Clinical Oncology News Hemotology Digital Edition - May 2012 by McMahon Group

Hematology/Oncology Edition

Independent News on Advances in Cancer Care

HEMATOLOGIC DISEASE

131 I-Tositumomab and Rituximab produce similar results in follicular lymphomas.

Rituximab then CHOP for posttransplant lymphoproliferative disorders. PRN

ASCO questions five common practices.

C linical Conundrums: A quiz on recent American Society of Hematology data for the practicing hematologist/ oncologist.

EXPERT COMMENTARIES FROM JOHNS HOPKINS

T FAP2E methylation and 5-FU efficacy linked.

Nilofer Azad, MD

E arly versus delayed stem cell transplants. Ivan Borrello, MD

SIR-Spheres® Microspheres: An Emerging Treatment for mCRC Liver Tumors See page 10

New Antibody Promising for Relapsed Lymphoma

U.S. Prepares Groundwork For Biosimilar Approvals

Obinutuzumab produces higher response rates than rituximab

With the recent release of FDA draft guidelines, launch of the first oncology biosimilars is looming

San Diego—In the first head-to-head comparison, obinutuzumab (GA101, Genentech) appeared to be more active than rituximab in relapsed CD20-positive indolent B-cell nonHodgkin’s lymphoma (NHL). Although only a Phase II study, the multinational, randomized investigation appears to validate the experimental evidence that GA101, a glycoengineered CD20 monoclonal antibody, provides a relatively high rate of antibody-dependent cellular cytotoxicity (ADCC). Based on the encouraging results, see ANTIBODY, page 7 

Len-Dex Induction Delays Progression in Smoldering Myeloma Induction therapy may be appropriate for high-risk patients San Diego—Patients with high-risk asymptomatic multiple myeloma, characterized as smoldering multiple myeloma (SMM), can delay their time to progression with an induction regimen of lenalidomide and dexamethasone (LenDex), according to the results of a randomized, Phase III study. After a median follow-up of 32 months, 15% of patients in the active treatment arm had symptomatic progression versus 59% of those in the treatment abstention, or watch-andwait, arm. The estimated hazard ratio see INDUCTION, page 4 

s biosimilar drugs make their way to American soil, clinicians, regulators, pharmaceutical executives and patients alike are asking: How long will it take for the first biosimilars to reach the U.S. market? How much lower will their prices be than the original Biologic drugs like monoclonal molecules they mimic? And how antibodies are 40 to 180 times the of small-molecule generic drugs like quickly will they be accepted by size aspirin (inset) and are vastly more complex. clinicians and patients? Biosimilar medications—also known as follow-on biologics—are virtually identical or highly similar versions of large and intricate biologic molecules like monoclonal antibodies. Brand-name biologics are already essential for the treatment of breast, see BIOSIMILARS, page 26 

The Challenge of Answering Multiple Questions in a Single Oncology Trial

he spectacular advances in able to participate in these studies our understanding of the and permit them to be completed in basic biology of malignancy and a reasonable time frame. the unique molecular factors drivIn light of these very realistic coning cancer progression in indistraints, it is not surprising that invesvidual tumors has led to a virtual tigators have attempted to address explosion of novel drugs and conand answer more than one specifcepts in disease management. ic, potentially highly clinically releMaurie As a result, there currently are Markman, MD vant question in a single trial. This far more therapeutic ideas that approach is certainly not irrational, are appropriate and should be examined particularly in the setting of an appropriin well-designed clinical trials than there ately sized randomized study with multiple see CHALLENGE, page 8  are potential research subjects willing and

McMahonMedicalBooks.com To order cancer therapeutic regimens or agents pocket guides, go to http://www. clinicaloncology.com/ PocketGuides.

New Drugs for Malignancy, An Issue of Hematology/ Oncology Clinics of North America Franco Muggia, MD See page 31.

Courtesy: FDA

clinicaloncology.com • May 2012 • Vol. 7, No. 5

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SOLID TUMORS

Clinical Oncology News • May 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

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

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

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Michigan Ann Arbor, MI

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

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

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

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

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

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

Steven Vogl, MD Medical Oncologist New York, NY

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

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

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

University of Texas, MD Anderson Cancer Center Houston, TX

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

Genitourinary Cancer Ronald M. Bukowski, MD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Pharmacy Mayo Clinic Rochester, MN

Leonard Saltz, MD

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Shaji Kumar, MD

Edward Chu, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Oncology Nursing

Hematologic Malignancies

Andrew Seidman, MD

Cathy Eng, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

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

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

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

Mission Statement

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 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. They then review the articles before they are published. Board members, in their area of specialty, are also 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 News 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.

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Multiple Myeloma

At a glance

100

INDUCTION continued from page 1 

(HR) for progression for those not given induction was 6.0 (P<0.0001). “The estimated three-year overall survival (OS) from inclusion in the trial was 93% for the Len-Dex arm and 76% for the no-treatment arm, which was of borderline significance [P=0.04], but the difference was more evident if we evaluate the OS from the moment of diagnosis [HR, 5.01; 95% confidence interval (CI), 1–22; P=0.03],” reported María-Victoria Mateos, MD, PhD, of the Hospital Universitario de Salamanca in Salamanca, Spain. In data presented at the recent annual meeting of the American Society of Hematology (ASH; abstract 991), Dr. Mateos reported that only one patient developed a grade 4 adverse event (AE), and the proportion of grade 3 AEs on active therapy was relatively low. In this study, only SMM patients at high risk for progression were included. The high-risk group was defined by the presence of a serum monoclonal component of 30 g/L or higher and 10% or more plasma cells in the bone marrow. For those patients who did not meet both criteria, high risk was defined by the presence of more than 95% of aberrant plasma cells by flow cytometry plus immunoparesis (reduction in uninvolved immunoglobulins of more than 25% with respect to the normal value). The 118 evaluable patients who met these criteria were randomized. The LenDex arm consisted of 25 mg lenalidomide on days 1 to 21 plus 20 mg of dexamethasone on days 1 to 4 of a 28-day cycle. After nine cycles, patients received 10 mg of lenalidomide daily on days 1 to 21 (every two months initially but the regimen was eventually changed to once monthly). The active therapy was compared with no treatment until progression, which is widely regarded as the standard of care in patients with SMM. In an intention-to-treat analysis, the objective response rate (ORR) was 81% with 56% achieving a partial response (PR), 11% achieving a very good PR (VGPR), 7% achieving a complete response (CR) and 7% achieving a stringent CR (sCR). In the 51 patients who ®

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 00896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Progression, %

In a well-characterized group of high-risk smoldering multiple myeloma patients, observation patients progressed to symptomatic disease at four times the rate of those given an induction regimen of Len-Dex during a 22-month period

60 46

40 20 0

10.5

Observation

Len-Dex Induction

Figure. Progression from smoldering multiple myeloma to symptomatic disease. en-Dex, lenalidomide and L dexamethasone

Estimated three-year survival was 17% higher in the Len-Dex arm, although the finding was of borderline significance

‘We have to wait to obtain results of other trials . . . to confirm the results, and probably in the near future we could offer to our patients an early treatment with the confidence that they are going to obtain a benefit.’

—María-Victoria Mateos, MD, PhD

completed nine cycles of Len-Dex, the ORR climbed to 87%, including 8% CR and 8% sCR rates. The sCR rose to 12% in those with a median of seven cycles of induction therapy. Of the nine patients who progressed to symptomatic disease while on therapy, four progressed while on maintenance lenalidomide and five progressed after discontinuing therapy. Among the 37 patients who progressed in the observation arm, 20 first developed symptoms due to bone lesions. The median time to progression (TTP) in the observation arm was 23 months. The median TTP has not been reached in the active treatment arm. Most of the AEs attributed to therapy occurred during the induction phase. Whereas there was only one grade 4 AE, the grade 3 events included anemia in one patient, asthenia in four patients, diarrhea in two patients and skin rash in one patient. Other notable AEs included grade 2 deep venous thrombi in two patients. During maintenance therapy, the only grade 3 AE was a case of infection. Two secondary malignancies occurred in the active-treatment group, but both cases had risk factors or potential signs of disease at the time of enrollment. Notably, 12 of the 51 patients who have been followed on maintenance therapy have developed biological progression. This triggered re-initiation of dexamethasone, according to the study protocol. In nine patients, progression was attenuated

by dexamethasone before symptoms developed. The median follow-up in this population is 11 months. In patients with asymptomatic multiple myeloma with a high risk for progression as defined in this study, the Len-Dex induction regimen followed by lenalidomide maintenance was associated with a highly significant prolongation of time to progression with a trend toward improving OS, according to Dr. Mateos. In addition, an intensification of the maintenance therapy appears to provide an opportunity to further delay the development of symptoms in patients with biological progression. Although no quality-of-life analyses were presented, the low rate of severe toxicities suggests that Len-Dex is superior to the current strategy of treatment upon progression. Dr. Mateos said that although this therapeutic approach is very promising for high-risk SMM patients, it should not be standard-ofcare treatment yet. “We have to wait to obtain results of other trials that are being conducted in this patient population in order to confirm the results, and probably in the near future we could offer to our patients an early treatment with the confidence that they are going to obtain a benefit,” Dr. Mateos said. S. Vincent Rajkumar, MD, a professor of medicine at Mayo Clinic, in

Rochester, Minn., agreed that the results are promising but countered that “there are some important caveats.” Particularly, he emphasized that the study was performed on a subset of patients with SMM who had very specific high-risk features and that the immunophenotypical definitions used for high risk in this study may not be widely available or utilized. “Moreover, the study tested a combination of lenalidomide and dexamethasone, and therefore the relative contribution of these drugs cannot be deciphered from this trial,” Dr. Rajkumar said. He agreed with Dr. Mateos that the standard of care for SMM remains observation, but that this and other interventions deserve multicenter testing. “The Eastern Cooperative Oncology Group is conducting a randomized trial of lenalidomide single-agent versus observation and I encourage participation in this trial,” Dr. Rajkumar said. “In the meantime, we need to continue to identify biomarkers that can discriminate patients with smoldering myeloma in whom the malignant switch has already occurred from those with pre-malignancy.” —Ted Bosworth

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María-Victoria Mateos, MD, PhD, has received honoraria from Celgene and Janssen. S. Vincent Rajkumar, MD, reported no potential conflicts of interest.

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HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Lymphoma

CHOP-RIT, CHOP-R Similar for Follicular Lymphomas San Diego—Radiolabeled iodine-131 tositumomab (RIT) and rituximab have similar efficacy and tolerability when either is combined with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) for newly diagnosed follicular non-Hodgkin’s lymphomas. Although the trial did not answer how either therapy fits with maintenance rituximab—a strategy that is being increasingly employed in follicular lymphomas (FL)—it is the first major study to compare these alternatives. “My conclusion is that the outcomes are excellent with either of these immunochemotherapies,” said Oliver Press, MD, PhD, the chair of lymphoma research at the Fred Hutchinson Cancer Research Center in Seattle. Presenting results of this Phase III trial, known as SWOG S0016, at the 2011 annual meeting of the American Society of Hematology (ASH), Dr. Press said that the administration of CHOP with either six doses of rituximab or a single dose of RIT “seems to confer similar benefit in terms of overall response rates, complete response rates, progression-free survival and overall survival.” The study was conceived in 1999, began enrolling patients in 2001 and was completed in 2008, but it required another three years of follow-up before there were sufficient events for the Data and Safety Monitoring Committee to release the data. The study started with three arms, but an arm with CHOP alone was discontinued when data from other trials made it clear that this was inferior. The study was then a two-arm trial comparing a standard CHOP regimen followed by either 375 mg/m2 rituximab on days 1, 6, 48, 90, 134 and 141 or a dosimetric infusion of RIT followed one to two weeks later by a therapeutic RIT dose sufficient to deliver 75 cGy. The median age of the study population, which randomized almost as many women as men, was approximately 55 years. Slightly more than half had high β2-microglobulin (b2m) levels. A small proportion of patients had stage II disease (which required a tumor mass >10 cm). The remainder had stage III or IV FL. Risk by Follicular Lymphoma International Prognostic Index (FLIPI) scores was relatively evenly distributed between low, medium and high. Of the 526 patients who were considered evaluable, 496 completed the course of the assigned therapy as specified in the initial study design. With a mean follow-up of 4.9 years, the differences in major outcomes were small and not statistically significant. For example, about 85% of patients in each arm achieved an objective response. Of these, 41% of those on CHOP followed by rituximab (CHOP-R) and 46% of those

Table. CHOP Plus Rituximab vs. CHOP Plus Iodine-131 Tositumomab CHOP-R

CHOP-RIT

P Values

Overall response rate (CR + PR)

224 (85%)

223 (86%)

0.90

Complete response rate (including unconfirmed CR)

108 (41%)

120 (46%)

0.25

2-y PFS

76%

80%

0.11

2-y OS

97%

93%

0.08

CR, complete remission; OS, overall survival; PFS, progression-free survival; PR, partial remission

The fact that CHOP-RIT does not appear to provide major advantages over CHOP-R other than a reduced number of immunochemotherapy infusions does not diminish the clinical importance of the very good long-term results achieved with either therapy. on CHOP-RIT achieved complete remission. Although the progression-free survival (PFS) score at two years was 76% on CHOP-R versus 80% on CHOP-RIT, the overall survival (OS) was 97% and 93% for these two groups, respectively. There also were no significant differences in total deaths or rate at which secondary malignancies developed. There was a greater number of acute myeloid leukemias or myelodysplastic syndromes in the CHOP-RIT group (seven vs. three), but, again, the difference was not significant. Grade 4 hematologic adverse events occurred in 36% of those receiving CHOP-RIT versus 30% of those randomized to CHOP-R. The biggest difference was in thrombocytopenia, which occurred with grade 3 or 4 severity

among 18% of those on CHOP-RIT versus 2% on CHOP-R, but Dr. Press reported that clinically significant events due to thrombocytopenia, such as bleeding or blood transfusions, were uncommon. Nonhematologic grade 4 events were characterized as rare, occurring in only 2% of each arm. Indeed, most of the adverse events in both arms were attributed to CHOP rather than the adjunctive immunochemotherapies. The prognostic markers lactate dehydrogenase (LDH), b2-microglobulinemia and FLIPI score were all highly statistically significant predictors of outcome in this study regardless of assigned therapy. In the data evaluated so far, there has been no clear evidence of a greater benefit from one treatment over another in any patient subgroup, such as those

At a glance CHOP-R and CHOP-RIT produce similar toxicity, response and two-year survival rates that are not significantly different 85% of patients in both arms achieved an objective response Most of the adverse events were CHOP-related rather than from the adjunctive immunochemotherapies To date, no subgroup of patients has shown a clear benefit with either therapy The relative role of CHOP-RIT versus CHOP-R in patients who receive rituximab maintenance is unknown

with high b2m levels, but Dr. Press reported that these analyses are still ongoing. The results in this Phase III study are consistent with a previous Phase II trial with CHOP-RIT (SWOG 9911) with a median follow-up that has now reached 11 years. The projected 10-year PFS in this study, which provided the impetus to pursue a Phase III investigation, is 60% with a 10-year OS of 79%. The fact that CHOPRIT does not appear to provide major advantages over CHOP-R other than a reduced number of immunochemotherapy infusions does not diminish the clinical importance of the very good long-term results achieved with either therapy. Although the results of a large-scale, multicenter Phase III comparison of immunochemotherapies in FL are welcome, Dr. Press acknowledged that important questions remain. In particular, the concept of rituximab maintenance in patients with FL was developed after this study was designed, and the relative role of CHOP-RIT versus CHOP-R in patients who receive rituximab maintenance is unknown. Asked if the results of this study are still helpful given the long interval between its design and final results, Rebecca Elstrom, MD, an assistant professor of hematology/oncology at Weill Cornell Medical College in New York City, said that “this is a far from simple question” because of the way therapeutic strategies have evolved over the past five to 10 years. “Both arms are ‘obsolete,’ but both lend insight into what we can do for people now,” Dr. Elstrom said. “In the context of other studies showing tolerability and suggesting efficacy of RIT after front-line rituximab-containing therapy, the major question is the role of maintenance rituximab versus consolidative RIT after initial rituximab-containing therapy, but as [the authors] pointed out, this study is unlikely to be done.” However, now that there is evidence that rituximab improves survival in patients with FL, “it is relevant that RIT seems to have provided that same benefit,” Dr. Elstrom said. Overall, “I do think it shows RIT still has a potential role in up-front therapy.” —Ted Bosworth Dr. Press reported receiving honoraria and consulting fees from Spectrum and honoraria, research funding and consulting fees from Roche/Genentech. Dr. Elstrom reported that she is on the speaker’s bureau of Genentech and has received research funding from GlaxoSmithKline.

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Lymphoma

ANTIBODY GA101 has already been entered into Phase III studies, said Laurie H. Sehn, MD, a clinical assistant professor with the BC Cancer Agency in Vancouver, Canada, at the 2011 meeting of the American Society of Hematology (ASH), where she presented the data from the Phase II trial (abstract 269). Dr. Sehn indicated that the data provide preliminary support for the premise that anti-CD20 antibodies may not be interchangeable in terms of clinical activity in relapsed patients. In this study, called GAUSS, 175 patients were enrolled, but the data presented by Dr. Sehn was restricted to the 149 patients with follicular lymphoma (FL). The data on the 26 patients with non-follicular indolent NHL were not presented. All of the patients in this study had achieved either a partial or complete response (CR) to a prior rituximab-containing regimen lasting at least six months. The median number of prior lines of treatment was two. The patients were randomized to four weekly infusions of either 375 mg/m2 of rituximab or 1,000 mg of GA101. The aim of the study was to compare both efficacy and safety. The objective response rate based on investigator assessment was 33.3% for those receiving rituximab and 44.6% for those receiving GA101, a difference that fell just short of statistical significance (P=0.08). However, the CR rate was more than double on GA101 (12.2% vs. 5.3%), and both of these relative differences were slightly greater when reviewed by a blinded independent radiology facility. In general, GA101 and rituximab showed similar degrees of safety and tolerability. Although patients receiving GA101 had more infusionrelated reactions (IRR) overall (72% vs.

At a glance Obinutuzumab (GA101) produced twice as many complete responses for relapsed CD20-indolent B-cell non-Hodgkin’s lymphoma as rituximab Obinutuzumab patients had more infusionrelated reactions; however, rituximab patients had more serious adverse events during induction and were more likely to discontinue therapy

Images courtesy of Genentech

continued from page 1 

49%) as well as more grade 3 or 4 IRR (11% vs. 5%), more rituximab patients experienced a serious adverse event in the induction period (nine vs. five) and more rituximab patients discontinued therapy (seven vs. four). One patient on rituximab died of cardiopulmonary arrest and one patient on GA101 died of pulmonary aspergillosis. Compared with rituximab and other earlier-generation monoclonal antibodies targeted at CD20-positive cells, GA101 has demonstrated a higher affinity to the CD20 type II epitope see ANTIBODY, page 8 

Clinical Oncology News wants to publish you! ANTIBODY

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National literary exposure! A voice in the marketplace of ideas!

