients on this therapy, thereby lowering ICERs. ICERs are rarely taken into account when cancer therapies are recommended, Dr. Wong noted. “In truth, ICERs and willingness-to-pay thresholds aren’t enforced when clinicians, especially clinicians in the United States, make decisions. However, payors could start using these data to inform coverage decisions and that would be how appropriate value-based limits are put into place.” —Christina Frangou Drs. Goldstein and Wong reported no relevant financial conflicts of interest.

‘There is a subset of patients with metastatic CRC who will do exceedingly well,’ which is an important take-home message from the study. —Alan P. Venook, MD include only the 1,137 patients with KRAS wild-type tumors. Median followup was 24 months. There were no significant differences in either overall survival (OS) or progression-free survival (PFS) between the treatment groups. OS and PFS were 29 and 10.8 months, respectively, in the bevacizumab plus chemotherapy group and 29.9 and 10.4 months, respectively, in the cetuximab plus chemotherapy group. The trial showed no new adverse events for any of the therapies. The most frequent toxicities associated with bevacizumab included hypertension (7%) and gastrointestinal events (2%). For cetuximab, adverse events included acne-like rash (7%) and diarrhea (11%). In one of the most notable findings, 10.9% of patients were disease-free after surgery and therapy. Median OS of these patients now exceeds 5.5 years. “There is a subset of patients with metastatic CRC who will do exceedingly well,” which is an important take-home message from the study, said Dr. Venook. “There may be some temptation to top-line this as a negative trial [because] the two arms are the same,” said Clifford A. Hudis, MD, the outgoing ASCO president and a medical oncologist at Memorial Sloan-Kettering Cancer Center, in New York City, during a press conference. “But the really important thing is that this sets an entirely new high standard and a new high bar for clinical trials in advanced CRC.” Some oncologists who heard the study results being presented said they would base their decisions about which drug regimen to use on patient preference and the side-effect profile of the agents. “It’s good to have two different choices, two different options,” said Marwan Fakih, MD, a professor of medical oncology and the director of gastrointestinal medical oncology at City of Hope Comprehensive Cancer Center, in Duarte, Calif. Commenting on the data presented at

the ESMO Congress in a press release, Dirk Arnold, MD, the director of the Department of Medical Oncology at the Tumour Biology Centre, in Freiburg, Germany, said, “We now know that using any monoclonal antibody with any standard chemotherapy in first-line treatment may give the patient the likelihood of surviving about 30 months. However, there is no clear winner in terms of [OS].”

Data Are ‘Tip of the Iceberg’ Questions remain, and there are still important subgroup analyses that need to be conducted, particularly those looking at additional RAS mutations. These analyses may help identify patients who will benefit most from particular combinations of therapies. One of the questions raised at the meeting was why this study differed from the FIRE-3 trial of FOLFIRI combined with cetuximab or bevacizumab, presented last year. Response rates were similar for both groups in the FIRE3 trial, but OS was three months longer in patients who received FOLFIRI plus cetuximab. “What’s important from [the Phase III CALGB/SWOG 80405 trial] is there will be more to learn from this study than what’s been presented,” said Dr. Fakih. The data are “just the tip of the iceberg. Maybe there are clinical biomarkers or molecular biomarkers that will define a percentage of patients who are superior responders with one regimen versus the other. Is one regimen associated with a higher rate of resection of metastatic disease? These are important questions to move the field forward. We’re all awaiting these data but it’s going to be a while. These things will trickle forward over the next year or so.” —Christina Frangou Dr. Venook reported financial relationships with Bristol-Myers Squibb, Genentech and Roche, and Dr. Fakih with Genentech.