Essays can relate to the topic in any way the author sees fit — how medicine has changed for the worse, how it should be changed for the better, or simply a reflection on the process of change itself. Essays will be judged on their eloquence and persuasiveness and should be a maximum of 3,500 words. Winners will be announced in the August issue. First place will receive $1,000, second place $500 and third place $250. All will receive recognition and prominent placement in Clinical Oncology News. Submissions should be emailed as a Word document to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com.

As part of the Clinical Oncology News inaugural writer’s contest, from now until June 30 the magazine will be accepting essays on the topic ‘Change in Medical Oncology or Hematology/Oncology’.

PRN

Clinical Oncology News • May 2012

Clinical Trials

CHALLENGE continued from page 1 

treatment arms. However, considering the required sample sizes, time constraints and resources necessary to conduct these types of studies, it is unlikely that more than a small fraction of oncology research can be conducted in this way. The more common route is to combine several concepts into a single therapeutic program. For example, it is routine for a new drug to be administered at a particular dose and on a particular schedule when in reality the optimal dose and schedule are unknown. This is particularly concerning when a number of novel anti-neoplastic strategies are being explored in a given therapeutic regimen. Multiple different approaches to timing, sequencing, drug dosing and scheduling ultimately may be relevant for defining the efficacy and toxicity of the regimen. It often is argued that if a trial is “positive,” future investigations can address the importance of the individual assumptions (e.g., dose and schedule) that characterized the original regimen design. The often-unstated assumption here is that if the trial is “negative,” there will be little—if any—interest in pursuing any individual component of the program. Thus, despite a concept itself remaining potentially valid, it is possible that this approach to testing therapeutic regimens will result in a failure to achieve the necessary outcomes to encourage future investigation. Likewise, the decision to continue the original regimen unmodified following a “positive trial” is equally concerning, and the clinically relevant components

may never be identified. These decisions have a very real potential of subjecting patients to unnecessary and excessive side effects. Two examples from the peerreviewed, published oncology literature—drawn from many that could have been raised—are illustrative. A welldesigned, Phase III randomized trial

one study in ovarian cancer, patients received paclitaxel on a weekly basis versus the “standard” every-threeweek regimen.2 However the total dose of paclitaxel given over each threeweek interval also was designed to be greater with the weekly program, the “dose-dense” approach. The preliminary report of this study revealed a tru-

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

‘There are currently far more therapeutic ideas that are appropriate and should be examined in well-designed clinical trials than there are potential research subjects willing and able to participate in these studies and permit them to be completed in a reasonable time frame.’

malignant disease. As a result, it is certain that future trials will continue to combine multiple concepts without initially defining the optimal use of each individual component. That being said, it is important that the oncology community fully appreciate the potential risks associated with this necessarily pragmatic strategy.

conducted more than two decades ago compared a standard cisplatin-based chemotherapy program in “poor prognosis” germ cell tumors with an investigative regimen that combined the concepts of adding a new agent (etoposide) and dose intensity (doubling the cisplatin concentration).1 This “positive trial,” measured in terms of survival, might have been interpreted as demonstrating the importance of substantially increasing the dose of cisplatin in routine cancer management in this specific clinical setting. Fortunately, subsequent research revealed that including etoposide, rather than doubling the cisplatin concentration, was the cause of the superior clinical outcomes with this primary chemotherapy program. A more recent example is the concept of dose density, often employing the major anti-neoplastic paclitaxel. In

ly impressive 11-month improvement in median progression-free survival and a statistically significant favorable effect on three-year overall survival with the weekly dose-dense approach. Unfortunately, it remains unknown whether the outcome resulted from increasing the dose density of therapy or from simply delivering the same cumulative concentration of paclitaxel but on a far more rational schedule i.e., once a week. (Note: The theoretical benefits of the “weekly program” include increased exposure of actively dividing cancer cells to this cycle-specific anti-neoplastic agent and the optimization of a recognized anti-angiogenic effect of the drug.) These concerns do not change the genuinely limited opportunities that currently exist for testing exciting novel approaches to the treatment of

References

lymphomas over the past decade,” the efforts to optimize monoclonal antibody therapies may be a necessary next step to further improve outcomes. “Relative to rituximab, obinutuzumab results in greater ADCC and induction of apoptosis in preclinical studies, and now has shown higher response rates in the randomized Phase II GAUSS study,” Dr. Stewart said. “These

data definitely support the ongoing randomized Phase III GALLIUM trial comparing chemoimmunotherapy with rituximab versus obinutuzumab as initial therapy for indolent B-cell lymphoma, and the similar GOYA trial for diffuse large B-cell lymphoma. We remain hopeful that results from these studies will lead to further improvements in survival for these

common lymphoma entities.”

1. Ozols RF, Ihde DC, Linehan WM, et al. A randomized trial of standard chemotherapy versus a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors. J Clin Oncol. 1988;6:1031-1040. 2. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: A phase 3, open-label, randomized controlled trial. Lancet. 2009; 374:1331-1338.

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

gmiller@mcmahonmed.com

HEMATOLOGIC DISEASE Lymphoma

ANTIBODY continued from page 7 

in experimental studies. This has produced an ADCC that has been up to 100-fold greater than with rituximab, not only producing greater depletion of B cells than rituximab in xenograft mouse models of B-cell malignancy but longer survival of these models as well. The GAUSS study is the first head-tohead, randomized comparison of GA101 in the clinical setting. Douglas Stewart, the chief of hematology and hematologic malignancies at the University of Calgary in Alberta, Canada, said that although the anti-CD20 rituximab “was the major treatment advance that significantly improved survival rates for B-cell

Images courtesy of Genentech

—Ted Bosworth Dr. Sehn reported receiving fees for consulting and honoraria and research funding from Roche/Genentech. Dr. Stewart reported receiving honoraria and research funding from Hoffmann-La Roche.

SOLID TUMORS

Clinical Oncology News • May 2012

Colorectal

Robotic Proctectomy Shows Lower Conversion Rate, Same Safety From Annals of Surgical Oncology

meta-analysis of seven comparative studies of robotic versus conventional laparoscopic resection for rectal cancer concludes that the new technology offers significant benefits with regard to efficacy without compromising safety. The analysis, published in the Feb. 16 issue of the journal Annals of Surgical Oncology (Epub ahead of print, PMID: 22350601), sought to compare existing data on the safety and efficacy of robotic and conventional laparoscopy for the management of rectal cancer. The team of researchers, led by Sameer Memon of the Peter MacCallum Cancer Center and the

EXPERT INSIGHT Elizabeth C. Wick, MD Assistant Professor of Surgery and Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

emon et al reported a meta-analysis of seven studies evaluating the

University of Melbourne in Australia, selected seven studies, two of which were matched and five of which were unmatched. The studies included in the meta-analysis were Park et al (Ann Surg Oncol 2010;17:3195-3202, PMID: 20589436), Kwak et al (Dis Colon Rectum 2011;54:151-156, PMID: 21228661), Kim et al (J Korean Soc Coloproctol 2010;26:377-387, PMID: 21221237), Leong et al (Surg Endosc 2011;25:29872992, PMID: 21484533), Bianchi et al (Surg Endosc 2010;24:2888-2894, PMID: 20526623), Baik et al (Ann Surg Oncol 2009;16:1480-1487, PMID: 19290486) and Patriti et al (JSLS 2009;13:176-183, PMID: 19660212). The seven studies encompassed 754 patients, of whom 353 underwent robotic-assisted laparoscopic

colorectal surgery and 401 underwent traditional laparoscopy. Based on the findings of these studies, roboticassisted surgery was associated with a significantly lower conversion rate to open surgery)—a risk difference of 7% (P=0.03)—than traditional laparoscopy. The authors also found that there was no significant difference in the complication rates between the two procedures (P=0.38). Interestingly, the meta-analysis also determined that there was no significant difference in operating time or hospital length of stay (LOS) between the two procedures, although it should be noted that not all of the studies included in the analysis assessed for these two outcomes. Of course, the use of robotic

technology in laparoscopic colorectal surgery is on the rise, despite the relatively high equipment costs. Indeed, the costs may be the primary barrier to routine use in proctectomy. Although the authors of this meta-analysis noted a distinct benefit in the use of the technology—the lower conversion rates associated with the procedure—they also emphasized that the benefits “may differ between population groups.” Additionally, taken together, the studies included in the meta-analysis reflect a relatively small patient population. Thus, the authors believe that further study—in the form of large, randomized controlled trials—is needed to properly assess the role of robotic-assisted laparoscopic surgery in the management of rectal cancer.

outcomes of patients undergoing laparoscopic versus robotic proctectomy for rectal cancer. To date, there has been no well-designed, controlled study that has clearly demonstrated that open, laparoscopic or robotic rectal cancer surgery is superior. Therefore, the authors used a meta-analysis of published studies to address the question. Although the number of patients included in each study was relatively low and the patient populations were heterogeneous, the authors concluded that robotic-assisted rectal cancer

surgery is associated with a lower rate of conversion to open surgery as compared with that of patients undergoing laparoscopic rectal cancer procedures. The focus is on short-term outcomes—operative duration, hospital LOS and anastomotic leak—and there was no difference in these other outcomes. No stringent analysis was done of the adequacy of the total mesorectal excision (TME) in each case. The authors comment that the most critical elements of rectal cancer care are appropriate preoperative staging, use of neoadjuvant

chemotherapy and radiation, and adjuvant chemotherapy; and, in addition, complete mesorectal excision without violation of the fascia propria of the rectum. The former elements are the responsibility of the team of treating physicians and the latter is in the hands of the surgeon. So, as they say, there are many ways to skin a cat and, in the case of rectal cancer, so that you can achieve a TME, they are probably all appropriate. Therefore, the surgeon should use the technique with which he or she is best able to achieve a TME.

Movie Review: Cut Poison Burn

t the heart of “Cut Poison Burn,” a compelling new documentary from director Wayne Chesler, is a premise that will make many cancer specialists uncomfortable. In the 40 years since Richard Nixon declared war on cancer, American medicine has fought the battle to a stalemate. Although progress has been made against some forms of the disease, such as testicular and cervical cancers, overall mortality in 2011 is basically unchanged from 1971. More distressing, just as the Vietnam era gave us the Orwellian notion of destroying a village in order to save it, much of the armamentarium used to fight cancer takes a brutal—and, the filmmakers argue, largely unjustifiable—toll on the human body. Based on a stage play by the same name, “Cut Poison Burn” mixes interviews with skeptical cancer researchers with often heartbreaking footage of patients and their families. The patient stories all have the same essential narrative: People with cancer, whether they try to stick with

conventional chemotherapy and radiation or seek alternative treatments that promise, if not a cure, then at least less punishment, are stuck in a maze whose only exits are bad outcomes. Standing in their way, according to the filmmakers, are arbitrary and intransigent bureaucrats at the FDA and a medical–industrial complex with no room for unprofitable experimental treatments and the researchers who stray outside the umbrella of the status quo. One such figure is Stanislaw Burzynski, MD, PhD, a Polish emigre whose eponymous clinic in Houston was the target of a costly government investigation. Dr. Burzynski claims to have produced cures for lethal tumors with what he calls antineoplastons, peptides in urine that, according to his theory, convert malignancies into normal cells. Dr. Burzynski has been labeled a quack and worse (he’s also the subject of another recent documentary, “Burzynski, the Movie”). He has published extensively in reputable, peer-reviewed journals,

yet whether his approach works is at best debatable. But the film is strongly sympathetic to him—or, at least, to two points regarding his work: Patients should be allowed to choose such controversial treatments without government interference, and money should be available to test experimental cancer remedies that don’t appeal to the drug industry. As the documentary makes clear (painfully so in the first instance), neither is true today. Always provocative, Chesler’s film occasionally oversteps. One of these involves the statement by Vincent DeVita, MD, who directed the National Cancer Institute for most of the 1980s, that the FDA would reject an application for aspirin today because the drug causes tumors in lab animals. Perhaps that’s true, yet much of the narrative stresses the hazards of key cancer therapies, such as tamoxifen, precisely for their propensity to cause cancers in patients. Viewers may reject the film’s vision of good and evil, but some points will hit the mark. How, for example, can the American Cancer Society justify a $1 million salary for its top executive while the group spends barely 10% of its $1 billion annual

budget on research efforts? Why did the medical establishment suppress the Pap test for so many years, condemning thousands of women to needless death from cervical cancer? And what kind of soulless legal system would threaten parents with prosecution for wanting to shield their dying child from the terrible effects of brain irradiation? As one of the talking heads in the film argues, in time doctors and patients will look back on the current state of cancer treatment the way we now view bloodletting: primitive, barbaric and ineffective. That remains to be seen. But “Cut Poison Burn” raises questions that physicians, patients, regulators and the biomedical industry should not ignore. —Adam Marcus “Cut Poison Burn” is available for downloading at cutpoisonburn.com.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

SIR-Spheres® Microspheres: An Emerging Treatment for mCRC Liver Tumors Divyesh G. Mehta, MD Chief, Hematology Oncology Division Maricopa Integrated Health System Professor of Medicine University of Arizona College of Medicine Phoenix, Arizona

Introduction Colorectal cancer (CRC) is a serious and relatively common disease; in 2011, approximately 141,000 new cases and approximately 49,000 deaths from CRC occurred in the United States.1 However, mortality rates from the disease have progressively declined since the mid-1980s due to the detection and removal of colonic polyps, detection of CRCs at earlier stages, and advances in treatment.2 “The treatment of CRC has come a long way. A decade or so ago, all that was available was 5-fluorouracil [5-FU]. Now, we have many different drugs and regional therapies available, and the ability to use these drugs and devices in combination or in sequence means that the median survival of 8 months in patients with metastatic disease has now increased to over 2 years. The ability to administer a second or third regimen once a patient becomes refractory to their current regimen means that these patients stand a better chance at survival,” explained Divyesh G. Mehta, MD, chief, Hematology Oncology Division, Maricopa Integrated Health System in Phoenix, Arizona. Despite increases in the 5-year survival rates for the overall set of patients with CRC over the past several decades, the 5-year survival rates for patients with metastatic CRC (mCRC) remains low at 11%.3 The liver is particularly vulnerable to the hematogenous spread of CRC; in fact, studies suggest that approximately 50% of patients with CRC will develop liver metastases, and without treatment, these patients have very

poor prognoses.4 Clinical strategies to manage liver metastases, such as surgical resection, systemic chemotherapy, and targeted biologic therapies, have specific limitations. For example, only an estimated 15% of liver metastases are initially amenable to surgical resection.4 Additionally, systemic chemotherapy and biologic therapies are associated with significant systemic adverse effects, and unfortunately, most patients with mCRC ultimately become refractory to these therapies. “This is particularly true for slow-growing tumors within the liver,” said Dr. Mehta. “They simply don’t respond well to chemotherapies.” Regional therapies, such as local tumor ablation, regional hepatic intra-arterial chemotherapy or chemoembolization, and selective internal radiation therapy (SIRT), have been used to downstage disease, thus allowing for resection. “Regional therapies, by themselves, are not curative in the majority of patients. However, when used as an adjunct to other available treatments, they allow bulk reduction of the tumor in patients who wouldn’t otherwise respond to chemotherapy alone. Then you can proceed with other agents that work in a systemic or a targeted manner. Furthermore, these local techniques have been shown to be effective in slow-growing tumors that might not otherwise respond to, or are refractory to, chemotherapy alone,” said Dr. Mehta.5,6 This monograph will discuss SIRT using yttrium-90 (Y-90)–labeled resin microspheres (SIR-Spheres microspheres, Sirtex), the only FDA-approved Y-90 microspheres for regional liver-directed therapy in patients with liver metastases caused by CRC.

SIRT for Liver Metastases Although radiation therapy is used widely for multiple tumor types, external beam radiation therapy typically is not used in patients with liver tumors because of the radiosensitive

nature of normal liver tissue. “My colleagues in oncology have had very bad experiences using external radiation, particularly with regard to radiation-induced liver failure,” said Dr. Mehta. As a result, the principle of SIRT has been employed in an effort to deliver radiation to liver tumors while simultaneously preventing radiation exposure to the normal liver parenchyma or other organs.7,8 This strategy capitalizes on the fact that although the normal liver parenchyma receives the majority of its blood flow from the portal vein, tumors within the liver are almost exclusively perfused by blood from the hepatic artery.7,9 Thus, infusing radioactive particles into the hepatic artery has the potential to deliver targeted radiation to the tumor while sparing the normal liver parenchyma from damage. SIR-Spheres consist of biocompatible polymer microspheres that range from 20 to 60 microns in diameter and contain Y-90, a radioactive isotope.7 When infused through a femoral catheter placed into the hepatic artery, preferential uptake ensures that SIRSpheres will travel to the tumor where they permanently lodge in the tumor microvasculature, inducing tumor cell death through both arterial microembolization and highdose interstitial radiotherapy (Figure).7 Y-90 is a beta-emitting isotope. “This means that the radiation spread is very localized—it spreads to a very small extent (mean path of 2.5 mm) from where the SIR-Spheres lodge within the tumor, and because its half-life is about 64 hours, most of the radiation is delivered over the first 2 weeks of implantation.7 A major advantage of Y-90 therapy is that the procedure generally is performed on an outpatient basis with patients going home the same day as the treatment,” said Dr. Mehta. “Compared with other regional or chemotherapeutic regimens, Y-90 treatment has a relatively benign safety profile, making it an excellent choice for many patient populations.”

Figure. SIR-Spheres microspheres mode of action. A) Y-90 therapy uses a transfemoral microcatheter to access the liver via the hepatic artery. B) The microspheres are administered into the hepatic arteries where they travel through the bloodstream to the tumors. C) The microspheres kill the cancer cells by delivering beta radiation directly to the tumor, while sparing normal liver tissue from damage. Y-90, yttrium-90 Based on reference 7. Images courtesy of Sirtex Medical Inc.

CLINICAL ONCOLOGY NEWS • MAY 2012

Optimal candidates for treatment with SIRSpheres include patients with liver tumors not initially suitable for surgical resection, patients without anomalous or abnormal hepatic vascular anatomy (eg, portal vein obstruction), and patients with minimal hepatic arteriovenous shunting, due to the risk for radiation damage to other organ systems.7,9

Clinical Studies of SIR-Spheres Microspheres “Various clinical studies have demonstrated that SIR-Spheres benefit patients with metastases that are dominant in the liver,” said Dr. Mehta. These benefits include the ability to bulk-reduce or downstage tumors, thereby allowing surgical resection, and the ability to complement chemotherapy, thereby prolonging survival. “In the treatment of liver-dominant disease, the ability to reduce tumor bulk can be very valuable. If you can drop the tumor burden by, say, 1 to 2 billion cells and then proceed with chemotherapy, you will see a much larger and more enduring effect,” added Dr. Mehta. The majority of studies with SIR-Spheres have been conducted in patients who have failed multiple prior regimens of chemotherapy. In a recent prospective evaluation of SIRSpheres therapy, 50 patients (most of whom had received at least 4 prior lines of chemotherapy) with liver metastases from CRC were treated with SIR-Spheres.5 The median overall survival (OS) was 12.6 months and the 2-year survival rate was 19.6%, which is a favorable response in these heavily treated patients.5 Furthermore, Hendlisz and colleagues performed a prospective, multicenter Phase III trial that randomized 44 patients with unresectable, chemotherapyrefractory, liver-limited mCRC to either 5-FU alone or with SIR-Spheres therapy.6 Both the median time to liver tumor progression (2.1 vs 5.5 months; P=0.003) and the median OS

Supported by

Investigator Pts, N

Treatment

ORR

TTP/PFS

Survival

SIR-Spheresa + HAC

44%

15.9 mo

72% at 1 y 39% at 2 y 17% at 3 y 3.5% at 5 y

First-line Gray et al, 2001

HAC

18%

9.7 mo

(P=0.01)b

(P=0.001)b

68% at 1 y 29% at 2 y 6% at 3 y 0% at 5 y

18.6 mo

29.4 mo

van Hazel et al, 2004

SIR-Spheres + 5-FU/LV

91%

5-FU/LV

0% 3.6 mo 12.8 mo (P<0.001)b (P<0.0005)b (P=0.02)b

Sharma et al, 2007

SIR-Spheresa + FOLFOX4

90%

9.3 mo

Not Reported

SIR-Spheresa (after failed 75% treatment with 5-FU)

5.3 mo

Not Reported

SIR-Spheresa (after failed 23% treatment with 5-FU, irinotecan, and/or oxaliplatin)

3.9 mo

Irinotecan plus SIR-Spheresa

48%

6 mo

12.2 mo

Hendlisz et al, 21 2010 23

SIR-Spheresa + 5-FU

10%

4.5 mo

10 mo

5-FU

0% (P=0.22)

2.1 mo (P=0.03)b

7.3 mo (P=0.8)b

Seidensticker et al, 2011

SIR-Spheresa

41%

5.5 mo

8.3 mo

BSC (matched-pairs)

Not Reported

2.1 mo

3.5 mo (P=0.001)b

SIR-Spheresa

24%b

3.7 mo

12.6 mo

224

SIR-Spheresa BSC

Not Reported

11.9 mo

Not Reported

Second-line Lim et al, 2005

van Hazel et al, 2009

Salvage therapy

Cosimelli et al, 50 2010 Bester et al, 2012

6.6 mo (P=0.001)b

BSC, best supportive care; 5-FU, 5-fluorouracil; FOLFOX4, oxaliplatin, leucovorin, 5-FU; HAC, hepatic artery chemotherapy; LV, leucovorin; ORR, overall response rate; PFS, progression-free survival; Pts, patients; TTP, time to progression a SIR-Spheres microspheres. b Data reached statistical significance (P≤0.05). Adapted from references 5, 6, and 10-16.

(7.3 vs 10 months) favored the SIR-Spheres arm.6 Although the OS data did not reach statistical significance, the results were confounded by the allowance of cross-over to the SIR-Spheres arm upon progression. Additionally, in a matched-pair comparison of 58 patients with chemotherapy-refractory, liver-dominant mCRC who received either best supportive care (BSC) alone or with SIRSpheres therapy, SIR-Spheres therapy was associated with prolonged survival rates compared with BSC alone (8.3 vs 3.5 months, respectively).10 Finally, a recent publication by Bester and colleagues included salvage setting data on 253 patients with mCRC. Patients treated with SIR-Spheres had a median OS of 11.9 months, compared with only 6.6 months in the BSC population (P=0.001).11 SIR-Spheres also have been studied as second-line therapy. Lim and colleagues12

studied the efficacy of SIR-Spheres in patients with liver metastases from CRC who previously were treated with 5-FU–based chemotherapy. Patients who previously had received only 5-FU had a significantly longer time to disease progression (5.3 months) compared with patients who had failed 5-FU, irinotecan, and/or oxaliplatin (3.9 months).12 Additionally, van Hazel and colleagues13 showed that the combination of irinotecan and SIR-Spheres resulted in favorable rates of progression-free survival (PFS; 6 months) and OS (12.2 months) when used as second-line therapy. SIR-Spheres also may have clinical utility in the first-line setting. In a pivotal randomized, controlled Phase III clinical trial, Gray and colleagues14 treated 70 patients with liver metastases from CRC with either regional hepatic artery chemotherapy (HAC) alone or with SIR-Spheres therapy. The 1-, 2-, 3-, and

5-year survival rates for patients who received SIR-Spheres were 72%, 39%, 17%, and 3.5%, respectively, compared with 68%, 29%, 6.5%, and 0%, respectively, for HAC alone, with a significant improvement in time to progression (median 15.9 vs 9.7 months, respectively). Furthermore, in a randomized study, van Hazel and colleagues15 evaluated the efficacy of first-line 5-FU/leucovorin chemotherapy alone or with SIR-Spheres in 21 patients with advanced colorectal liver metastases. Once again, median survival rates were significantly longer for patients who received combination therapy (29.4 vs 12.8 months). Additionally, Sharma and colleagues16 reported that first-line therapy with SIR-Spheres along with modified FOLFOX4 (oxaliplatin, leucovorin, and 5-FU) was associated with favorable PFS rates (9.3 months) in 20 patients with unresectable liver metastases caused by CRC. The results of these clinical trials are summarized in the Table.5,6,10-16 Treatment with SIR-Spheres generally was well tolerated by patients in these trials. The most commonly reported adverse events (AEs) were fatigue, abdominal pain/nausea, and sometimes, mild gastrointestinal ulceration.7 Radiation-induced liver disease was uncommon and responded to symptomatic management in the majority of cases.5,6,10 Hendlisz and colleagues reported that grade 3 AEs were experienced more frequently in the 5-FU–only arm, whereas the more manageable grades 1 and 2 AEs were reported in the radioembolization plus 5-FU arm.6 A randomized comparative study, the SIRFLOX (FOLFOX6m Plus SIR-Spheres Microspheres Versus FOLFOX6m Alone As a First Line Treatment In Patients With Nonresectable Liver Metastases From Primary Colorectal Carcinoma) study, is being conducted to assess the efficacy of SIR-Spheres for firstline combination therapy. The SIRFLOX study will include approximately 450 patients with nonresectable liver metastases from CRC.17 The primary end point is PFS, and the study is expected to be fully enrolled in late 2012.

Conclusion Liver metastases from CRC are common and are associated with poor outcomes. A significant number of patients with liver metastases are not candidates for curative surgical resection or will rapidly become refractory to chemotherapy and/or targeted agents. “Similar to the paradigm of using surgical bulk reduction in patients with ovarian or headand-neck cancer, liver-directed therapy with selective internal radiation using SIR-Spheres in patients with liver-dominant metastases from CRC can result in the downstaging of disease to allow for surgical resection. It also can act to complement systemic and biological chemotherapy, significantly prolonging survival,” said Dr. Mehta. SIR-Spheres microspheres currently are the only FDA-approved microspheres for the treatment of colorectal liver metastases. Since approval in 2002, more than 20,000 doses have been administered across more than 400 sites worldwide, with the treatment

now available at all major cancer centers in the United States. Much of the clinical efficacy of SIR-Spheres has been proven in the salvage setting, but the ongoing large, prospective, randomized study, SIRFLOX, is expected to characterize the clinical utility of this agent in the first-line setting.

References 1. American Cancer Society. Colorectal cancer facts and figures 2011-2013. http://www.cancer.org/ acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-028323.pdf. Accessed March 15, 2012. 2. Grenon MS. The evolving care of metastatic colorectal cancer. Oncology Nurse. 2011;25(7):1-2. 3. National Cancer Institute. SEER Registry. http://seer. cancer.gov/statfacts/html/colorect.html#survival. Accessed March 15, 2012. 4. Van den Eynde M, Hendlisz A. Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials. 2009; 4(1):56-62. 5. Cosimelli M, Golfieri R, Cagol PP, et al. Italian Society of Locoregional Therapies in Oncology. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer. 2010;103(3):324-331. 6. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28(23):3687-3694. 7. SIR-Spheres (yttrium-90) microspheres [package insert]. Woburn, MA: Sirtex Medical Inc; 2011. 8. Stubbs RS, Wickremesekera SK. Selective internal radiation therapy (SIRT): a new modality for treating patients with colorectal liver metastases. HPB (Oxford). 2004;6(3):133-139. 9. Wang SC, Bester L, Burnes JP, et al. Clinical care and technical recommendations for 90yttrium microsphere treatment of liver cancer. J Med Imaging Radiat Oncol. 2010;54(3):178-187. 10. Seidensticker R, Denecke T, Kraus P, et al. Matchedpair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases. Cardiovasc Intervent Radiol. 2011 July 29. [Epub ahead of print] 11. Bester L, Meteling B, Pocock N, et al. Radioembolization versus standard care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse events in salvage patients. J Vasc Interv Radiol. 2012;23(1):96-105. 12. Lim L, Gibbs P, Yip D, et al. A prospective evaluation of treatment with selective internal radiation therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy. BMC Cancer. 2005;5:132. 13. van Hazel GA, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009;27(25):4089-4095. 14. Gray B, van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001; 12(12):1711-1720. 15. van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/ leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88(2):78-85. 16. Sharma RA, van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25(9):1099-1106. 17. FOLFOX6m Plus SIR-Spheres Microspheres Versus FOLFOX6m Alone As a First Line Treatment In Patients With Nonresectable Liver Metastases From Primary Colorectal Carcinoma (SIRFLOX). http://clinicaltrials. gov/ct2/show/NCT00724503?term=sirflox&rank=1. Accessed March 15, 2012. SIR-Spheres is a Registered Trademark of Sirtex SIR-Spheres Pty Ltd. 534-U-0312.

CLINICAL ONCOLOGY NEWS • MAY 2012

BB121

Table. Clinical Studies of SIR-Spheres Microspheres

SOLID TUMORS

Clinical Oncology News • May 2012

Melanoma

Promising Phase II Results With Vemurafenib for Melanoma From The New England Journal of Medicine

he oral BRAF inhibitor vemurafenib (Zelboraf, Genentech/ Daiichi Sankyo) achieved positive outcomes in more than half of patients with BRAF V600-mutant metastatic melanoma who received the drug. The results of this multicenter, Phase II clinical trial, published in the Feb. 23 issue of The New England Journal of Medicine (2012;366:707-771, PMID: 22356324), echo the findings of a Phase I trial published in 2010, also in NEJM (2010;363:809-819; PMID: 20818844). Results of a Phase III study have also since been published. According to recent research, as

EXPERT INSIGHT Evan Lipson, MD Instructor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

his Phase 2 study of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma is another important step in what is a rapidly changing landscape for melanoma therapy.

many as half of those with metastatic melanoma harbor activating V600 mutations in the serine-threonine protein kinase BRAF. To date, outcomes associated with the disease have been poor. Studies have estimated median overall survival to be only six to 10 months. In addition, BRAF mutation has been associated with shortened survival in patients with metastatic disease. Treatment options are limited. To assess the efficacy of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma (as determined by the results of an FDA-approved diagnostic test), an international team of researchers administered the drug to 132 patients at a dose of 960 mg per day until the

development of “unacceptable toxic effects or disease progression.” The study was funded by Hoffmann-La Roche, the parent company of Genentech, one of the manufacturers of the study drug. After a median follow-up of 12.9 months, the confirmed overall response rate was 53% (6% of patients had a complete response and 47% had a partial response). The median duration of response was 6.7 months, and the median progression-free survival was 6.8 months. Median overall survival was 15.9 months. Primary progression occurred in only 14% of the patients enrolled in the study. The most common adverse events (AEs) were grade 1 or 2 arthralgia, rash, photosensitivity,

fatigue and alopecia. Similar to other BRAF inhibitors, vemurafenib has been associated in previous studies with the development of cutaneous squamous cell carcinoma or keratoacanthoma. Cutaneous squamous cell carcinomas (the majority of keratoacanthoma type) were diagnosed in 26% of patients. Generally, these toxic events were not severe or life-threatening in most cases. However, 45% of the patients in the study had their dose of the study drug reduced and dose interruptions were required in 64% of patients as a result of AEs. Of note in these findings is the study’s longer follow-up period, which has not yet been achieved in other clinical trials involving vemurafenib.

This trial echoes the results seen in a Phase I trial, including relatively high response rates and reasonable tolerability. In addition, the authors report a median survival of 16 months. Although this trial did not contain a control arm, these results are certainly encouraging. Looking forward, two areas of ongoing study may suggest ways to increase the efficacy of BRAF inhibitors by using them in combination with other therapies. First, one trial currently under way explores the combination of a BRAF inhibitor with a MEK inhibitor.1 Indeed, as the authors point out, myriad mechanisms of targeted therapy resistance have been suggested,

including downstream activation of MEK. Inhibition of a secondarily activated pathway may extend the time until a tumor acquires resistance to pathway blockade therapy. Second, combining targeted therapy such as vemurafenib with immunebased therapy may provide synergistic anti-tumor activity. One such trial in progress combines vemurafenib with the anti-CTLA-4 antibody ipilimumab.2 Some preclinical studies have suggested that blocking the BRAF/MAPK (mitogen-activated protein kinase) pathway could decrease the production of anti-inflammatory cytokines, such as IL-10, and augment tumor recognition by T-cells.3,4 In this way,

combinatorial therapy may be more effective than each component of the regimen used by itself.

References 1. ClinicalTrials.gov identifier: NCT01072175. 2. ClinicalTrials.gov identifier: NCT01400451. 3. Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006;203:1651-1656. 4. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213-5219.

ASCO Releases List of Top Five Procedures To Question

he American Society of Clinical Oncology (ASCO) has identified a list of the top five most common and costly procedures in oncology that it says are not supported by evidence and should be questioned. As a participant in the American Board of Internal Medicine Foundation’s Choosing Wisely campaign, ASCO is one of nine specialty societies that have produced such top five lists within their respective fields. Developed by cancer specialists on ASCO’s Cost of Cancer Care Task Force, the top five list for oncology was based on a review of published studies and current guidelines. Oncology professionals from community and academic settings, state societies and cancer advocacy groups vetted the list. “Backed by the expertise of more than 30,000 member oncologists, ASCO is in a unique position to identify opportunities to prevent the misuse and overuse [of ] cancer tests and treatments that are not supported

by clinical evidence,” Lowell E. Schnipper, MD, the chair of ASCO’s Cost of Cancer Care Task Force, said in a statement. “We hope this list will help oncology providers make more informed decisions and provide their patients with the best possible care.” In an article published in the Journal of Clinical Oncology (2012 Apr 3 [Epub ahead of print], PMID: 22493340), Schnipper et al discussed the top five procedures in detail. For example, item 1, about cancerdirected therapy, is based on evidence that cancer-directed treatments are likely to be ineffective for patients with solid tumors who meet these criteria, according to the ASCO report. Stopping anti-cancer treatment should always be accompanied by appropriate palliative and supportive care and referral to hospice, the authors recommend. —George Ochoa

ASCO Top Five procedures to question: 1. “Don’t use cancer-directed therapy for solid tumor patients with the following characteristics: low performance status (3 or 4), no benefit from prior evidence-based interventions, patient not eligible for a clinical trial and no strong evidence supporting the clinical value of further anti-cancer treatment.” 2. “Don’t perform PET [positron emission tomography], CT [computed tomography] and radionuclide bone scans in the staging of early prostate cancer at low risk for metastasis.” 3. “Don’t perform PET, CT and radionuclide bone scans in the staging of early breast cancer at low risk for metastasis.” 4. “Don’t perform surveillance testing (biomarkers) or imaging (PET, CT and radionuclide bone scans) for asymptomatic individuals who have been treated for breast cancer with curative intent.” 5. “Don’t use white cell stimulating factors for primary prevention of febrile neutropenia for patients with less than 20% risk for this complication.”

PRN

Clinical Oncology News • MAY 2012

Community Oncology

Clinical Conundrums

Prepared by

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

Highlights from the American Society of Hematology 2011 Annual Meeting—Malignant Hematology Part II: Focus on Lymphoma and Chronic Leukemias

QUESTIONS

True or False: Alisertib (Millennium), an aurora A kinase inhibitor, is associated with manageable toxicities and promising overall response rates (ORR) in patients with relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL) but did not show any activity in T-cell NHL.

patients with accelerated-phase CML (CML-AP) resistant or intolerant to more than two tyrosine kinase inhibitors (TKIs) including imatinib.

11. True or False: In the multicenter,

True or False: The preliminary results of the open-label Phase II GAUSS trial of rituximab (Rituxan; Biogen Idec, Genentech) versus obinutuzumab (GA101, Roche) for relapsed follicular lymphoma (FL) demonstrated better ORR with induction obinutuzumab compared with rituximab.

True or False: In patients with FL and low tumor burden who received front-line, single-agent rituximab, no significant difference in time-to-treatment failure was observed between those who received maintenance rituximab and those who received rituximab retreatment at progression.

4. True or False: In the SWOG S0016/

CALGB 50102 trial for patients with previously untreated FL, inferior outcomes were observed with maintenance rituximab versus tositumomab/131I-tositumomab (CHOP-RIT; GlaxoSmithKline) following cyclophosphamide, doxorubicin (Doxil, Janssen), vincristine and prednisone (CHOP) therapy.

5. True

or False: The six-gene expression-based risk model is able to predict clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with the CHOP-R regimen.

chemotherapy is administered during the second and third trimesters of pregnancy, minimal maternal complications or fetal detriment is observed.

True or False: The STIM (Stop Imatinib) trial showed that discontinuing imatinib (Gleevec, Novartis) in patients with chronic myeloid leukemia (CML) who achieved complete molecular remission (CMR) for at least two years resulted in 39% of patients maintaining CMR for 36 months.

True or False: Dasatinib (Sprycel, Bristol-Myers Squibb) therapy for chronic-phase chronic myeloid leukemia (CML-CP) produced major molecular response (MMR) rates of 70% at 18 months.

9. True or False: Dasatinib- and ima-

tinib-induced reductions in BCR-ABL transcript levels below 10% at three months are associated with improved responses in patients with newly diagnosed CML-CP.