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Adjuvant Chemo Still Underused in Late Colon Cancer Chicago—Roughly one-third of patients with stage III colon cancer may not be receiving the recommended adjuvant chemotherapy, according to a study presented at the 2014 annual meeting of the American Society of Clinical Oncology. The data suggest that age and insurance status were among the factors that influenced physicians to forgo the potentially life-prolonging treatment (abstract 3576). “This is the largest, most recent study to determine the use of chemotherapy in stage III colon cancer. Older age was the biggest factor. People who were above the age of 60 years were less likely to receive chemotherapy,” said the study’s lead author Vijaya Bhatt, MBBS, a hematology-oncology fellow at University of Nebraska Medical Center, in Omaha. In 1990, the National Institutes of Health Consensus Conference recommended that patients with stage III colon cancer receive adjuvant chemotherapy, based on clinical trials demonstrating that it improved survival in

Table. Factors Associated With Adjuvant Chemotherapy for Colon Cancer

patients who were given a 5-fluorouracil–based regimen. Since then, investigators have determined that this practice has not been adopted completely. A study by Milburn et al, for example, found that use of adjuvant chemotherapy in stage III colon cancer patients increased from 39% in 1991 to 64% in 2002 (JAMA ( 2005;294[21]:2703-2711), thus falling short of the NIH recommendation that all such patients be given the treatment.

The new study looks at more recent data that show that although use of adjuvant chemotherapy has continued to rise, it still does not reach all patients. Dr. Bhatt and her colleagues identified roughly 200,000 patients diagnosed with stage III colon cancer between 2000 and 2011 through the National Cancer Database (NCDB), which contains information on approximately 70% of all new cancer diagnoses in the United States. They found

that the use of chemotherapy increased over time, from 59% between 2000 and 2002, to 62% between 2003 and 2006, and 64% between 2007 and 2011. Provision of chemotherapy was most influenced by patient age, gender and insurance status (Table). Chemotherapy use was lowest for patients with Medicare (52%), followed by Medicaid (70%), no insurance (73%) and private insurance (77%). see ADJUVANT CHEMO, O page 23

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Premenopausal Breast Cancer

Potential New Treatment Standard Is Emerging Chicago—After effective resection of hormone receptor–positive breast cancer in premenopausal women, recurrence is less likely among those treated with ovarian function suppression (OFS) along with exemestane rather than tamoxifen, according to a combined analysis of two large studies called TEXT and SOFT. The data suggest a potential for a new standard, pending longer-term survival analyses. Previously confined to use in postmenopausal women, now adjuvant exemestane combined with OFS “provides a new treatment option” in the premenopausal setting, said Olivia Pagani, MD, the clinical director of the Breast Unit at the Institute of Oncology of Southern Switzerland, in Lugano, presenting the results of the combined trials during the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). After five years of follow-up, disease-free survival (DFS) was 91.1% for patients randomized to the aromatase inhibitor (AI) exemestane plus OFS versus 87.3% for those randomized to tamoxifen plus OFS. This 3.8% absolute difference represented a statistically significant 28% reduction ((P<0.001) in the hazard ratio for DFS, the primary end point. Freedom from breast cancer, a secondary end point, also significantly favored exemestane ((P<0.001). The combined analysis of the two multinational trials, which also was published online by The New England Journal of Medicine (Pagani et al; 2014 Jun 1. [Epub ahead of

print]), was preplanned. IIn TEXT (Tamoxifen and Exemesttane Trial), 2,672 premenopausal womeen were randomized within 12 weeks o of definitive surgery for breast cancerr to receive exemestane or tamoxifen,, both initiated with the gonadotropin-releasing pin-releasing hormone agonist triptorelin to achieve OFS. Bilateral oophorectomy or ovarian irradiation was allowed in TEXT after six months of triptorelin. If chemotherapy was given, it was initiated with OFS. In SOFT (Suppression of Ovarian Function Trial), 3,066 patients were randomized to one of the same two treatment groups or to a third group

given tamoxifen alone. Follow-up in the tamoxifen tamoxifen-only only a r m i s o n g o i n g, a n d , t h u s , t h e data presented at ASCO were restricted to the 2,030 patients in the OFS arms. Although SOFT differed from TEXT in some design elements, such as timing of OFS, the patient populations recruited were similar. In the combined groups, the average age was 42 years, the median follow-up was 5.7 years,