6. True or False: In Hodgkin’s lym- 10. True phoma (HL) and NHL, when standard

or False: Omacetaxine (Omapro, ChemGenex) is active in

non-randomized Phase II TIDEL-II (Therapeutic Intensification in DE-novo Leukemia) trial for patients with CMLCP on first-line imatinib, early imatinib dose escalation or switch to nilotinib (Tasigna, Novartis) was a useful treatment strategy following failure to meet time-dependent molecular treatment targets.

12. True

or False: In patients with newly diagnosed CML-CP, the 36-month data from the the ENESTnd trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) demonstrated continued superiority of front-line nilotinib 300 mg twice a day or 400 mg twice a day compared with imatinib 400 mg once daily, but with a much higher incidence of pancreatitis.

13.

True or False: The MMR rates at 24 months were similar in patients with CML-CP receiving either bosutinib (Pfizer) or imatinib.

14. True or False: Ponatinib (Ari-

ad) is active in patients with heavily pretreated and multidrug-resistant CML including patients harboring T315I mutations.

15. True or False: The 12-year follow-up results of the NCIC CTG/ECOG HD6 trial demonstrated a disease-free survival rate of 88% for patients with

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newly diagnosed non-bulky stage I-IIA HL with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy.

16. True or False: Six cycles of

BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) followed by positron emission tomography (PET)-guided radiation therapy (RT) are more effective and less toxic than eight cycles of therapy in patients with advanced-stage HL.

17.

True or False: In newly diagnosed patients with HL, brentuximab vedotin (Adcetris, Seattle Genetics) cannot be safely administered in combination with ABVD.

18.

True or False: Brentuximab vedotin cannot be safely administered in patients with relapsed or refractory HL, especially prior to reduced-intensity conditioning (RIC) allogeneic transplant (allo-HCT) due to higher risk of graft-versus-host disease (GVHD) and graft rejection.

19. True or False: In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), combination therapy of rituximab or ofatumumab (Arzerra, GlaxoSmithKline) with lenalidomide (Revlimid, Celgene) is active.

20.

True or False: PCI-32765, a potent Bruton’s tyrosine kinase inhibitor, is well tolerated and associated with high rates of six-month progression-free survival (PFS) in relapsed and refractory CLL. for answers see CONUNDRUMS, page 18 

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SOLID TUMORS

Clinical Oncology News • May 2012

Colorectal

Experts Debate Pros and Cons of Molecular Profiling San Francisco—Is molecular profiling for stage II colon cancer ready for prime time? If you ask many oncologists and surgical oncologists, you will not find a consensus. At the recent Gastrointestinal Cancers Symposium, two experts faced off on this issue in a pro and con debate.

said Dr. Chang. Presenting data from the QUASAR study, he showed that patients classified by the Oncotype test as lowrisk had an absolute risk reduction (ARR) from chemotherapy of 3.1%. Intermediate-risk patients had a 4.7% ARR and high-risk patients had a 5.7% ARR (J Clin Oncol 2011;29:4611-4619, PMID: 22067390). “We can use these signatures to stratify patients to make our treatment decisions

Most patients with stage II colon canThree molecular tools have been vali- measures guanylyl cyclase-C gene cer will be cured by surgery alone and dated for stage II colon cancer thus far. expression (GC-C). “When GC-C is presthe majority will not benefit from adju- The 12-gene Oncotype DX colon cancer ent in the lymph nodes, it may be a markvant chemotherapy. In the often-cited assay (Genomic Health) requires for- er for micrometastatic disease,” said Dr. QUASAR (Quick and Simple And Reli- malin-fixed, paraffin-embedded tumor Chang. A small study demonstrated that able) study, the addition of 5-fluorouracil tissue and yields a continuous recur(5-FU) and folinic acid resulted in a 3% to rence score corresponding to estimat‘What really matters is how much an 5% absolute reduction in risk for recur- ed risk for recurrence at three years. It rence at five years in patients with stage divides patients into low-, intermediateindividual patient, at an individual level II disease (Lancet 2007;370:2020-2029, and high-risk categories and has been of risk, will benefit with the application PMID: 18083404). Other studies have validated on tumor specimens from the established that 5-FU–based adjuvant QUASAR and Cancer and Leukemia of adjuvant therapy.’ therapy does not help the 15% to 20% of Group B 9581 trials. Roughly 25% of —Neal Meropol, MD patients with deficient mismatch repair patients are classified as high-risk. (DMMR). The 18-gene ColoPrint test (Agendia) Doctors currently use clinical patho- uses fresh frozen tissue and classifies this test has promise, but a larger valida- and make our treatments more efficient,” logic factors, such as T4 disease, to iden- roughly 40% of patients in the high-risk tion study is ongoing. said Dr. Chang, referring to the MOSAtify high-risk patients, but these factors category and 60% as low-risk, based on IC (Multicenter International Study of do not adequately identify patients who time to relapse. This test has been vali- Pro Argument Oxaliplatin/5-Fluorouracil/Leucovorin Dr. Chang was given the assignment to in the Adjuvant Treatment of Colon Canmay benefit from chemotherapy (Table). dated on two separate single institution In a study of Medicare patients identified data sets and a multi-institution study is argue the pros of using molecular tools cer) trial (N Engl J Med 2004;350:2343in stage II colorectal cancer. In an ideal 2351, PMID: 15175436) that established with stage II colon cancer, adjuvant che- currently under way. motherapy did not substantially improve The 634-gene ColDx (Almac) uses for- world, he said, physicians would be able a 5% threshold for using oxaliplatin in overall survival, regardless of whether or malin-fixed, paraffin-embedded tissue, to identify patients who would benefit patients with stage III colon cancer, and not the patient had poor prognostic fea- classifies patients into low- and high-risk from chemotherapy. With the current- adding that a 5.7% threshold for 5-FU is tures (J Clin Oncol 2011;29:3381-3388, groups, based on time to events, and was ly available tools, however, physicians reasonable in stage II. PMID: 21788561). In patients with low risk, he said, you validated in a study of 144 patients. Prog- can only identify patients at high risk for “Clearly, the current paradigm for nosis in all three tools is independent of recurrence, and thus in the greatest need would need to treat 50 patients for one for adjuvant chemotherapy benefit, and patient to benefit, whereas in patients identifying high-risk patients is imper- standard clinical criteria. fect,” said George J. Chang, MD, MS, an A fourth test, Previstage (Diagnocure), patients at low risk for recurrence who with high risk, 5%, you would only have could be safely observed. to treat 20 patients to benefit one patient. associate professor of Surgi“The [tools] yield a If physicians observe patients who have cal Oncology and a co-assoTable. Clinical Pathologic Factors proportional hazard for DMMR and treat patients who have T4 ciate medical director of the Used To Determine Risk benefit that is across tumors, he argued, then they are still Colorectal Center at the Unithe spectrum of high- making an uninformed decision about versity of Texas MD Anderson • Presence of T4 disease • Lymphovascular invasion and low-risk patients,” chemotherapy in 70% of patients. PhysiCancer Center in Houston. cians can use molecular profiling to strat• High-grade tumors • Perineural invasion ify patients based on risk and thus make • Signet ring histology • Perforation informed treatment decisions in 100% of • Number of lymph nodes • Obstruction their patients, Dr. Chang said. A study presented at the 2011 Gastrointestinal Cancers Symposium shows that the molecular tools can be cost-effective. Investigators used a statistical model to assess outcomes associated with the use of the Oncotype recurrence score in adjuvant therapy decisions in stage II disease, excluding T4 tumors and those with deficient DNA mismatch repair. The model showed a net 17% reduction in chemotherapy use, an improvement in quality-adjusted life-years of 0.035, and a reduction in net costs of $2,971 (J Clin Oncol 2011;29[suppl 4]: abstr 491). “The addition of molecular profiling stratifications to current treatment algorithms maximizes potential benefit while minimizing treatment-related toxicity. It can identify high-risk patients who are most likely to benefit from adjuvant therapy, similar to oxaliplatin for stage III, and identify low-risk patients who may be safely observed,” Dr. Chang said.

SOLID TUMORS

Clinical Oncology News • May 2012

Colorectal

‘The addition of molecular profiling FILE SLUG

Con Argument Neal Meropol, MD, the chief of Hematology and Oncology at University Hospitals Case Medical Center and Case Western Reserve University in Cleveland, was assigned to present the con side of the argument for using the currently available molecular profiling tools. He said that regardless of the stratification of risk, the decision for therapy is ultimately one that has to be made by the individual patient. Patients will ask themselves whether the therapy will be helpful and if so, how helpful will it be. What are the side effects? What are the costs and inconvenience of therapy? What is the uncertainty surrounding these outcomes and what is important to me? Doctors, he said, often try to simplify things by quantifying risk. “What really matters is how much an individual patient, at an individual level of risk, will benefit with the application of adjuvant therapy,” said Dr. Meropol. Dr. Meropol said the gold standard of a predictive marker is one that has a greater relative risk reduction as risk increases. “At this point, none of the platforms that have been described so far meets this bar,” he said. He argued that none of the tools single out a truly useful high-risk group. “To really be useful, you have to enrich the high-risk group for really being at high risk,” he said. A useful test must place a high proportion, 50% to 75%, of patients in the low-risk group. The Oncotype DX recurrence score doesn’t meet this criterion and has a short follow-up period. “The high-risk group is not a very high-risk group, having only a 22% risk for relapse at three years,” said Dr. Meropol. He also pointed out that many of the patients in the validation study had less than 12 lymph nodes obtained at the time of surgery, suggesting an incomplete surgical approach or incomplete assessment. Notably, he said, the benefit of 5-FU in the study set was twice as great as the benefit of 5-FU in the underlying population from the QUASAR study. Dr. Meropol pointed out that ColDx has a more useful high-risk group, predicting a 55% risk for relapse, but the validation study was small and the mismatch repair status in the study population was unknown. “Only six lymph nodes were required for eligibility and there was really no treatment information with regard to the patients in this study,” he said. Additionally, low- and high-risk groups were defined retrospectively by recurrence status, rather than by a population-based prospective assessment of the assay. The ColoPrint high-risk group also was lacking in that it had only a 26% risk for relapse, and because the study population was able to receive adjuvant therapy, it was not a clean validation set, Dr. Meropol said. “The overall prognosis was very good, raising the question as to the representativeness of the validation

STATUS & HISTORY

Current file:

stratifications to current treatment

Full name of project

Senior editor potential benefit algorithms maximizes

MN113_A_ad.indd

1ST PROOF LAYOUT APPROVED INITIALS AND DATE

FINAL OK INITIALS AND DATE

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while minimizingCopy treatment-related editor

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toxicity.’ rev 1

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Sales

—George J. Chang, MD, MS Production

May 3, 2012 5:18 PM

Editorial date/time

set and there was a high discordance Trim size with clinical risk stratification,” he said. Previstage has Color specs not been validated, but again hasFilea path subpar high-risk group that MN113_A_ad.indd has only a modest 27% risk for relapse, according to Dr. Meropol.

MAX sign-off

“The validation sets we have seen today are COMMENTS: either small or were not entirely representative of the modern completely staged population,” said Dr. Meropol. They do not identify patients at the very highest risk and there is no demonstrated

predictive value of the molecular classifiPICKED UP FROM: PROOF 1: 1/17 cationREVschemes. There isAPPLIED also TO: an uncertain 1: REV of 2: oxaliplatin in these high-risk impact AD LAYOUT EXPT’D: REV 3 AD LAYOUT RECEIVED: populations, and it is unclear how to inteREV 4 EDIT LAYOUT EXPT’D: grate REV mismatch repair testing and how to 5 EDIT LAYOUT RECEIVED: REV 6 address the discordance of clinical and REV 7 EDITOR: Jen Kulpa molecular results, he argued. ART DIRECTOR: Blake REV 8 REV 9 REV 10

—Kate O’Rourke

REV 11

Dr. Chang has consulted for Genomic KEYWORDS: Health and received research funding from Agendia. Dr. Meropol has consulted for Genomic Health and Precision Therapeutics and received research funding from Genomic Health.

Now Available... Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113” Release Date: October 1, 2011

Expiration Date: October 1, 2012

This activity is based on a live educational symposium held May 21, 2011, in Philadelphia, Pennsylvania.

Learning Objectives

Co-Chairs

Tessa Cigler, MD, MPH

Assistant Professor of Medicine, Weill Cornell Medical Center Attending Physician, NewYork-Presbyterian Hospital New York, New York

Paula D. Ryan, MD, PhD Associate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer Center Philadelphia, Pennsylvania

Target Audience

Oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). There are no prerequisites or fees.

Credit Designation

Global Education Group designates this enduring 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. Jointly sponsored by

Upon completion of this activity, participants will be better prepared to:

1 Review recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or MBC. 2 Describe a treatment algorithm that reflects evidence-based management of advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance. 3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide CME for physicians.

Method of Participation

To receive CME credit, participants should complete the pre-test, read the monograph, and complete the post-test and evaluation either online at www.CMEZone. com (enter keyword MN113). Completed forms also can be faxed to (303) 6485311 or mailed to 5575 S. Sycamore Street, Suite 200, Littleton, CO 80120. CME certificates will be issued within 6 to 8 weeks upon receipt of completed evaluations. A score of at least 70% is required to complete this activity. Supported by an educational grant from

Distributed via

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113”

SOLID TUMORS

Clinical Oncology News • May 2012

Colorectal

TFAP2E Methylation and Nonresponse to 5-FU Therapy Linked From The New England Journal of Medicine

lthough recent treatment advances have improved outcomes in advanced colorectal cancers (CRCs), research efforts continue to identify biomarkers that can effectively predict treatment response. One such initiative, spearheaded by a team of researchers from Germany, has determined that hypermethylation of the gene-encoding transcription factor AP-2 epsilon (TFAP2E), genomic and epigenetic alterations of which are common in many human cancers, may ultimately prove to be a viable predictive factor. Their findings were published in the Jan. 5 issue of The New England Journal of Medicine (2012;366:44-53, PMID: 22216841).

EXPERT INSIGHT Nilofer Azad, MD Assistant Professor of Oncology The Johns Hopkins University School of Medicine The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

bert and colleagues present important data regarding the potential

In a study performed in multiple hospital centers across Germany, as well as in one center in Ireland and another in Seattle, the authors analyzed the expression, methylation and function of TFAP2E in in vitro CRC cell lines and in patients with CRC. The initial cohort included 74 patients, and subsequent cohorts encompassed 220 patients undergoing chemotherapy or chemoradiation to treat the disease. TFAP2E, one of five AP-2 transcription factor genes, was identified because gene-encoding dickkopf homolog 4 protein (DKK4), a potential downstream target of TFAP2E, has been “implicated in chemotherapy resistance,” the authors noted. Functional assays performed as part of this research confirmed TFAP2Edependent resistance is mediated via

DKK4. For this study, chemotherapeutic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In the initial cohort, TFAP2E was hypermethylated in 38 patients (51%), leading to decreased expression. The resulting overexpression of DKK4 caused increased chemoresistance to fluorouracil (5-FU). In the remaining cohorts, TFAP2E was hypermethylated in 93 patients (42%); among these patients, 81 (87%) were treatment nonresponders (P<0.001), whether they received 5-FU or other forms of treatment. In all, the authors identified “a strong association between TFAP2E methylation” and a lack of response to 5-FU–based chemotherapy in four independent cohorts of patients with CRC. Conversely, the

authors noted, among patients with TFAP2E hypomethylation, the probability of response was “approximately six times that in the entire population.” Because treatment differed across the four cohorts of patients with CRC included in the study, the authors believe that alterations of TFAP2EDKK4 may represent “a more global chemotherapy-resistance marker.” In their concluding comments, the authors noted that “the molecular mechanisms underlying TFAP2EDKK4–mediated chemoresistance” remain unknown. They added that, “[their] studies did not reveal an association with genes encoding fluorouracil catalyzing enzymes or genes underlying microsatellite instability or Wnt signaling.”

role of epigenetic biomarkers in predicting treatment outcome in patients with CRC. They find that silencing of the TFAP2E gene through methylation is associated with a lack of response to chemotherapy, while hypomethylation of TFAP2E correlated with an increased chance of treatment response, in particular with 5-FU–based therapy. Strengths of this study are that they found their biomarker in an initial cohort of patients with CRC and then tested their hypothesis in four subsequent cohorts of patients.

The correlation they found between TFAP2E methylation and chemoresistance was borne out in the four subsequent cohorts, with a robust differential disease response in patients with TFAP2E methylation. Weaknesses of the study include that the analysis was done retrospectively, that the patient cohorts received different treatments and that the preclinical work done to explore the mechanism behind the chemoresistance was not fully developed. This study has the potential for future

clinical applicability, but needs to be tested in a prospective clinical trial. Like many biomarker studies that evaluate a biomarker for its predictive value regarding therapeutic options, we now need to assess if choosing treatment for patients based on TFAP2E methylation would result in either improved survival or decreased toxicity with maintenance of the same survival. The work does suggest a new possible paradigm for better assessing risk versus benefit when choosing treatment for patients with CRC.

New York Approves Blood Test To Assess Colorectal Cancer Risk Questions raised by independent expert

he New York State Department of Health has approved Enzo Clinical Labs’ use of ColonSentry, a bloodbased test for assessing a patient’s risk for colorectal cancer. The Torontobased GeneNews, the test’s original developer, granted New York–based Enzo Biochem, Inc., exclusive rights to use of the product in the New York metropolitan area. Enzo Biochem is offering the test through its subsidiary, Enzo Clinical Labs. Independent expert Sidney J. Winawer, MD, the Paul Sherlock Chair in Medicine, Gastroenterology and Nutrition Service at Memorial Sloan-Kettering Cancer Center in New York City, raised questions about the data supporting ColonSentry: “I do not feel that it is ready for clinical use.” The company defended its test. ColonSentry uses RNA contained in

blood to measure the level of expression of seven genes that serve as biomarkers, potentially allowing physicians to identify patients who have an increased current risk for colorec-

and interim president of Enzo Clinical Labs, said, “We hope to drive people to colonoscopy because it’s the best tool we have out there.” He added: “If you’re not identified as higher than normal

2010;126:1177-1186; J Exp Clin Cancer Res 2010;29:128). “The problem with the test is that there is considerable overlap between patients with colorectal cancer and

‘We have [been] down this road before with bloodbased markers. A screening test needs to be shown to detect early curable cancers to be effective. Detecting late-stage cancers is of no benefit.’ —Sidney J. Winawer, MD tal cancer, according to an Enzo Biochem press release. Patients at higher risk may receive a strong recommendation for colonoscopy. David Goldberg, MS, MBA, vice president of corporate development at Enzo Biochem

risk, you should have regular screening. One hundred percent of people should be compliant.” Dr. Winawer commented on ColonSentry after reviewing two published studies of the test (Int J Cancer

controls,” Dr. Winawer said in an email to Clinical Oncology News. “In addition, there is no data on the stage of the cancers. We have [been] down this road before with blood-based markers.