Less Frequent Zoledronic Acid Schedule Gets Thumbs Up CHICAGO—Administering IV zoledronic acid (Zometa, Novartis) every 12 weeks is as effective as giving it every four weeks to prevent skeletal-related events (SREs) in women with metastatic breast cancer, according to results from the Phase III OPTIMIZE-2 trial presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract LBA9500). The FDA has approved zoledronic acid at a dose of 4 mg every three to four weeks to reduce the risk for SREs in patients with metastatic bone disease. Similar to other bisphosphonates, however, zoledronic acid comes with safety concerns, such as the risk for osteonecrosis of the jaw, atypical fractures of long bones and chronic impairment of kidney function. The OPTIMIZE-2 investigators hypothesized that less frequent dosing of zoledronic acid would decrease these potential adverse events. They enrolled 412 patients with breast cancer and bone metastases who had received prior therapy with at least nine doses of zoledronic acid or pamidronate. Patients were randomized to receive zoledronic acid every four or 12 weeks. At a median follow-up of 11.9 months, outcomes in the therapy every four weeks having at least one SRE compared with 23.2% of those receiving therapy every

12 weeks (P=0.724). The times to first on-study SRE were similar in the two arms (hazard ratio, 1.06; 95% confidence interval, 0.70-1.60; P=0.792). The group receiving less frequent infusions had fewer adverse events leading to dose adjustment or interruption (10.6% vs. 5.4%) and fewer renal function impairments (9.6% vs. 7.9%). Gabriel Hortobagyi, MD, a professor of medicine at the University of Texas MD Anderson Cancer Center, in Houston, who presented the study, said the results should be interpreted with caution because the trial size was relatively modest. Despite the trial size, Patricia Ganz, MD, the director of the Division of Cancer Prevention and Control Research at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, considers OPTIMIZE-2 “a high-quality, randomized controlled trial.” Dr. Ganz, who was not involved with the study, said the results translate into less frequent trips for patients to doctors’ offices, less toxicity and decreased costs, and she noted that she was comfortable using the every-12-week schedule for her patients. —Kate O’Rourke Dr. Hortobagyi disclosed relationships with Novartis. Dr. Ganz reported no relevant financial conflicts of interest.

and the majority of patients (57%)— particularly those with positive nodes or tumors greater than 2 cm—received chemotherapy. Grade 3/4 adverse events were observed in 30.6% of those randomized to exemestane and 29.4% of those randomized to tamoxifen. Fractures, musculoskeletal symptoms and dyspareunia were more commonly reported among those taking exemestane, and hot flushes, thromboembolic events and urinary incontinence were more commonly reported amo among those taking tamoxifen. Qu uality-of-life analyses did not faavor one treatment over the otther. Thee data indicate that the five-yeear likelihood of DFS iss very good with either therapy, but exemestane provided a significant advantage over tamoxiifen in reducing the risk for rrecurrence after definitive excision of breast cancer in n premenopausal women. The relatiive advantage of the AI in the context o of comparable tolerability suggests that exemestane should be the preferred the therapy. However, when asked to comment on the meaning of these data for community oncologists, Harold J. Burstein, MD, PhD, a breast oncologist at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, in Boston, was more cautious. Lead author of a recent update of the ASCO Practice Guidelines for Adjuvant Endocrine Therapy (Burstein et al. J Clin Oncol 2014 May 27. [Epub ahead of print]), Dr. Burstein said that the optimal therapy “remains controversial,” even though the SOFT and TEXT trials, of which he was a co-author, have been “very important in answering the many questions about these therapies.” Dr. Burstein told Clinical Oncology News that, so far, the SOFT/TEXT data “suggest small differences between women getting ovarian suppression with AI or tamoxifen.” Pointing to the results of the ABCSG (Austrian Breast and Colorectal Cancer Study Group) 12 trial, which “showed no differences at all,” he said, “In light of that, I continue to use tamoxifen with ovarian suppression (in women getting ovarian suppression), but if the patient prefers an AI or does not tolerate tamoxifen, it is good to know that AI therapy is effective, too.” —Ted Bosworth Drs. Pagani and Burstein reported no relevant financial conflicts of interest.

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Checkpoint Inhibitors Move Ahead for Metastatic RCC Chicago—Immune checkpoint inhibitors are rapidly moving into Phase III trials for metastatic renal cell carcinoma (mRCC) based on impressive activity exhibited in early-phase studies. Even in heavily pretreated patients, immunotherapy with nivolumab, whether used as a monotherapy, in combination with another checkpoint inhibitor or with tyrosine kinase inhibitors, showed remarkable clinical efficacy, according to a series of studies presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Several receptors expressed on tumor cells, characterized as checkpoints, deactivate T cells, preventing them from eradicating malignancy. Immune checkpoint inhibitors block this effect so that T cells remain activated. Ipilimumab (Yervoy, Bristol-Myers Squibb), which inhibits the CTLA-4 checkpoint, has already been approved for treatment of metastatic melanoma. The next malignancy treated with an approved checkpoint inhibitor may be mRCC. Although based on early-phase data, the degree of activity and the duration of survival observed with checkpoint inhibitors in mRCC studies at ASCO are unprecedented in late-stage disease.

‘The median OS values in this large Phase II trial are the highest of any of the studies’ recently conducted, such as those with sunitinib, everolimus or temsirolimus. —Robert J. Motzer, MD In the largest of the studies, nivolumab, which inhibits the PD-1 checkpoint, produced a median overall survival (OS) that was about 50% longer than that reported previously with other treatment options (abstract 5009). In this study, which evaluated nivolumab as a monotherapy, 168 mRCC patients who had received at least one antiangiogenic therapy were randomized to one of three doses of nivolumab (0.3, 2 or 10 mg/kg) administered every three weeks until progression or unacceptable toxicity. Most had two or more metastatic sites and 40% had received three prior lines of therapy. The median duration of progressionfree survival for the treatment arms ranged from 2.7 months for the lowest dose to 4.2 months for the highest, a nonsignificant difference. The objective response rate was approximately 20% in all three groups (Table). However, the median OS rates were impressive, ranging from 18.2 months in the lowest dose

group to 25.5 and 24.7 months in the 2and 10-mg/kg dose groups, respectively. “The median OS values in this large Phase II trial are the highest of any of the studies” recently conducted, such as those with sunitinib, everolimus or temsirolimus, reported the principal investigator of this study, Robert J. Motzer, MD, an attending physician in the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, in

Table. Objective Responses in Dose-Ranging Phase II Trial of Nivolumab for mRCC Objective Responses

0.3 mg/kg (n=60)

2 mg/kg (n=54)

10 mg/kg (n=54)

Complete response, %

Partial response, %

Stable, %

Progressive disease, %

Not evaluable, %

mRCC, metastatic renal cell carcin carcinoma noma

see CHECKPOINTS, S page 23

Cases in Hyponatremia: Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com

Release Date: August 25, 2014

Expiration Date: August 25, 2015

Faculty

Goal

Juan Carlos Ayus, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor of Medicine Division of Nephrology University of Texas Health Science Center San Antonio, Texas

Michael L. Moritz, MD Associate Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Associate Professor Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment strategy. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka.

Distributed via CMEZone

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CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

Progress Seen in Immunotherapy for Lung Cancer Approach looks promising but may require combined strategies Chicago— Checkpoint inhibitors may prove critical to remission of advanced lung cancer but probably not as monotherapy. Although dramatic tumor shrinkage has been documented repeatedly in a minority of patients receiving a checkpoint inhibitor, in early-phase studies, including new studies presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), the future seems very likely to be a checkpoint inhibitor plus something else. “We have a number of very diverse approaches being tested clinically in lung cancer that seem likely to allow us to substantially increase immunotherapy response,” said Drew M. Pardoll, MD, PhD, the director of cancer immunology at Johns Hopkins University School of Medicine, in Baltimore. Summarizing the progress in the field in a session at the meeting, Dr. Pardoll maintained that treatment of lung cancer is “being transformed” by immunotherapy, but he indicated that the challenge is moving from a handful of responses to the promise of a fully activated, dependable and reproducible T-cell attack on lung cancer and other forms of cancer. Checkpoints are part of a complex crosstalk of coinhibitory and costimulatory ligands through which tumors downregulate the ability of T cells to recognize and attack malignant cells. Of the numerous checkpoints identified, only two, PD-1/PD-L1 and CTLA-4, have been evaluated so far as immunotherapy targets in clinical studies, but activity rates in a minority of patients have been impressive. Citing one study with nivolumab, an anti-PD1 monoclonal antibody, Dr. Pardoll noted that more than 20% of patients were alive at two years, a proportion far greater than anticipated from the advanced state of disease at the time of study entry. In new data presented at the ASCO meeting, rates of significant antitumor activity with singleagent checkpoint inhibitors also hovered around the 20% range. For example, in one study of more than 200 patients with advanced lung cancer, the objective response rates with MK-3475, a selective PD-1 antibody that blocks the interaction between PD-1 on T cells and PD-L1 and PD-L2 on tumor cells, reached 24% in those who entered the study with PD-L1 expression on immunohistochemistry analyses, according to the first author, Edward B. Garon, MD, the director of the Medical Oncology Program in Thoracic Malignancies at the David Geffen School of Medicine at University of California, Los Angeles (abstract 8020). In this series,