SOLID TUMORS

Clinical Oncology News • MAY 2012

Prostate

Dutasteride or Active Surveillance for Low-risk Prostate Cancer? From The Lancet

ith mounting evidence pointing to overtreatment of lowrisk prostate cancer via aggressive means, researchers are now devoting significant attention to more conservative approaches, including active surveillance. A study published online in January by The Lancet (2012; Jan 23. [Epub ahead of print], PMID: 22277570) highlights this trend as it was designed to assess the safety and efficacy of the 5α-reductase inhibitor dutasteride (Advodart, GlaxoSmithKline) in the treatment of prostate cancer progression in men with low-risk disease

EXPERT INSIGHT Emmanuel S. Antonarakis, MD Assistant Professor of Oncology The Johns Hopkins University School of Medicine The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

his is the first prospective clinical study to examine the use of a pharmacologic agent as an adjunct to active surveillance in men with low-risk localized prostate cancer (defined by clinical stage T1c-T2a, Gleason score ≤6, serum prostate-specific antigen [PSA] ≤11 ng/ mL, <4 positive cores and <50% involvement of any core). Of note, these men differed slightly from the traditional very-low-risk patients, according to

A screening test needs to be shown to detect early curable cancers to be effective. Detecting late-stage cancers is of no benefit. The test needs extensive clinical trials to demonstrate its sensitivity and specificity and PPV [positive predictive value] for early-stage cancers.” Dr. Winawer added: “I would like to emphasize that a sensitive and specific blood-based marker to identify people who have advanced adenomas and early-stage cancer would be very desirable. We could then target a small subset of the general population for diagnostic and therapeutic colonoscopy. This could be a very effective strategy to reduce the incidence and mortality of colorectal cancer without the need for screening colonoscopy in the larger general population.” Mr. Goldberg responded to Dr.

opting for active surveillance. The research for the REDEEM (Reduction by Dutasteride of clinical progression Events in Expectant Management) trial was funded by GlaxoSmithKline. The team of researchers, representing hospital centers in both the United States and Canada, randomly selected 302 patients from 65 academic medical centers and/or outpatient clinics in North America. Of these, 289 patients had undergone at least one biopsy procedure from baseline and thus were included in the analysis. The patients in the final study population, all of whom selected active surveillance, ranged in age from 48 to 82 years. The participants were randomized to receive either dutasteride (0.5 mg) or

matching placebo once daily for three years. Patients attended follow-up visits every three months for the first year and every six months thereafter. After three years, 54 (38%) of the men in the study drug group had progressive disease (pathologic or therapeutic) compared with 70 (45%) in the control group (P=0.009). Median time to progression was 1,092 days in the dutasteride group versus 987 days in the control group. There were no prostate cancer–related deaths or cases of metastatic disease. The incidence of adverse events was similar between the two groups, with 35 (24%) of the men in the dutasteride group and 23 (15%) in the control group reporting sexual side effects (i.e.,

impotence and/or altered or decreased libido) or breast enlargement/tenderness. In both groups, 5% of the men reported cardiovascular-related adverse events, the most common being ischemic coronary artery disorders or atherosclerosis. Differences in reported cases of ejaculation disorders, common with use of 5α-reductase inhibitors, between the two groups were not statistically significant (5% vs. 1%; P=0.06). The authors concluded that although they noted “nonsignificant differences” in pathologic and therapeutic progression between the dutasteride and control groups, a larger study is needed to confirm the study drug’s benefits in patients with low-risk prostate cancer.

Epstein criteria (clinical stage T1c, Gleason score ≤6, PSA density <0.15 ng/mL per gram, <3 positive cores and <50% involvement of any core), who are often managed by active surveillance. The present study (REDEEM) concluded that, when compared with placebo, daily administration of the 5α-reductase inhibitor dutasteride prolonged prostate cancer progression, defined as a composite end point that included pathologic progression or the initiation of prostate cancer therapy. The study also showed that men receiving dutasteride were more likely to have negative repeat biopsies than those receiving placebo. These findings suggest that dutasteride may reduce the volume of low-grade prostate cancers, while its effect on highgrade disease is more controversial. Although these findings are important and the trial met its prespecified

primary end point, the significance of these results might be called into question, especially in light of the recent decision by the FDA not to approve dutasteride for the purposes of prostate cancer prevention (based on the results of the REDUCE [Reduction by Dutasteride of Prostate Cancer Events] trial, a study of dutasteride versus placebo in men without a known prostate cancer diagnosis). The REDEEM trial, although well conducted, has several limitations. First, the study did not examine longterm outcomes such as metastasis-free survival or overall survival. Therefore, it remains unknown whether slowing prostate cancer progression at 3 years equates to better clinical outcomes. In addition, although this was designed as a placebo-controlled study, blinding may have been ineffective because of dutasteride’s ability to lower PSA

levels. To this end, decisions to initiate prostate cancer treatment (a component of the primary end point) could have been influenced by clues about treatment allocation. In this light, examining pathologic progression as the primary end point may have been a more objective measure of treatment effect (although in a secondary analysis, time to pathologic progression did not differ significantly between study groups). Finally, this study did not address the very relevant question of whether men with low-risk prostate cancer require treatment at all. Because of the generally good prognosis of low-risk prostate cancer patients (and the potential morbidities associated with radical therapy), active surveillance alone remains a reasonable standard of care in this population, and the addition of dutasteride cannot be recommended at this time.

Winawer’s comments in an email to Clinical Oncology News: “ColonSentry is not a screening test—it has been cleared by the New York State Department of Health to assess the risk for a patient having colon cancer at a particular point in time. It is not a test designed to ‘stage’ cancers. What ColonSentry is designed for is to give primary care physicians a tool [with] which to help assure compliance with regular colonoscopy screening. … By helping to identify those [who] might be [at] greater risk for having the disease, it is hoped that such compliance can be increased especially in those individuals.” Requiring a small blood sample, ColonSentry can be incorporated readily into annual physical examinations, according to a company press release. “It fits in with the routine work of

the clinician,” said Mr. Goldberg. The report that is delivered to the ordering physician is easy to interpret, he noted. “Green is good, red is bad. The higher the risk score, the more potential for having colorectal cancer at that point in time.” The idea of a blood-based test to aid in colorectal cancer detection is not new. For example, Quest Diagnostics already offers ColoVantage (methylated Septin 9), a test based on one gene. Mr. Goldberg distinguished the two tests: According to the Quest Diagnostics Web site, a physician has to submit 10 mL frozen EDTA plasma (5 mL minimum), whereas Enzo’s test, said Mr. Goldberg, requires only a “regular tube of blood. We wanted to make it as seamless as possible for doctors.” He also stated that no competitor’s test “is

as comprehensive as seven genes.” Wendy H. Bost, spokeswoman for Quest Diagnostics in Madison, N.J., responded in an email to Clinical Oncology News: “We … do not believe the specimen amount is a barrier to adoption of the test.” Referring to the basis of ColoVantage—DNA methylation of the Septin 9 gene—she noted: “This marker has been more rigorously studied than any other gene marker for aiding the detection of colon cancer via blood testing. Several companies are working on or have introduced tests based on it.” —George Ochoa Dr. Winawer reported no relevant financial disclosures. Mr. Goldberg and Ms. Bost reported only their stated company affiliations.

PRN

Clinical Oncology News • April 2012

Community Oncology

CONUNDRUMS continued from page 13 

ANSWERS

1. False. Alisertib is associated with manageable toxicities and a promising ORR of 32% (95% confidence interval, 18%-48%) in patients with relapsed or refractory aggressive B- and T-cell NHL. Early data suggests better response rates in patients with aggressive T-cell lymphoma.

Friedberg J, Mahadevan D, Jung JA, et al. Phase 2 trial of alisertib (MLN8237), an investigational, potent inhibitor of aurora a kinase (AAK), in patients (pts) with aggressive B- and T-cell nonHodgkin’s lymphoma (NHL). ASH Annual Meeting Abstracts. 2011;118(21):95.

2. True. The Phase II GAUSS trial is

the first head-to-head study of rituximab versus obinutuzumab, a novel anti-CD20 monoclonal antibody in relapsed CD20+ indolent NHL. Superior ORR at the end of induction with obinutuzumab versus rituximab in patients with relapsed FL was observed (P=0.01). Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. ASH Annual Meeting Abstracts. 2011;118(21):269.

True. The interim analysis of the Eastern Cooperative Oncology Group E4402 trial RESORT (Rituximab Extended Schedule or Retreatment Trial) also demonstrated that time to cytotoxic therapy is slightly longer with maintenance rituximab than retreatment, but at a cost of 3.5 times more rituximab. The investigators recommend rituximab retreatment as a strategy for patients with FL and low tumor burden receiving front-line rituximab monotherapy. Kahl BS, Hong F, Williams, ME et al. Results of Eastern Cooperative Oncology Group protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. ASH Annual Meeting Abstracts. 2011;118(21):LBA6.

4. False. In this prospective, random-

ized Phase III trial, similar outcomes were achieved with both CHOP-R and CHOP-RIT in patients with previously untreated FL. Median times to progression have not yet been reached for either regimen. Future studies are ongoing (SWOG S0801; ClinicalTrials.gov identifier: NCT00770224) to assess CHOPRIT with additional rituximab maintenance therapy to elucidate the additive benefit.

Press O, Unger JM, Rimsza LM, et al. A phase III randomized intergroup trial (SWOG S0016) of CHOP chemotherapy plus rituximab vs CHOP

chemotherapy plus iodine-131-tositumomab for the treatment of newly diagnosed follicular nonHodgkin’s lymphoma. ASH Annual Meeting Abstracts. 2011;118(21):98.

True. Microarray analysis of prospectively archived patient tissue from the U.S. intergroup trial E4494 demonstrated that five- and six-gene risk score–based models predict clinical outcome in patients with DLBCL who are treated with CHOP or R-CHOP, respectively. The gene-risk score model was largely independent of International Prognostic Index score and was obtainable by unstained formalin-fixed, paraffin-embedded tissue despite more than 10 years of storage. Winter JN, Hong F, Rimsza LM, et al. Gene risk scores based on expression of 6 genes quantitated by nuclease protection assay in formalin fixed paraffin-embedded tissue (FFPET) specimens from CHOP and RCHOP treated patients with diffuse large B-cell lymphoma (DLBCL) predict outcome: an ECOG and SWOG study. ASH Annual Meeting Abstracts. 2011;118(21):87.

6. True. A retrospective analysis of

patients treated from 1998 to 2011 with HL or NHL during pregnancy showed that treatment with various regimens during the second (n=18) and third (n=9) trimesters of pregnancy was associated with minimal maternal complications or fetal detriment.

Evens AM, Advani R, Lossos IS, et al. Lymphoma in pregnancy: excellent fetal outcomes and maternal survival in a large multicenter analysis. ASH Annual Meeting Abstracts. 2011;118(21):94.

True. In the multicenter, prospective, non-randomized STIM trial, the probability of maintaining CMR at 12 months was approximately 43% with discontinuation following three years of front-line imatinib therapy in patients who had CMR for at least two years. A risk model combining Sokal risk score and imatinib therapy duration predicted the probability of maintaining 24-month CMR (P=0.007). Of note, imatinib discontinuation was appropriate only in the clinical trial setting with close molecular monitoring. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: update results of the STIM study. ASH Annual Meeting Abstracts. 2011;118(21):603.

8. False. Dasatinib therapy for CML-

CP resulted in MMR rates of 90% at 18 months. Pemmaraju N, Kantarjian HM, Luthra R, et al. Results of a phase II trial of dasatinib as frontline therapy for chronic myeloid leukemia (CML) in chronic phase. ASH Annual Meeting Abstracts. 2011;118(21):1700.

True. An analysis of the Phase III DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CMLCP Patients) trial comparing dasatinib

with imatinib in patients with newly diagnosed CML-CP demonstrated that patients who achieved a BCR-ABL transcript level of no more than 10% by three months had a lower probability of transformation, a higher probability of PFS and MMR at 24 months, and a higher probability of complete cytogenetic response by 12 months. Dasatinib yielded faster and more robust decreases in BCR-ABL transcript levels than imatinib in this study. Hochhaus A, Saglio G, Chuah C, et al. Dasatinib and imatinib-induced reductions in Bcr-Abl transcript levels below 10% at 3 months are associated with improved responses in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): analysis of molecular response kinetics in the DASISION trial. ASH Annual Meeting Abstracts. 2011;118(21):2767.

10. True. Omacetaxine is active in

diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 36-month (mo) follow-up. ASH Annual Meeting Abstracts. 2011;118(21):452.

13.

False. The multicenter, randomized, open-label Phase III BELA (Bosutinib Efficacy and safety in chronic myeloid LeukemiA) study compared bosutinib with imatinib in newly diagnosed CML-CP patients and reported 24-month follow-up data. MMR rates were 61% and 50% (P<0.05) for bosutinib and imatinib, respectively. Molecular response improved with bosutinib but not with imatinib in Sokal low-risk subgroups (59% vs. 45%, respectively). The rates of treatment failures and transformations to accelerated-phase or blastphase CML were lower with bosutinib than with imatinib.

patients with CML-CP or CML-AP and resistance to or intolerance of at least two TKIs including imatinib. This new drug inhibits protein synthesis independent of BCR-Abl binding and induces anti-CML activity by decreasing levels of anti-apoptotic regulatory proteins. Approximately 20% of the patients achieved major cytogenetic response and 27% of patients achieved major hematologic response in CML-CP and CML-AP, respectively.

Cortes JE, Maru A, De Souza CAA, et al. Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia: BELA trial—24-month follow-up. ASH Annual Meeting Abstracts. 2011;118(21):455.

Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine-kinase inhibitors including imatinib. ASH Annual Meeting Abstracts. 2011;118(21):3761.

Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Initial findings from the PACE Trial: a pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. ASH Annual Meeting Abstracts. 2011;118(21):109.

Kantarjian H, le Coutre P, Cortes J, et al. Phase 1 study of INNO-406, a dual ABL/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010;116:2665-2672.

11.

True. Imatinib was started at a dose of 600 mg daily; the dose was escalated to 800 mg on day 22 if imatinib trough level was less than 1,000 ng/ mL or molecular time-dependent targets were not met. The latter group of patients, cohort 1 (n=105), were switched to nilotinib 400 mg twice daily if molecular targets still were not met with three months of escalated imatinib therapy. Cohort 2 (n=105) patients were immediately switched to nilotinib 400 mg twice daily if molecular targets were not met. At 12 months, the MMR and CMR rates were similar in both cohorts. Yeung DT, Osborn M, White DL, et al. Upfront imatinib therapy in CML patients with rapid switching to nilotinib for failure to achieve molecular targets or intolerance achieves high overall rates of molecular response and a low risk of progression: an update of the TIDEL-II Trial. ASH Annual Meeting Abstracts. 2011;118(21):451.

12. False. There

were no major changes in the 36-month safety analysis since the two-year update. No new cases of pancreatitis or hepatic events were reported. Saglio G, LeCoutre PD, Pasquini R, et al. Nilotinib versus imatinib in patients (pts) with newly

14. True. Ponatinib, a novel oral

inhibitor of native and mutant Bcr-Abl tyrosine kinases, is active against T315I mutant CML. This drug is generally well tolerated with a recommended dose of 45 mg daily.

15. True. For patients with lim-

ited-stage HL, ABVD improves overall survival compared with treatment that includes subtotal nodal irradiation, including combined modality therapy and is associated with fewer deaths from causes other than HL. It is important to note the eligibility criteria of this study. Eligible patients had non-bulky clinical stage I-IIA HL; patients with sub-diaphragmatic disease were eligible if their disease was confined to the iliac, inguinal and/or femoral regions. Prior to randomization, patients were stratified into low- and high-risk categories; low-risk patients had all lymphocyte-predominant or nodular-sclerosis histology, age younger than 40 years, erythrocyte sedimentation rate below 50 and involvement of no more than three disease site regions. All others were high risk.

Meyer RM, Gospodarowicz M, Connors JM, et al. Final analysis of a randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy (RT) in patients with limited-stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6. ASH Annual Meeting Abstracts. 2011;118(21):590.

16. True. Results of a PET scan following therapy completion were used to assess patients with advanced HL in partial response who had a persistent mass

reV 6:

Clinical Oncology News • MAY 2012

measuring 2.5 cm or more in the GHSG (German Hodgkin Study Group) HD15 trial. Only those patients who were positive on centrally reviewed PET received additional RT with 30 Gy. This approach resulted in less morbidity and mortality. Complete response was achieved in 94.2% and 90.1% of patients after six and eight cycles of BEACOPPescalated, respectively. Engert A, Haverkamp H, Kobe C, et al. Reduced intensity of chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin lymphoma: the GHSG HD15 final results. ASH Annual Meeting Abstracts. 2011;118(21):589.

reVisiOn #

reV 2

sales

layOUT DaTe/ TiMe

May 3, 2012 5:18 PM

PrODUCTiOn

eDiTOrial DaTe/TiMe

CirCUlaTiOn

TriM siZe

COMMenTs:

PRN Community Oncology

19. True. In relapsed or refractory

COlOr sPeCs

KeywOrDs:

Annual Meeting Abstracts. 2011;118(21):1788.

20. True.

2012 OPT-in w-CarD.inDD CLL, lenalidomide in combination with rituximab or ofatumumab demonstrated an ORR of 66% and 65%, respectively. The CR rates were 12% and 15% with rituximab and ofatumumab combinations, respectively.

File PaTH

A follow-up analysis of the Phase Ib/II PCYC-1102 study showed PCI-32765 to be highly active and tolerable in patients with relapsed and refractory CLL. Sixty-one patients with relapsed or refractory CLL were enrolled (420-mg cohort, n=27; 840mg cohort, n=34). The median followup time for the 420-mg cohort was 10.2 months and 6.5 months for the 840-mg cohort. The ORR was 70% and 44% in the patients taking this oral drug at a dose of 420 mg and 820 mg, respectively.

Badoux XC, Keating MJ, O’Brien S, et al. Final analysis of a phase 2 study of lenalidomide and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). ASH Annual Meeting Abstracts. 2011;118(21):980. Ferrajoli A, O’Brien S, Wierda WG, et al. Combination therapy with ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL): results of a phase II trial. ASH

O’Brien S, Burger JA, Blum KA, et al. The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): follow-up of a Phase Ib/II study. ASH Annual Meeting Abstracts. 2011;118(21):983.

Questions or feedback on this month’s

Clinical Conundrums? Write to Dr. Abutalib at

syed.abutalib@ctca-hope.com

17.

False. The safety profile data from 31 patients with newly diagnosed HL treated with brentuximab vedotin in combination with either ABVD or AVD was reported by Anas Younes, MD, and colleagues at the University of Texas MD Anderson Cancer Center, in Houston. The group reported combination treatment with either regimen was generally well tolerated, with no dose-limiting toxicity observed up to 1.2 mg/kg.