‘We have a number of very diverse approaches being tested clinically in lung cancer that seem likely to allow us to substantially increase immunotherapy response.’ —Drew M. Pardoll, MD, PhD

conducted in patients with few or no remaining treatment options, MK-3475 was characterized as generally tolerable, with an incidence of grade 3 or higher adverse events (AEs) below 10%. In another study with MEDI4736, a human immunoglobulin G1 antibody that binds to PD-L1 to prevent activation of PD-1 and CD80 receptors, three of 13 patients (24%) with non-small cell lung cancer (NSCLC) achieved a partial response, with two others showing more modest tumor shrinkage (abstract 8021). According to Julie R. Brahmer, MD, an associate professor of oncology at Johns Hopkins University who presented these data, safety was acceptable, with low rates of grade 3 or higher AEs. Recruitment for an extended study is ongoing. In a third study presented at the ASCO meeting, the objective response rate with nivolumab in 50 patients with advanced NSCLC was approximately 30%, with several patients achieving more than 80% tumor bulk reduction, according to Scott N. Gettinger, MD, an associate professor of medicine (oncology) at Yale Cancer Center, in New Haven, Conn (abstract 8024). PD-L1 expression was found to correlate with response, which typically occurred rapidly after therapy

was initiated and was sustained in some patients. In one, progression-free survival endured for 45 weeks. Although each of these studies provides evidence that checkpoint inhibition is active in lung cancer, Dr. Pardoll focused on the 70% to 80% of patients who are not achieving a meaningful response to evaluate where this field is going. This includes multi-checkpoint blockade, based on evidence that the pathways regulated by different checkpoints are not entirely overlapping, as well as combining checkpoint inhibition with strategies that stimulate T-cell activity. Whether this stimulation is achieved through vaccines, addressing the epigenetics that modify immune response or applying targeted therapies known to increase antigen expression, the opportunities involve targets both in the tumor and in immune system regulation. “The crosstalk between tumors and the immune system is bidirectional,” Dr. Pardoll explained. When PD-1 is expressed on tumor cells, its interaction with ligands PD-L1 and PD-L2 downregulates the immune response, but an adaptive resistance also turns off antigen production, release and presentation. It is not just the activity of T cells that

is suppressed but also a much broader array of processes involved in gearing up the immune system. Vaccines represent an obvious strategy to induce an antigenic response, but Dr. Pardoll predicted there could be synergies between immunotherapy and targeted tyrosine kinase inhibitors or other treatments capable of boosting antigenic activity. “Treatments that increase T-cell infiltration to tumor sites are also going to increase PD-1 expression, and, therefore, anti-PD1 therapies provide the opportunity to enhance the net antitumor effect of other immunotherapies,” Dr. Pardoll said. Citing early-phase studies, he provided several examples. In one, an antiPD1 agent was combined with 5-azacytadine plus a histone deacetylase inhibitor. The goal, set after deep and durable responses were seen in a small series of patients, was to block the upregulation of PD-1 that develops when demethylating agents induce an antigenic response. He also suggested that there may be synergy between anti-PD1 inhibitors and inhibitors of BRAF, which increase antigen production by inducing tumor penetration of CD8 lymphocytes. Although Dr. Pardoll believes that checkpoint inhibitors are going to “rejuvenate vaccines in the treatment of lung cancer,” particularly as progress is made in developing new vectors and better antigens, the key point is that progress in immunotherapy is likely dependent on addressing multiple signaling pathways. Whether or not checkpoint inhibitors are best combined with vaccines, treatments that address the epigenetic controls on the inflammatory response, tyrosine kinase inhibitors that help stimulate antigen expression or other strategies that boost the ability of T cells to mount an attack on malignant cells, the research appears to be at a pivotal stage. “We are looking at some very exciting opportunities to move forward in the treatment of lung cancer,” Dr. Pardoll said. Although he said there is “solid evidence that immunotherapy is effective,” he cautioned that “we still have a lot of landscape to cover” in identifying how to translate the relatively modest rates of objective response now being observed with checkpoint inhibitors in single-agent trials into the types of strategies that might offer durable disease control even when treatment is initiated in late stages. —Ted Bosworth Drs. Pardoll and Gettinger reported no relevant financial conflicts of interest. Dr. Garon reported a financial relationship with Merck and Dr. Brahmer with MedImmune.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • AUGUST 2014 • CLINICALONCOLOGY.COM