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Younes A, Connors JM, Park SI, et al. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. ASH Annual Meeting Abstracts. 2011;118(21):955.

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18.

False. Brentuximab vedotin prior to RIC allo-HCT in HL can yield prolonged disease control without a delay in engraftment, increase in nonrelapse mortality, acute GVHD, chronic GVHD and post-transplant infectious complications. According to Robert W. Chen, MD, and colleagues at City of Hope in Duarte, Calif., this strategy may allow more patients with relapsed or refractory HL to gain sufficient pretransplant disease control and undergo a potentially curative procedure. Chen RW, Forman SJ, Palmer J, et al. Brentuximab vedotin (SGN-35) enables successful reduced intensity allogeneic hematopoietic cell transplantation in relapsed/refractory Hodgkin lymphoma. ASH Annual Meeting Abstracts. 2011;118(21):664.

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SOLID TUMORS

Clinical Oncology News • May 2012

Pancreatic

Prognostic Factors for Salvage Therapy for Pancreatic Carcinoma From Clinical Oncology

econd-line or salvage therapy “may be beneficial” for patients with advanced pancreatic adenocarcinoma, a new study has revealed. The study, published in the March issue of Clinical Oncology (2012;24:105111, PMID: 21382702), was performed by a team of researchers from Korea University Anam Hospital, in Seoul. The researchers designed the study to identify prognostic factors for longterm survival in patients on salvage therapy. The prognosis for patients with advanced or metastatic pancreatic adenocarcinoma is poor with a fiveyear survival rate, according to existing data, of 5%. The precise role of salvage

EXPERT INSIGHT Lei Zheng, MD Assistant Professor of Oncology and Surgery Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

hile chemotherapy in advanced pancreatic cancer and in the adjuvant setting for resected pancreatic cancer start to show a proven benefit, the role of second-line chemotherapy after the failure of first-line therapies remains to be established. There is now an increasing body of

therapy in this setting has not yet been established and its initiation remains controversial. The authors analyzed 90 patients who received salvage therapy after failing first-line therapy, typically with gemcitabine (Gemzar, Eli Lilly) or gemcitabine-based regimens. The salvage therapy regimens used were mitomycin plus 5-fluorouracil plus leucovorin; epirubicin (Ellence, Pfizer) plus cisplatin plus oral 5-FU plus leucovorin; gemcitabine plus oral 5-FU; gemcitabine plus oxaliplatin (Eloxatin, Sanofi-aventis); and gemcitabine plus erlotinib (Tarceva, Genentech/Astellas). Among the 90 patients enrolled in the study, the median age at the time of second-line chemotherapy administration was 61.9 years; the median Eastern

Cooperative Oncology Group (ECOG) performance status was 1. Using multivariate analysis, the authors found that nonresponse to first-line therapy, an ECOG performance status of 2 or more, and an albumin level of less than 3.5 mg/dL were independent prognostic factors for decreased overall survival for all the patients. They stratified the study population into three prognostic groups—“good,” “intermediate” and “poor”—based on the number of prognostic factors present. Those with zero or one prognostic factor (50 patients) were included in the “good” group; those with two prognostic factors (24 patients) were included in the “intermediate” group; and those with three prognostic factors (16 patients) were included in the “poor” group.

Overall survival in the “good” group was 5.5 months, compared with 3.3 months in the “intermediate” group and 2.1 months in the “poor” group (P<0.001). For all patients cumulatively, median overall survival for secondline chemotherapy was 4.5 months. Median progression-free survival was 2.1 months (1.9 months in the “intermediate” group and 1.2 months in the “poor” group). Based on these findings, the authors concluded that the use of salvage therapy in those with “intermediate” or “poor” prognosis may not be warranted. Generally, none of the patients achieved complete response after salvage therapy, although nine achieved partial response and 25 had stable disease.

evidence to support the benefit of second-line chemotherapy, particularly provided by the recently completed CONKO-003 study showing the addition of oxaliplatin to the combination of 5-FU and folinic acid, which offers improved survival in patients with gemcitabine-refractory pancreatic cancer. However, the question remains: Who will benefit from receiving second-line chemotherapy? In the present study, by Kim et al, a prognostic model including poor performance status, lack of response to firstline chemotherapy, and low albumin level was proposed to identify patients with advanced pancreatic adenocarcinoma who are unlikely to benefit from second-line chemotherapy. As indicated by the authors of this study, a patient’s

performance status often deteriorates rapidly after the failure of first-line treatment. The identification of such prognostic factors could be of extreme value, as this would allow the identification of those who may benefit from second-line chemotherapy and the selection of those with poor prognosis who may be treated only with supportive therapy. Nonetheless, more studies, particularly those with a prospective design, are warranted before a prognostic index can be identified and applied to our routine clinical practice in selecting patients for second-line chemotherapy. The study conducted by Kim et al is limited by its retrospective nature and small sample size. With FOLFIRINOX (infusional 5-fluorouracil, folinic acid, irinotecan and oxaliplatin) now

being an option for first-line chemotherapy, and because it has demonstrated a higher clinical response rate than gemcitabine (NEJM 2011;364:18171825, PMID: 21561347), some parameters used in the prognostic index proposed by Kim et al may be less valuable. Moreover, gemcitabine used as a second-line treatment may be better tolerated by patients with poor performance status. As many as 70% of patients in the FOLFIRINOX arm of the Phase III PRODIGE 4/ACCORD 11 trial have received gemcitabine after they failed FOLFIRINOX. Thus, it will be intriguing to test prospectively whether the patients with a poorer performance index benefit from receiving gemcitabine after they have failed FOLFIRINOX.

Post-op Radiation for Elderly Lung Cancer Patients Questioned For certain locally advanced lung cancers, postoperative radiation does not prolong survival, SEER data says

new study calls into question the widespread practice of offering radiation therapy to older people with resected stage III non–small cell lung cancer (NSCLC) with N2 disease. Using population-based data, researchers found that postoperative radiation therapy (PORT) does not prolong survival in elderly patients with this cancer subtype. Survival was similar across all groups, regardless of radiotherapy, chemotherapy or adjustments for time trends. “While some analyses have shown improvement with PORT, the data are not strong enough to support using it as a standard of care in older adults

with this type of lung cancer,” said Juan Wisnivesky, MD, DrPH, the vice-chair of research in the Department of Medicine at Mount Sinai School of Medicine in New York City, and the lead author of the study. “Our results show that we need more information about the potential benefits of radiation therapy before it is used routinely to treat these patients, especially considering the side effects associated with it.” The study was published in the Feb. 13 online edition of Cancer, a peer-reviewed journal of the American Cancer Society (Cancer 2012; doi: 10.1002/cncr.26585, PMID: 22331818). Dr. Wisnivesky called on clinicians

to refrain from widespread use of postoperative radiation in elderly patients with this cancer subtype outside of clinical trials. PORT in elderly populations should primarily be reserved for randomized clinical trials, of which one is currently under way, he said. This trial is expected to provide a definitive answer to the issue of postoperative radiation in this group of patients. The report is “an important study on a controversial question,” but it does not effectively answer whether PORT is indicated for patients with resected lung cancer involving mediastinal nodes, said Jeffrey Bradley, MD, the S. Lee Kling Professor of Radiation Oncology at

Washington University School of Medicine in St. Louis. “Analyses of the SEER [U.S.

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Multiple Myeloma

Timing of Stem Cell Transplantation for Multiple Myeloma Studied From Cancer

arly and delayed autologous stem cell transplantation (SCT) result in similar overall survival in patients with multiple myeloma, even in those cases where immunomodulatory therapies have been used, a new study has found. It has long been known that these two SCT approaches produce comparable outcomes in multiple myeloma patients; however, with the introduction of several new therapies for transplant-eligible patients over the past decade—including thalidomide (Thalomid, Celgene), lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Takeda/Millennium)— the management of these patients has

EXPERT INSIGHT Ivan Borrello, MD Associate Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

he benefit of autologous SCT in the treatment of myeloma stems from data from the Intergroupe Français

Surveillance, Epidemiology, and End Results program] database such as this one should be interpreted with caution,” he said. Retrospective data collection is subject to selection bias and SEER data does not contain detailed information such as why the patient received treatment. Moreover, there is no analysis of radiation dose, radiation volume or timing with chemotherapy. “All these things are important but are not available within the SEER database,” Dr. Bradley said. Many patients with NSCLC with N2 lymph node involvement undergo postoperative radiation in an effort to reduce the risk for recurrence. According to this study, just over half of patients aged 65 years and older with stage III N2 disease receive postoperative radiation. Yet, the widespread use of PORT is not supported by substantial clinical evidence. Some studies—including a recent international randomized trial—have shown a survival benefit for N2 patients who receive postoperative radiation (Int

changed significantly, and some have questioned how, if at all, this would affect SCT in this setting. Traditionally, early transplantation has been favored because of the side effects associated with older-line therapies. However, this has changed with the advent of new, immunomodulatory therapies that are relatively well tolerated, even for extended periods. In a study published in the March 15 issue of Cancer (2012;118:1585-1592, PMID: 22009602), an international team of researchers representing the Mayo Clinic and the San Giovanni Molinette Hospital in Turin, Italy, studied 290 multiple myeloma patients who received first-line therapy with immunomodulatory agents, which included 123 patients who

had received treatment with thalidomide plus dexamethasone and 167 who had received lenalidomide plus dexamethasone prior to SCT. The 173 patients who underwent SCT within 12 months of diagnosis and within two months of stem cell harvest were considered “early” transplant patients; 112 patients who underwent SCT more than a year after diagnosis were considered “delayed” transplant patients. The study, led by Shaji Kumar, MD, was funded in part by the Mayo Clinic Cancer Center’s Hematological Malignancies Program and by a grant from the National Cancer Institute. At the time the Cancer article was submitted for publication, 42 patients had undergone SCT. The estimated median time to transplantation was

5.3 months in the early group and 44.5 months in the delayed group. The fouryear overall survival rate was 73% in both groups (P=0.3). Four-year overall survival also was comparable among those who received thalidomide plus dexamethasone (68% in the early group versus 64% in the delayed group) and those who received lenalidomide plus dexamethasone (82% in the early group versus 86% in the delayed group). In addition, the time to disease progression for the early (20 months) and delayed (16 months) groups did not differ significantly. The authors concluded that these findings illustrate that multiple myeloma patients “have the option of delaying SCT and continuing with initial therapy if that is their preference.”

du Myelome (IFM 90) French study (NEJM 1996;335:91-97, PMID: 8649495) demonstrating superiority of SCT as compared to 4-6 cycles of cytotoxic chemotherapy in both disease-free survival and overall survival. Conventional chemotherapy has shown both significant cumulative toxicity and minimal efficacy. The introduction of novel, non-cytotoxic agents such as lenalidomide and bortezomib have dramatically changed the treatment landscape. These agents can be administered for more cycles with significantly less toxicity that traditional cytotoxic chemotherapy.

More importantly, they impart complete response rates that exceed what has traditionally been observed with SCT, resulting in improved overall survival results. This greater response rate coupled with lower toxicity has prompted a shift toward delayed SCT for many newly diagnosed patients. In light of this new reality, Kumar and colleagues performed a retrospective analysis of patients treated with thalidomide or lenalidomide with dexamethasone who underwent either early or late SCT. They show that patients treated with lenalidomide had a superior

overall survival compared to those treated with thalidomide. More importantly, early or delayed transplant resulted in similar overall survival. These data raise interesting questions about both the impact of induction therapy in influencing the overall treatment outcome as well as the role and/or optimal timing of SCT. The ongoing trial of bortezomib, lenalidomide and dexamethasone (VRD) induction with subsequent randomization to SCT or additional VRD with SCT at relapse will hopefully shed light on these critical questions in a prospective manner.

J Radiat Oncol Biol Phys 2008;72:695701, PMID: 18439766). Yet, meta-analyses demonstrate no statistically significant survival effect for patients with stage III disease (Cochrane Database Syst Rev. 2005;[2]:CD002142, PMID: 15846628; Lancet 1998;352:257-263, PMID: 9690404). Moreover, other stud-

Survival at one and three years was not improved in the group receiving PORT compared with the group that did not receive it. Analyses that were limited to patients who did or did not receive chemotherapy, who received intermediatecomplexity or high-complexity radiotherapy planning, or adjusted for time

‘The data are not strong enough to support using [PORT] as a standard of care in older adults with this type of lung cancer … We need more information.’ —Juan Wisnivesky, MD, DrPH ies have shown that large volumes of radiation therapy can be detrimental. The National Cancer Institute’s SEER database integrates data from 17 different cancer registries. Dr. Wisnivesky and colleagues identified 1,307 patients with primary, completely resected NSCLC who had N2 lymph node involvement diagnosed between 1992 and 2005. Of these, 710 patients —54%—received PORT after their tumor was removed.

trends all produced similar results. Some specialists believe that if there is an overall survival benefit with PORT for resected lung cancer, it is in the range of only 5% to 10% and only in cases where small volumes of radiation therapy are directed to areas of high risk. This retrospective study did not include enough patients to show an advantage that is less than 10%, said Dr. Bradley. However, a randomized trial called

LungART (Lung Adjuvant Radiotherapy Trial) is currently accruing across Europe and is designed to study approximately 1,400 patients, which should be large enough to demonstrate a small advantage, if indeed there is a survival advantage. The first results are several years away. In the meantime, the investigators advise physicians to carefully discuss the evidence supporting various treatment options with their patients. “I think physicians should carefully discuss the lack of definitive answers regarding the potential benefits of radiation for this subgroup of patients,” said Dr. Wisnivesky, adding that these patients should receive adjuvant chemotherapy. Physicians should “probably not use [postoperative radiation] routinely as [if ] it was standard of care,” he said. Some patients may still choose this therapy, but they should be aware of the potential for toxicity and the lack of evidence from randomized controlled trials, he said. —Christina Frangou

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Myeloma

Lenalidomide for Myeloma Requires Surveillance for Second Tumors From Blood

elapsed/refractory multiple myeloma patients receiving therapy that includes lenalidomide (Revlimid, Celgene), a standard approach, are at increased risk for second primary malignancies, a pooled analysis of results from multiple clinical trials has revealed. However, the authors of the analysis concluded that the overall risk– benefit profile of lenalidomide in this patient population “remains positive” because of the drug’s “observed survival benefit,” as long as clinicians evaluate for second primary malignancies using standard screening methods. In a study published in the March 22 issue of Blood (2012;119:2764-2767,

EXPERT INSIGHT Ivan Borrello, MD Associate Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

he addition of lenalidomide to the treatment armamentarium of myeloma has been significant and is adding to the increased response rate and disease-free and overall survival rates as shown in the relapsed/refractory setting in two randomized studies of lenalidomide-dexamethasone versus placebo-dexamethasone (M009 and

PMID: 22323483), the team of researchers, led by Meletios A. Dimopoulos of the University of Athens, Greece, reviewed the results of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma, analyzing data from a total of 3,846 patients to determine their risk for the development of second primary tumors. Multiple myeloma, they noted, is associated with an increased risk for second primary tumors, including acute myeloid leukemia, particularly in younger patients aged 70 years or less at the time of diagnosis. Funding for the drafting of their final report was provided by Celgene, the manufacturer of the study drug. The median age of the patients in the pooled analysis was 64 years. The

overall incidence rate for second primary tumors was 3.62 per 100 patientyears. In all, 52 invasive second primary tumors were reported, including five cases of myelodysplastic syndrome and one case of acute myeloid leukemia, making the incidence rate for invasive second primary tumors 2.08 per 100 patient-years. In the pooled analysis, 313 patients had received lenalidomide-based treatment for a minimum of 24 months (based on the available follow-up data, median overall survival was not reached). The incidence rate of second primary tumors in this subset of patients was 2.35 per 100 patient-years. However, in a separate pooled analysis of pivotal Phase III clinical trial data (703 patients; median age 63 years), the overall incidence rate of second primary

tumors was 3.98 per 100 patient-years for patients administered lenalidomide plus dexamethasone therapy versus 1.38 for those receiving placebo plus dexamethasone therapy. Incidence rates for invasive second primary tumors were 1.71 and 0.91 per 100 patient-years for the lenalidomide and placebo patients, respectively. Median duration of lenalidomide therapy in this patient population was 9.8 months. The invasive second primary tumors in the lenalidomide group included six solid tumors and two cases of myelodysplastic syndrome. Based on these findings, the authors concluded that patients, particularly those with a history of cancer, should be evaluated for second primary tumors prior to and during the administration of lenalidomide-based therapy.

M010).1,2 More recent studies examining the role of lenalidomide maintenance postautologous stem cell transplant (SCT) as well as maintenance in the non-transplant setting with melphalan-prednisone-lenalidomide (MPR) revealed an increase in secondary primary malignancies (SPM). Several of the following factors may be contributing: 1) the spontaneous increase in cancer with increased age, which may be relevant considering the median age at diagnosis of 69 years; 2) ineffective immune surveillance due to endogenous defects in both humoral and cellular immunity, or possibly other factors, a hypothesis supported by a recent report by Landgren and colleagues of an incidence ratio of 11.1 for developing AML/MDS in MGUS patients with M-spikes greater

than 1.5g/dL3; and 3) a potential association of lenalidomide-related SPM with melphalan. This analysis of two non–melphalancontaining lenalidomide trials shows a considerably lower incidence of SPMs than previously reported with melphalan-based studies. Furthermore, no significant difference of invasive SPMs was seen compared to placebo or the expected incidence in the general population. The lower incidence in these studies is potentially reassuring but also supports the role of melphalan in lenalidomideassociated SPMs. However, this toxicity must both be discussed with patients and taken in the context of the considerable therapeutic benefit these combinations offer patients. Even roses have their thorns!

References 1. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-2142, PMID: 18032763. 2. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-2132, PMID: 18032762. 3. Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, Landgren O. Second malignancies after multiple myeloma: from 1960s to 2010s. Blood. 2012;119(12):2731-2737, PMID: 22310913.

Infliximab Not Associated With Increased Risk for Cancer Ongoing evaluation of TREAT registry shows infliximab safe at 5-year follow-up National Harbor, Md.—The use of infliximab does not appear to increase the risk for cancer in patients with Crohn’s disease (CD), although several other independent factors may, according to the latest findings from the TREAT (Crohn’s Therapy, Resource, Evaluation and Assessment Tool) registry presented at the American College of Gastroenterology’s annual meeting, held last November. Gary Lichtenstein, MD, professor of medicine, University of Pennsylvania School of Medicine, Philadelphia, and colleagues prospectively evaluated patients in the registry to examine whether an association between malignancies and anti-tumor necrosis factor

(TNF) therapy exists. The TREAT registry, set up primarily to examine the safety of infliximab compared with other treatment therapies for CD, now includes 6,273 patients from more than 200 different centers (80% community centers, 20% academic centers), with a mean length of time in the registry of 5.2 years. During that time, records have been kept on 3,674 patients receiving infliximab and 2,509 receiving other treatments, including azathioprine, 6-mercaptopurine (6-MP), methotrexate, corticosteroids, mesalamine and antibiotics, at the discretion of their physician. “There was no difference in incidence per 100 patient-years of malignancy or

lymphoma in the two groups,” said Dr. Lichtenstein, also director of the Center for Inflammatory Bowel Diseases at the University of Pennsylvania Health System in Philadelphia. “We found that baseline age, disease duration, smoking and immunomodulator therapy— but not infliximab use—were significant predictors of malignancy.” Although patients taking azathioprine or 6-MP have an increased risk for malignancy, the addition of infliximab to other treatments did not increase this risk in patients on other treatments alone. Dr. Lichtenstein’s group previously reported a meta-analysis highlighting a fourfold increase in the standard incidence

ratio of patients with lymphoma who were exposed to azathioprine or 6-MP. Comparing findings from the TREAT registry with those in the National Institutes of Health Surveillance, Epidemiology and End Results (SEER) database, which examines cancer incidence in the general population, the researchers found that breast cancer was less common in the TREAT registry, but the standardized incidence ratio for lymphoma was twice that of the background population in individuals in both the infliximab-treated and other treatment–only cohorts. “This is consistent with other reports see INFLIXIMAB, page 24 

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INFLIXIMAB continued from page 22 

in the literature,” Dr. Lichtenstein said. “Crohn’s disease patients may have a higher lymphoma risk than the general U.S. population,” which he has attributed to azathioprine/6-MP use or potentially disease activity. Chromosomal changes that occur in users of azathioprine and 6-MP have been well described in the literature. Dr. Lichtenstein hypothesized that it is possible that taking azathioprine and

6-MP induces these mutations and may play a causal role in lymphoma. “But to date no one has done an adequately sized study of this, because the current belief among gastroenterologists is that it is still safe to use azathioprine and 6-MP as a general treatment in patients with Crohn’s; although the risk for lymphoma in patients is elevated, it still represents a rare event,” Dr.

Lichtenstein said. Based on a recent population-based meta-analysis his group conducted, Dr. Lichtenstein estimates that one in 500 to one in 600 patients using azathioprine and 6-MP may develop a lymphoma. But, he added, “There are certainly many more patients who gain an advantage with the medication compared with the risk.

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“We have good data to show that antiTNF therapy is very effective, so knowing infliximab did not increase the risk for lymphoma when compared with conventional therapy is comforting; however, work will be ongoing to look at this with longer use.” Stephen Hanauer, MD, who was not involved in Dr. Lichtenstein’s study, also considers these recent findings comforting. “This is an important ongoing study that continues to add evidence regarding the long-term safety of infliximab therapy,” said Dr. Hanauer, a professor of medicine and clinical pharmacology, and chief of Gastroenterology, Hepatology & Nutrition at the University of Chicago Medical Center. “We’re probably approaching 10 years of experience and the numbers aren’t shifting dramatically,” Dr. Hanauer said. “We are not seeing accumulating toxicities over time. The more immunosuppressants you give someone, the greater the risk for both infection and neoplasia, but overall, I look at this as very reassuring that we do not see an independent risk related to long-term therapy with infliximab.” The recent findings, he said, are consistent with what’s been reported in the past. “The story continues to follow the same theme, which is that the major risks for patients are not the biologic therapies, but the steroid therapies, which have been associated with risks for infection and death.” The complexity, Dr. Hanauer added, is how to separate the risks of immunosuppressant agents from the risks of biologic therapy, since many patients are treated concomitantly with both. “My interpretation of the literature, including the TREAT registry, is that the biggest risk is that of steroid therapy, that immunosuppressants are associated with a greater risk for lymphoma. That risk may be associated with antiTNF therapy as well, but it’s really hard to separate that individual risk with the risk associated with immunosuppressants,” he said. “Although these data are reassuring, there are limitations to this observational study and we still need to acknowledge that the FDA has placed a warning on all anti-TNF agents regarding the risk for lymphoma, in particular for young males who are susceptible to the very rare hepatosplenic T-cell lymphomas, which also have an increased risk with combination therapy with immunosuppressants. In all cases, the risks of combination therapy must be balanced against the benefits of the combination of infliximab and azathioprine observed in the SONIC [Study of Biologic and Immunomodulator-Naive Patients in Crohn’s Disease] trial,” Dr. Hanauer concluded. —Monica J. Smith

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2012

Lymphoma

Rituximab Then CHOP Extends Survival in PTLD

Administered to patients who had failed to respond to a reduction in their regimen of immunosuppression, the sequential rituximab-CHOP regimen was evaluated in the largest prospective trial ever undertaken in PTLD. “We think that these data show that it is reasonable to treat CD20-positive PTLD with a sequence of four courses of rituximab followed by four cycles of CHOP chemotherapy,” said Ralf Trappe, MD, PhD, Charité University Hospital in Berlin. Presenting these results at the most recent annual meeting of the American Society of Hematology, Dr. Trappe indicated that the median survival was at least two times greater than that reported in previous PTLD series. The goal of testing a sequential regimen of rituximab and CHOP was to increase the survival time associated with rituximab alone and to reduce the toxicity associated with CHOP alone. According to Dr. Trappe, whose summary of this study was recently published (Lancet Oncol 2012;13:196-206, PMID: 22173060), median survival on rituximab monotherapy has been less than two years, whereas treatment-related deaths on CHOP, which is far more effective for controlling disease, has been as high as 31%, “meaning death due to treatment in every third to fourth patient.” In this Phase II study, 70 patients from 20 participating centers in four

At a glance Adding CHOP to rituximab monotherapy Increased complete response rate from 20% to 68% Resulted in 11% treatmentrelated death rate

countries received the sequential therapy of 375 mg/m2 of rituximab administered weekly for four weeks followed by four 21-day cycles of standard CHOP (750 mg/m2 cyclophosphamide on day 1, 50 mg/m2 doxorubicin on day 1, 1.4 mg/ m2 vincristine on day 1, and 50 mg/m2 oral prednisolone given on days 1 to 5). Patient characteristics differed markedly when subdivided into those who did or did not have PTLD histological-

survival was 6.6 years. Risk factors for disease progression included a lack of EBV association and partial remission rather than CR after sequential therapy. However, the activity of the sequential regimen of rituximab and then CHOP appeared to be high whether or not PTLD was EBV-associated. Overall, the regimen generated disease control superior to that produced by previous treatment regimens. “For comparison the three rituximab monotherapy studies yielded median survivals of only 1.3 to 3.5 years,” Dr. Trappe said. Overall, this regimen “provided a better response rate and a better overall survival than any other published prospective trial in the treatment of PTLD.”

Overall, this regimen ‘provided a better response rate

100

Remission, %

San Diego—Four cycles of rituximab monotherapy followed by four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy improved survival in patients with post-transplant lymphoproliferative disorder (PTLD) in a German study.

PR 12

60 PR 40

40 20 0

CR 20

CR 68

Rituximab monotherapy

Rituximab plus CHOP

Figure. Response rates after rituximab monotherapy and rituximab plus CHOP. CHOP, cyclophosphamide, doxorubicin, vincristine and prednisolone

and a better overall survival than any other published prospective trial in the treatment of PTLD.’ —Ralf Trappe, MD, PhD ly associated with Epstein-Barr virus (EBV). EBV-associated PTLD patients (44% of the study population) had a younger median age (43.5 vs. 55.3 years; P=0.0082), had a shorter median time from transplant (0.7 vs. 9.3 years; P<0.0001), and were less likely to have an Eastern Cooperative Oncology Group performance status of 0 or 1 (56% vs. 89%). On an intention-to-treat basis, the objective response rate after rituximab and CHOP was 90% and the complete response (CR) rate was 68% (rising from 20% after rituximab alone). Although the median duration of response has not yet been reached with the most recent analysis, the median time to progression was 6.5 years. Of those with a CR, 69% were progression-free at two years and 66% were so at five years. Of the eight patients with a CR who relapsed, five did so within six months. The remaining three had late relapses at 2.8, 2.9 and 6.1 years. All but one died as a result of progressive PTLD. The median progression-free survival was four years, and the median overall

Although the median number of courses was four for both rituximab and CHOP, four patients did not go on to CHOP after rituximab. Of the 66 who did, 18 (27%) received less than the planned four courses. Five of these patients had disease progression but seven had early death from infection or hemorrhage, producing an 11% rate of treatment-related death. It is notable that 25 of the 28 nonresponders to rituximab went on to CHOP and 16 achieved a response. However, five of the seven CHOP-related deaths occurred in rituximab nonresponders. Several strategies are being considered for further reducing the risk for CHOPrelated treatment deaths but this may be difficult. Although the treatment-related mortality was lower than that associated with previous studies of up-front CHOP, the high rates of disease control appeared to be related to immediate sequential initiation of CHOP after rituximab. It is not yet clear whether risk factors can be identified to consider some delay or modification in CHOP to reduce the risk for toxicity.

“We are currently testing whether risk stratification according to patients’ response to rituximab can be useful to further reduce toxicity,” Dr. Trappe reported. Andrew M. Evens, DO, the director of the lymphoma program at the University of Massachusetts Medical School in Worcester, said, “This initial report represents a major advance in the treatment of PTLD.” However, he too expressed interest in efforts to improve safety. “One note of caution, however, was the 11% treatment-related mortality with CHOP. This is partly related to the higher-risk population [immunosuppressed] of PTLD. We await final results of the analysis whereby the investigators amended the study for patients to receive chemotherapy only if complete remission was not achieved with singleagent rituximab,” Dr. Evens observed. —Ted Bosworth

Dr. Trappe reported receiving research funding from Amgen, CSL Behring, Mundipharma and Roche as well as honoraria from CSL Behring and Roche. Dr. Evens, DO, has received research funding and is on an advisory board for Millennium.

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

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Clinical Oncology News • May 2012

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BIOSIMILARS continued from page 1 

colorectal, esophageal, gastric, head and neck, kidney and non-small cell lung cancers; and Hodgkin’s and non-Hodgkin’s lymphoma. They also are vital in the treatment of cancer- and chemotherapy-induced anemia and neutropenia. The hope is that biosimilars will significantly improve the affordability of, and access to, cancer medications. The clock is already ticking toward the entry of biosimilars into the American market. This is because the 12-year patent-protection period will soon end for some brand-name products (Table 1). For the epoetin-alfa products Epogen (Amgen) and Procrit (Janssen Products), as well as Aranesp (darbepoetin alfa, Amgen) and Neupogen (filgrastim, Amgen), protection will run out in 2013. Some monoclonal antibody products, such as Rituxan (rituximab, Genentech/Biogen Idec), will likely lose their exclusivity protection as soon as the fourth quarter of 2015 and early 2016. Critically, on Feb. 9, 2012, the FDA released its draft guidance outlining the regulatory pathway required for the development and licensing of biosimilars. Several companies have already started to move proposed biosimilar products toward approval and as of mid-February the FDA had received requests to discuss drug approval of biosimilars for at least 11 different biologic drugs. In fact, a few started immediately after President Barack Obama signed the Biologics Price Competition and Innovation (BPCI) Act of 2009 into law on March 23, 2010, as part of the Affordable Care Act. Like the Drug Price Competition and Patent Term Restoration Act of 1984 for biologics, known colloquially as the “Hatch-Waxman Act,” the BPCI provides a legal framework for the approval of biosimilars in the United States.

Cost Savings From Biosimilars In no other field are biologics as important as in oncology and biosimilars are expected to be equally dominant players. Six of the 10 top-selling biologics in the United States are used in oncology, according to a 2011 review of biosimilars by Bradford Hirsch, MD, and Gary Lyman, MD, MPH (J Natl Compr Canc Netw 2011;9:934-942, PMID: 21900222). And they are very expensive: The number one money-earner in 2009 was bevacizumab (Avastin, Genentech), with sales of $5.8 billion. It was followed closely by rituximab at $5.7 billion. At $5 billion and $4.9 billion respectively, the markets for epoetin alfa and trastuzumab (Herceptin, Genentech) were not far behind.

Table 1. FDA Approval Dates of Some Oncology Biologics Reference Product

Approved

Guaranteed Data Exclusivity

Bevacizumab (Avastin)

Feb. 6, 2004

2016

Cetuximab (Erbitux)

Feb. 12, 2004

2016

Darbepoetin (Aranesp)

Sept. 17, 2001

2013

Epoetin alfa (Epogen/Procrit)

June 1, 1989

Filgrastim (Neupogen)

Feb. 20, 1991

2003

Pegfilgrastim (Neulasta)

Jan. 31, 2002

2014

Rituximab (Rituxan)

Nov. 26, 1997

2009

Trastuzumab (Herceptin)

Sept. 25, 1998

2010

‘[Europeans] are a number of years ahead of us and have a lot of clinical data.’ —FDA Office of Medical Policy Director Rachel Sherman, MD In Europe, draft biosimilar development guidelines were released in 2004. The first product—epoetin alfa Hexal (Hexal)—was approved in August 2007 and now more than a dozen biosimilars are on the market. Erythropoiesis-stimulating agent biosimilars such as epoetin alfa account for 35% of the market (NCCN Biosimilars White Paper. J Natl Compr Canc Netw 2011;9:S1-S22, PMID: 21976013) and are marketed at a 25% to 30% discount from the “originator” or “reference” product, according to Drs. Hirsch and Lyman. This also has led to

price reductions of the reference products themselves. The European Generic Medicines Agency estimated in a “Vision 2015” document that the European Union (EU) saved 1.4 billion euros (US$1.8 billion) from biosimilar use in 2009. Another analysis projects the total savings to exceed 8 billion euros (US$10.6 billion) by 2020. Most experts believe that overall, biosimilars will cost 20% to 30% less than reference products. Some project that in the United States, this will result in

55%

45%

Nonbiologic: $3848.21

Biologic: $4679.36

Figure 1. Biologics vs. nonbiologics distribution of drug expenditures of the top 20 antineoplastic drugs in outpatient clinics (in millions of dollars). Data from Doloresco F, Fominaya C, Schumock GT, et al. Projecting future drug expenditures—2011. Am J Health Syst Pharm. 2011;68:921–932, PMID: 21546644.

$25 billion in savings per decade. Others peg the windfall as high as $108 billion in the first 10 years and $378 billion over 20 years (Targ Oncol 2012 Jan. 17. [Epub ahead of print]). Biosimilar versions of simple, unmodified biologics may well be approved and accepted relatively quickly in the United States because companies have gained experience with biosimilar approval in Europe. Thus, it is possible that they will be marketed for less than their European equivalents. However, the price reductions with biosimilars will never be in the same ballpark as generics. Generics can be accompanied by price tags that are as much as 90% lower than their brandname counterparts. Biosimilars are made in living systems and are much more complex, and the steps regulators require for product testing and approval are concomitantly more onerous in both the United States and Europe. The estimated cost to bring a biosimilar to market is $10 million to $40 million and the time frame is six to nine years, compared with $1 million to $2 million and three years for generics.

New FDA Draft Guidance on Biosimilars The American biosimilar regulatory bar has been set high. The BPCI Act requires biosimilars to be “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and have “no clinically meaningful differences” from the reference product in terms of “safety, purity and potency.” The biosimilars also must have “the same mechanism or mechanisms of action” for the approved indications and the same route of administration, dosage form and strength. The BPCI Act also deems that biosimilars may be determined to be interchangeable with the reference product based on several criteria, including a demonstration “that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once in an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” On Feb. 9, 2012, the FDA released three draft guidance documents on the pathway for biosimilar development based on the framework set out by the BPCI Act and on feedback received in 2010 at public meetings. The FDA emphasized that it “intends to consider the totality of the evidence” and use a “stepwise approach” to determine the safety, efficacy, purity and potency of

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Clinical Oncology News • May 2012

At a glance each proposed biosimilar. The regulations allow “bridging”— that is, companies can use offshore data for compounds that have been tested or marketed as biosimilars in other countries. Firms can apply to have the compounds designated as being interchangeable—in other words, suitable for substitution for the original or “reference” product—although this will be subject to go ahead on a state-by-state basis. They also can apply for a period of exclusivity during which no other interchangeable version of a reference product can be launched into the U.S. market.

First Guidance Document: The Science of Demonstrating Biosimilarity The first draft guidance document summarizes the scientific requirements for a biosimilar to reach the market. These range from analyses of its structure and function to manufacturing process considerations, and animal and human studies that may be required, including evaluating clinical immunogenicity. It also describes the framework for postmarketing safety monitoring that companies must set up for every product. “That is the document that lays out our expectations that a sponsor will, if you will, squeeze out every bit of knowledge they can from the structure of their molecule, then come and talk to the agency … so we give the right good advice on the extent and scope of the necessary animal and clinical testing,” Rachel Sherman, MD, director of the FDA’s Office of Medical Policy, said in a news teleconference on the day the documents were released. “The law requires three, if you will, buckets of information: the physical-chemical testing, the animal studies and then the human studies, although it does permit us to waive any of the above.” She added that although the overall process is “not ‘one size fits all,’… it’s not conceivable to me that we can make an interchangeability determination without clinical data.” Dr. Sherman noted, in response to a question from a European journalist, that the FDA “would like to be able to bridge the European data. That would be product-specific, but we would try very hard to make that bridge, because you guys are a number of years ahead of us and have a lot of clinical data.” Robert Bell, PhD, who has occupied senior drug development positions in several companies, supports this approach. “Data [from biosimilars that have been approved in other countries] is very relevant here, and would accelerate the approval process,” said Dr. Bell, president of Drug & Biotechnology Development, LLC, in Clearwater, Fla., in an interview with Clinical Oncology News. “Specifically, data accumulated from the epoetin and myeloid growth factor

biosimilars that have been approved in Europe potentially could be used to meet the FDA requirements. Because … while typically the FDA likes to see data from clinical trials in the U.S., if there are data available from comparable populations, in Europe or other countries, that should suffice.”

Second Guidance Document: Quality Considerations for Demonstrating Biosimilarity The second document provides details about the “extensive, robust comparative physicochemical and functional studies” required to show that the proposed biosimilar and the reference product are virtually identical in structure and function. The tests may include bioassays, biological assays, binding assays and enzyme kinetics. “If you use current modern analytical technologies and the resulting data from the biosimilar can be superimposed on data from the reference compound— showing for example that they are highly similar—you will have fewer issues demonstrating clinical comparability,”

At a glance Cost and time of bringing follow-on products to market Small molecule generic: 3 years, $1 million to $2 million Biosimilar: 6 to 9 years, $10 million to $40 million

Interchangeability Generic is biosimilar to the reference product Produces the same clinical result as the reference product in any given patient Safety and efficacy are not affected by alternating or switching between reference product and biosimilar Biosimilar may be substituted for the reference product without the authorization of the health care provider

Dr. Bell said, citing the evolution of mass spectrometry, which can now detect differences between monoclonal antibodies as small as 32 Da or about 5 µ 10-26 kg. “But as the proteins become more complex, the analytical methodology may not be able to detect all relevant structural and functional differences between the proteins so the sponsor, in a stepwise approach, will have to further rely on preclinical and clinical studies to demonstrate comparability.” He gave a practical example of the importance of these analyses: the debacle with Eprex in Europe (erythropoietin alpha, Johnson & Johnson). In 1998, the company began to use rubber stoppers for the product’s prefilled syringes. This led to more than 200 reported cases of pure red cell aplasia in patients with chronic kidney disease

‘The landscape is going to change very rapidly in the U.S.—in Europe it’s already changed.’ —Arnold G. Vulto, PharmD, PhD Table 2. Fundamental Differences Between Small Molecule and Biologic Drugsa

Small Molecule Drugs

Biologic Drugs

Synthesis

Chemical

Made in living cells

Structure

Well defined

Heterogeneous, mixtures of related molecules

Size

<800 Da

30,000-150,000 Da

Characterization

Easy

Difficult

Stability

Relatively stable

Variable, sensitive to environmental conditions (e.g., light and temperature)

Immunogenicity

Not an issue

Can be a problem

rom “Development of biosimilars is not an easy matter.” Generics and Biosimilars Initiative. F http://gabionline.net/Biosimilars/Research/Development-of-biosimilars-is-not-an-easy-matter.

Patient Care

over the next five years. Many experts believe this is what spurred European—and later, U.S.—regulators to create their very rigorous biosimilar approval criteria. A team eventually found the source of the problem: Using high-pressure liquid chromatography of Eprex batches they detected a contaminant, a leachate, originating from the rubber stoppers (Nephrol Dial Transplant 2005;20:iii33-iii40, PMID: 15824129).

Third Guidance Document: Implementing the BPCI The third draft document is a 15-page Q&A. It covers everything from when company officials should ask the FDA for a first meeting to whether applicants can extrapolate clinical data supporting a biosimilar application to one or more additional indications. The Q&A summarizes many of the most important issues expanded on in the previous two guidance documents, while also defining several ways in which biosimilars may be different from their reference products (e.g., differences in formulation or delivery device).

Going Down the Regulatory Pathway For all the detail contained in the FDA’s draft guidance, nobody knows what the entire regulatory process will entail and how long it will take for any product to be approved as a biosimilar. “It’s relatively difficult to foresee the complete development path because companies have to go step by step and don’t know ahead of time what will be required,” said Bernd Meibohm, PhD, a professor of pharmaceutical sciences at the University of Tennessee Health Sciences Center in Memphis. “So I think this is going to be a learning experience on both sides. The FDA and the companies will go hand in hand and walk down the path set down by the draft guidance and try to make something out of it.” He believes that it will be a couple of years until the first biosimilar appears on the U.S. market, and that it will take much longer for the first one to be deemed interchangeable. “In Europe if you’re a biosimilar, you’re a biosimilar—they don’t have a system for determining interchangeability. Here it’s built into the legislation, and I think the scary part [for companies] is this is a different hurdle, and a much higher hurdle.” Some companies have already sprinted ahead in the biosimilar approval marathon. Dr. Sherman said at the Feb. 9 news conference that agency officials had received 35 pre-Investigational New Drug (IND) inquiries and were reviewing nine INDs. An IND is the first step toward approval of a product. The agency’s goals for 2013 are to see BIOSIMILARS, page 28 

POLICY & MANAGEMENT

Clinical Oncology News • May 2012

Patient Care

Not at all familiar

High interest

36%

Slightly familiar

Moderate interest

19%

Somewhat familiar

10%

Need more information to make a decision

No interest

15%

Extremely familiar

35%

Low interest

23%

Moderately familiar

27%

15%

20%

25%

30%

35%

40%

Percentage of Respondents

Figure 2. Familiarity among physicians, nurses and pharmacists with biosimilars.a,b

26%

10%

15%

20%

25%

30%

35%

40%

Percentage of Respondents

Figure 3. Interest in prescribing FDA-approved biosimilars in clinical practice.a,b a

N=277.

From NCCN Trends Survey conducted March 10-11, 2011, at the 16th Annual NCCN Conference in Hollywood, Fla.

BIOSIMILARS continued from page 27 

“review and act on 70% of original biosimilar biological product application submissions within 10 months of receipt, and to review and act on 70% of resubmitted original biosimilar biological product applications within six months of receipt.” These percentages will be increased to 90% by 2017. None of the information submitted by companies in the approval pathway is publicly accessible except studies that have been published in peer-reviewed journals or presented at conferences. Companies are very likely following a similar sequence as in Europe, submitting applications first for smaller molecule biosimilars and later for monoclonal antibody biosimilars. Teva Pharmaceuticals anticipates that Phase II trials of its proposed rituximab biosimilar will be completed this year—putting it in a good position for application for biosimilarity status in Europe, where the patent-protection period for the reference product, Rituxan (Biogen Idec), expires in 2013. Since Rituxan’s patent protection ended in the United States in 2009, a biosimilar application by Teva to the FDA may also be in the foreseeable future.

Large Manufacturers at an Advantage Small companies for the most part will not participate in this potentially very lucrative market. This is because the regulations are onerous. Alternately, firms that already market or will soon market biosimilars in Europe or other countries such as Canada and Japan have a huge

head start. In fact, a number of large pharma and biotech companies are lining up to start the march toward manufacturing and selling biosimilars in the United States. Many are doing this by making linkages with muscular generic firms. For example, in December 2011 the large biotechnology company Amgen and U.S. generic manufacturer Watson Pharmaceuticals announced a worldwide collaboration for the development and commercialization of several as-yet-unspecified cancer antibody biosimilars. Biogen Idec and Samsung made a similar announcement that month. Pfizer, Merck and Novartis also intend to plunge into making biosimilars in the United States and elsewhere. This shift first took place in Europe. “I see now that almost every company [that makes reference products] has its own subsidiary producing biosimilars [for the European market],” said Arnold G. Vulto, PharmD, PhD, deputy head of hospital pharmacy at Erasmus University Medical Center in Rotterdam, The Netherlands. “So I think the landscape is going to change very rapidly in the U.S.— in Europe it’s already changed.” Dr. Vulto is co-creator of the Generics and Biosimilars Initiative (GaBI) and the Web site www.GaBIonline.net where he and other experts monitor biosimilarrelated developments around the world. Another observer of the biosimilarity field, Kristie C. Kuhl, JD, senior vice president at Makovsky + Company in New York City, also sees this as a significant sea change. “This is an interesting transformation for the industry,” said Ms. Kuhl. “Before, there were generics and there were innovators. And now we’re seeing

more of a confluence of the two. The large companies are pursuing both innovation and intellectual property that’s in the public domain and seeing what they can do with that.”

Survey: Interest in Biosimiliars Is High, but Understanding Is Lacking Meanwhile, clinicians and members of the public are anticipating that biosimilars will cut the cost of cancer care considerably. A survey of 277 health care professionals conducted by the National Comprehensive Cancer Network (NCCN) Work Group and presented at the NCCN’s 2011 annual conference indicated 66% had a high or moderate interest in biosimilars (Figures 1-3). Between 17% and 23% said they would use a biosimilar as soon as it was available, depending on the product, and 55% to 60% said they would require review and discussion before using a biosimilar. However, more than half were either not at all familiar or only slightly familiar with recent developments surrounding biosimilars, a fact that points to the necessity of education about these medications, according to the investigators. The NCCN Work Group also queried patients about their views of biosimilars. Clinicians can expect to hear from patients who want to be sure biosimilars are safe and effective and that the therapy they provide is as high quality as that of the reference products. Another survey by the pharmaceutical and biotech consulting firm Decision Resources showed that more than 50% of surveyed U.S. physicians would begin

prescribing a biosimilar epoetin within six months of its launch and 88% would start using it within a year. Ultimately, there are both similarities and differences between the European biosimilar market and the one unfolding in the United States. There are many unsettled regulatory questions; nevertheless large shifts already are occurring as a result of the imminent arrival of biosimilars. “I would think that the biggest thing we can ‘take to the bank’ is that biosimilar regulatory review and approval processes will be dramatically different from anything we’ve been accustomed to with generic drugs here in the U.S.,” said Dwight Kloth, PharmD, the director of pharmacy at Fox Chase Cancer Center in Philadelphia. “With generics, the issue is documenting that it is the same molecule, has the same purity, and if it’s a tablet, that dissolution rates are the same, the bioavailability of the compound is the same, and so forth. But if you’re talking about a delicate monoclonal antibody that’s produced by recombinant DNA technology and which can be denatured if it’s subjected to temperature extremes and where the biologic activity may be altered by seemingly minor differences in the manufacturing process, it’s a much more complicated question. Uncertainty always tends to make regulators worry and I think that’s a good thing.” —Rosemary Frei, MSc Drs. Bell, Kloth, Meibohn and Vulto, and Ms. Kuhl, do not have any conflicts of interest to disclose.

SOLID TUMORS

Clinical Oncology News • May 2012

Breast

First cycle G-CSF for high-risk chemotherapy …

EDITORIAL BOARD COMMENTARY

Of Course!

Steven Vogl, MD Medical Oncologist, New York City

Dawn Hershman, MD, of Columbia University in New York City, recently published an article in the Journal of Clinical Oncology noting the rapid uptake of dose-dense AC-Taxol (doxorubicin and cyclophosphamide followed by paclitaxel [ddAC-T]).1 Widespread use of ddAC-T followed the initial results of Cancer and Leukemia Group B (CALGB) study 9471 presented by Marc Citron, MD, at the 2002 annual meeting of the American Society of Clinical Oncology.2 Using the Surveillance, Epidemiology and End Results (SEER)-Medicare database, Dr. Hershman noted a concomitant rapid rise in the use of pegfilgrastim (Neulasta, Amgen) with the dose-dense regimen. Dr. Hershman also

benefit to adding paclitaxel to AC for women with HER2-negative, ER-positive tumors.5 The Oxford meta-analysis, to be fair, did show some benefit from taxanes in the ER-positive population. I am not writing to take up the question of dose-dense therapy for women with ER-positive tumors. The evidence is sufficiently weak that I would

when selecting patients for ddAC-T. It also suggests they were insufficiently vigilant in monitoring for toxicity with blood counts between cycles and in modifying doses based on early-cycle toxicity and changes in organ function that affect drug metabolism and performance status. In contrast to Dr. Hershman’s anal-

‘State-of-the-art patient care demands that when we give chemotherapy that is more than minimally myelosuppressive, we closely monitor the patient for toxicity and give supportive medications like G-CSF that render trips to the emergency department for febrile neutropenia a nightmare of the past.’

noted the uncertain benefits of dosedense therapy in women with estrogen receptor (ER)-positive tumors and noted that the adoption of first-cycle pegfilgrastim did not seem to decrease the high baseline rate of billings for febrile neutropenia over the period of 1999 to 2005.3 It remained 15% to 20% per patient—not per cycle. An accompanying editorial also noted the questionable benefit of dose-dense therapy in women with ER-positive tumors.4 Indeed, there is ample evidence to suggest that adjuvant anthracycline—rather than methotrexate—has little benefit in women with ER-positive, HER2-negative tumors and a large CALGB trial suggested there is no

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to gmiller@mcmahonmed.com

only consider reserving ddAC-T for the highest-risk ER-positive women—perhaps those with more than 10 involved nodes—who also are in sufficiently robust health to tolerate it. However, I am concerned that Dr. Hershman’s analysis of the lack of efficacy of pegfilgrastim in preventing hospitalization for febrile neutropenia will contribute to an ongoing movement to make it more difficult to give granulocyte colony-stimulating factor (G-CSF) therapy to fragile patients at high risk for neutropenia, fever and sepsis. In the past, high risk has been defined as more than 20% per cycle. I believe that a percycle risk of 2% to 3% is too high and warrants prophylactic G-CSF as well as great care in chemotherapy dosing and monitoring. My point is that if AC is given, be it every 2 or 3 weeks, to elderly or impaired patients, prophylactic G-CSF also should be given and patients should be carefully followed for toxicity. The treatment program should be modified to keep the toxicity acceptable; by my estimation that means a white blood cell count never less than 1,500 and a platelet count never less than 30,000. The persistent high hospitalization rate for febrile neutropenia reported by Dr. Hershman is unacceptable and suggests that the physicians giving the chemotherapy were insufficiently cautious

ysis of Medicare claims, Dr. Citron’s prospective CALGB trial reported a marked reduction in grade 3/4 neutropenia in the dose-dense arms that was clearly attributable to prophylactic G-CSF. However, probably less than 10% of the women in CALGB 9471 were older than age 65 years at entry, whereas nearly all of the women in Dr. Hershman’s analysis were older than 65, since they had Medicare. Further, only 25% of the 2,005 women in CALGB 9471 actually received ddAC-T. This means that only an estimated 50 women in CALGB 9471 over the age of 65 actually received ddAC-T. These 50 women were selected

chemotherapy population. I do not conclude that G-CSF does not ameliorate and shorten neutropenia and thereby prevent fever and infection. The problem is that sloppy physicians assume that G-CSF is so effective that they can send the patient home after fulldose AC or paclitaxel with no interval follow-up. Clearly, G-CSF is not that effective! In my practice I warn every patient who gets chemotherapy of the associated risks, including febrile neutropenia, septic shock and death. Part of the pact I make with each patient is that I will do everything possible to reduce these risks and to keep the patient out of the emergency department and hospital. I reassure each patient that the rate of success is greater than 99% in my hands. Emergency departments are to be avoided. They are crowded; plagued by long waiting times for care and systemic antibiotics; and staffed by non-oncologists who have little patience with complicated histories, who wait for blood and radiologic test results before taking action, who cannot be reached by phone, and who “hand off ” cases with three-line histories to the next shift’s physician. I believe hospitals also should be avoided because of the frequency of resistant bacteria and nosocomial infections; because restrictions on house staff duty hours have left the care of many patients in the hands of “moonlighters” and physician assistants of variable experience and training; and because, despite Joint Commission efforts, there still are high rates of medication and other errors during the hos-

‘The problem is that sloppy physicians assume that G-CSF is so effective that they can send the patient home after full dose AC or paclitaxel with no interval follow-up.’ by protocol entry criteria—organ function, prior cancer, blood counts and performance status—as well as by their physicians to be among the healthiest cancer-bearing elderly. The women in Dr. Hershman’s analysis were not. I conclude from the data reported by Dr. Hershman that there is indeed a problem with febrile neutropenia in the Medicare adjuvant breast

pital stays of complicated patients. It is far better, and probably cheaper, to keep the patient out of the hospital and the emergency department. Is it possible to judiciously use G-CSF and dose modification to prevent neutropenia, febrile neutropenia, emergency room visits and hospitalizations? It is! In my practice, I went from admitting see FIRST CYCLE, page 30 

SOLID TUMORS

Clinical Oncology News • May 2012

Breast

FIRST CYCLE continued from page 29 

more than 750 patients annually in the mid-1980s—a substantial portion for the management of toxicity—to less than a dozen annually in the past decade, with febrile neutropenia being much less of a problem than toxic diarrhea. That G-CSF and pegfilgrastim are expensive does not mean that we should not give them. I suggest that the United States, as well as the European Union, make a strong effort to find a way to make G-CSF cheaper and thus more widely available. In my professional lifetime, the administration of chemotherapy has gone from a terrible subjective experience for the patient—often punctuated by hospitalizations for life-threatening toxicity—to an entirely office-based experience with mild subjective toxicity. We owe it to our patients to zealously guard what we have achieved for them. In my practice I routinely use G-CSF for all but the mildest chemotherapy (CMF [cyclophosphamide, methotrexate and fluorouracil] and fluorouracil and single-agent pegylated liposomal doxorubicin being examples of chemotherapy with very little

myelosuppression). I prefer daily injections of G-CSF to long-acting pegfilgrastim because the former allow me to adjust doses to avoid a very high white blood cell count and pain from bone marrow expansion. I tailor the dose and duration of G-CSF based on the patient’s inter-cycle blood counts. If a patient receiving adjuvant chemotherapy for breast cancer has a white blood cell count below 1,000 for more than a day or two, I consider modifying the doses for the next cycle. Large interpatient heterogeneity has been reported for the metabolism of both doxorubicin and cyclophosphamide, each of which is metabolized in the liver; the latter is also activated in the liver. There is no good reason to assume that the “standard dose” based on height and weight is the best dose for a given patient. Dose modifications should not be taken lightly, especially when “cure” is possible. A quantitative estimate of the risks associated with continuing a known toxic dose should be weighed against the evidence of how a slightly reduced dose— often 10% to 5% will make a big difference—will adversely and substantially affect the outcome. In her current paper, Dr. Hershman cites an earlier study by her group in which Medicare beneficiaries receiving

adjuvant chemotherapy for breast cancer had higher rates of acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) if they received G-CSF. Claims–based analyses like these are unable to account for variations in bone marrow function; host drug metabolism and host marrow toxicity, which often correlate; and prior treatment of the host with myelotoxic and leukemogenic therapies. In a similar analysis by Roy Smith, MD, a professor of medicine at the University of Pittsburgh, of a National Surgical Adjuvant Breast and Bowel Project trial that employed very high-dose cyclophosphamide in double or quadruple doses, the risk for AML/MDS correlated with G-CSF dosage.6 The G-CSF dosage, however, could not be separated from the efficacy and toxicity of the high-dose cyclophosphamide. There is still no convincing evidence that G-CSF causes AML/MDS except to the extent that it allows safe administration—in the short term—of higher doses of drugs that do cause AML/MDS. State-of-the-art patient care demands that when we give chemotherapy that is more than minimally myelosuppressive, we closely monitor the patient for toxicity and give supportive medications like G-CSF that render trips to the

emergency department for febrile neutropenia a nightmare of the past.

References 1. Hershman DL, Wilde ET, Wright JD, et al. Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer. J Clin Oncol. 2012;30:806-812, PMID: 22312106. 2. Citron M, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439, PMID: 12668651. 3. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. 2006;295:1658-1667, PMID: 16609087. 4. Hillner, BE. Wiser use of dose-dense adjuvant therapy in breast cancer. J Clin Oncol. 2012;30:772-774, PMID: 22312107. 5. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in nodepositive breast cancer. N Engl J Med. 2007;357:1496-14506, PMID: 17928597. 6. Smith RE, Bryant J, DeCillis A, et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21:1195-1204, PMID: 12663705.

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