ADJUVANT CHEMO continued from page 19

Dr. Bhatt said age alone was not a valid reason to skip chemotherapy for patients with colorectal cancer. A recent analysis of four large data sets of patients older than 75 years with stage III disease showed that adjuvant chemotherapy reduced the risk for death by as much as 40% (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.530.68) ((J Clin Oncol 2012;30:2624-2634). Patients were treated with various combinations of fluorouracil, leucovorin,

capecitabine and oxaliplatin. In an earlier study of pooled trial data by Sargent et al, adjuvant therapy with fluorouracil plus leucovorin or levamisole reduced patients’ risk for death by 24% (HR, 0.76; 95% CI, 0.68-0.85), and patients were just as likely to receive benefit from treatment if they were older than 70 than if they were in three other age groups (≤50, 51-60, or 61-70) (N ( Engl J Med 2001;345:1091-1097).

clinical investigations at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, in Chicago, said the study was “important” and continues to demonstrate that a standard-ofcare treatment is not being administered to a large enough percentage of patients. “Treatment guidelines should be followed based on evidence,” Dr. Benson told Clinical Oncology News. “Even for patients with comorbidities, guidelines, such as those from the NCCN [National Comprehensive Cancer Network], include treatment approaches for patients who might be

Standard of Care Not Met Al Benson III, MD, a professor of medicine and the associate director for

considered for less intensive therapy.” He recommended that strategies be employed to ensure that all patients are informed about the reported benefits of adjuvant chemotherapy in colon cancer and provided access to this standard of care. For example, for patients with limited or no insurance, it is important to involve social workers to assist them with accessing appropriate care. —Kate O’Rourke Drs. Bhatt and Benson reported no relevant financial conflicts of interest.

CHECKPOINTS continued from page 21

New York City. He emphasized that he showed these differences not as a definitive comparison but to “point to overall survival as a valid end point for Phase III trials” that are being planned. Several are being considered, including a comparison of nivolumab with everolimus. Parallel clinical development is being pursued with nivolumab in combination with other agents that have shown activity in mRCC. In a Phase I study with nivolumab in combination with sunitinib or pazopanib for mRCC patients who had received at least one prior systemic therapy (abstract 5010), including one prior tyrosine kinase inhibitor, the objective response rates of 52% and 45% were substantially higher than those reported with either therapy alone, according to the principal investigator, Asim Amin, MD, PhD, the co-director of the Levine Cancer Institute, in Charlotte, N.C. In another study evaluating the combination of nivolumab and ipilimumab in two different doses, the objective response rate was 48% for the most effective combination, according to Hans J. Hammers, MD, PhD, an assistant professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in Baltimore (abstract 4504). In this study, as in the other two studies, the rate of grade 3 or higher adverse events was modest, an important consideration if the therapy fulfills its promise to prolong survival. In the context of the efficacy and safety observed so far, these data suggest that Phase III trials may be the best clinical option for patients with mRCC once enrollment begins. In the context of continued evidence of activity and absence of unexpected toxicities, development of these agents for mRCC is expected to move quickly. —Ted Bosworth Dr. Hammers reported no relevant financial relationships. Dr. Motzer reported financial relationships with AVEO, Bayer, Genentech, Merck and Pfizer. Dr. Amin reported a financial relationship with Bristol-Myers Squibb.

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key eﬃcacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Monteﬁore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify eﬀective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics. 4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour