August 2011 Clinical Oncology Digital Edition

Independent News on Advances in Cancer Care

Oncology Edition clinicaloncology.com • August 2011 • Vol. 6, No. 8

SOLID TUMORS

6

A look at what happened at the FDA Avastin meeting.

8

Pazopanib improves progressionfree survival in advanced sarcoma.

22

Colon cancer study leads to surprising finding about KRAS mutations.

PRN

12

Clinical Conundrums: a quiz for the community oncologist.

16

News from recently published journal studies.

HematOlogic DISEASE

26

S teven Vogl, MD, discusses where we are in treating large B-cell lymphoma.

CLINICAL TRIALS

30

Recently launched Phase II and Phase III clinical trials.

EDUCATIONAL REVIEW

Metastatic Castration-Resistant Prostate Cancer Between pages 16 and 17.

Evidence Builds for Use of Abiraterone in Prostate Cancer

Mixed News on PARP Inhibitors Presented at ASCO Meeting

New Agent Treats Bone Metastases and Improves Survival Chicago—Abiraterone acetate not only improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC), but it also doubles the time to skeletal-related events (SREs).

This news comes from results of the updated Phase III COU-AA-301 trial. The study revealed that abiraterone (Zytiga, Centocor Ortho Biotech) provided a highly statistically significant 3.5-month increase (P<0.001) in overall survival (OS) in patients with mCRPC see ABIRATERONE, page 9 

EDITORIAL BOARD COMMENTARY

The Concept of ‘Unrealistic Optimism’ In Early-Phase Trials

O

ncologists may not be fully aware of a relatively new term introduced by ethicists to describe certain patients who agree to participate in early-phase canMaurie cer clinical trials. Some researchers believe that Markman, MD these individuals express unrealistic optimism, which apparently means that despite understanding the limited statistical probability of experiencing clinical benefit from a particular management plan, they have a strong belief see ‘UNREALISTIC’, page 14 

A pathological specimen of ovarian carcinoma and model of PARP1.

Chicago—The results of several new trials of different PARP inhibitor drugs for treatment of ovarian cancer and breast cancer were reported at the recent annual meeting of the American Society for Clinical Oncology. In some cases, experts called the results “exciting,” and in others, “disappointing.” see PARP, page 5 

POLICY & MANAGEMENT

Consolidation: Is It Really What It Looks Like?

R

eimbursement continues to decline and providers are looking at options for their future. Consolidation is one option that is being driven by several factors.

Declining reimbursement means small independent physician groups can’t survive. And small hospitals are losing money on operations. So, hospitals are merging, practices are merging, and hospitals and practices are merging with each other— all to create economies of scale. Another

driver of consolidation is the changing perspective of physicians about owning their practice. The growing base of younger physicians overwhelmingly is looking for employment and has no interest in ownership. This population is shaping state lobbying groups to their interests, see CONSOLIDATION, page 29 

WWW.CMEZONE.COM

McMahonMedicalBooks.com DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology

FDA News

Vincent T. DeVita, Steven A. Rosenberg, Theodore S. Lawrence

Lazanda (Archimedes) approved for breakthrough cancer pain.

For more information, see page 32.

See page 25.

COMING SOON

ADCETRIS and the ADCETRIS logo are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. Š 2011 Seattle Genetics, Inc., Bothell, WA 98021. All rights reserved.

Printed in USA

05/11

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • August 2011

EDITORIAL BOARD

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

Breast Cancer

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

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

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

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

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

Harry Erba, MD, PhD University of Michigan Ann Arbor, MI

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung, and Head and Neck Cancers

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

Oncology Nursing

Paul J. Ford, PhD

Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

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

Policy and Management

Pharmacy

Mary Lou Bowers, MBA Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

The Pritchard Group Rockville, MD

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. 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.

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

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

Cleveland State University Cleveland, OH

Mercy Medical Center St. Louis, MO

University of Texas, MD Anderson Cancer Center Houston, TX

Richard J. Gralla, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

John W. Finnie, MD

Edward S. Kim, MD

Lung Cancer, Emesis

Susan K. Seo, MD

Community Oncology

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

Bioethics

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

Genitourinary Cancer Ronald M. Bukowski, MD

Infection Control

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

McMahon Publishing is a 38-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.

Charles F. von Gunten, MD

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved.

University of California, San Diego, CA

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

3

4

SOLID TUMORS

Clinical Oncology News • August 2011

Neuroblastoma

New Standard Emerges for High-Risk Neuroblastoma Chicago— Busulphan combined with melphalan (BuMel) significantly increased eventfree survival (EFS) during a large multicenter Phase III trial of patients with high-risk neuroblastoma, leading the authors of the study to suggest that BuMel should be a new treatment standard.

Compared with a combination of carboplatin, etoposide and melphalan (CEM), BuMel was superior for EFS, the primary end point, and with respect to the proportion of patients alive at three years. Additionally, “the acute myeloablative toxicity profile favored the BuMel regimen,” reported investigator Ruth Ladenstein, MD, from St. Anna Children’s Hospital and Research Institute, in Vienna. The superiority of the experimental myeloablative regimen led the investigators to prematurely stop the trial, called HR-NBL1/SIOPEN (European

Neuroblastoma Group of the International Society for Paediatric Oncology).

Presenting the results at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 2), Dr. Ladenstein noted that the superior efficacy of BuMel was consistent across disease stages, including stage 4.

The trial randomized 563 patients over the age of 1 year at diagnosis who had high-risk neuroblastoma, defined by such characteristics as stage 4 disease or stage 2 or 3 disease with myc myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) amplification. For entry and prior to randomization, patients had to have achieved complete cytomorphologic bone marrow remission, with no more than three metaiodobenzylguanidine-positive spots after receiving a rapid induction of cisplatin, vincristine, carboplatin, etoposide and cyclophosphamide (COJEC) with or without two courses of topotecan, vincristine and doxorubicin. The median age at randomization was 3 years.

The CEM regimen, a previously described standard, was modified if the glomerular filtration rate fell below 100 mL/min/1.73m2. The BuMel regimen initially included oral busulphan (four doses of 150 mg/m2), but it was switched to an infusion of comparable intensity (based on body weight) after 2006. Melphalan was administered in a dose of 140 mg/m2 per day.

An interim analysis demonstrated sufficiently significant differences in the three-year EFS that the Data and Safety Monitoring Committee recommended that the trial be closed prematurely.

EFS was superior for BuMel whether patients were randomized before or after 2006 (50% vs. 35%; P=0.034 and 47% vs.

in the CEM group (P=0.012). When compared for specific grade 3 and 4 toxicities, veno-occlusive disease was more common in the BuMel group (18% vs. 4%), but almost all other specific types of adverse effects—including infections, fever, stomatitis, nausea and vomiting, and renal toxicity—were more common in the CEM

Table. Event-free Survival BuMel Randomized Before 2006

CEM

P Value

BuMel Randomized After 2006

CEM

P Value

50%

35%

0.034

47%

31%

0.002

(COG) ( J Clin Oncol 2008;26: Abstract 10011 and N Engl J Med 2010;363:13241334). The EFS rates for CEM in the COG studies were substantially higher and similar to that achieved on the BuMel arm in the SIOPEN trial. Noting that there were different induction regimens used in COG (modified Memorial Sloan-Kettering regimen) and SIOPEN studies (rapid COJEC), Dr. Park questioned whether the SIOPEN induction regimen may have negatively influenced the outcome for those patients who received CEM. Although there are many problems with cross-trial comparisons, Dr. Park emphasized that the results of SIOPEN show BuMel to be superior to CEM in the context of rapid COJEC induction but that these results may not be applicable to the current COG treatment regimens.

Although the discrepancies between studies complicate the effort to declare a standard regimen, Dr. Park said that the

An interim analysis demonstrated sufficiently significant differences in the three-year EFS that the Data and Safety Monitoring Committee recommended the trial be closed prematurely.

Microscopic view of a typical neuroblastoma with rosette formation.

31%; P=0.002, respectively) (Table). The overall survival (OS) at three years was 61% vs. 48%; P=0.003) for the BuMel and CEM groups, respectively.

“The primary basis for the superiority of the BuMel regimen was a lower relapse rate,” reported Dr. Ladenstein, who noted that the advantage of BuMel over CEM was most apparent in patients who entered the study with residual disease.

BuMel was also relatively well tolerated, with a lower rate of severe toxicity in the first 100 days after treatment initiation–4% in the BuMel group versus 10%

group. Fewer acute toxic deaths occurred in patients taking BuMel than in those taking CEM (3% vs. 5%).

The ASCO-invited discussant, Julie R. Park, MD, Hematology and Oncology Division, University of Washington School of Medicine, Seattle, generally agreed with the conclusions of the SIOPEN investigators, but she noted a discrepancy between the EFS rates following CEM as delivered in the SIOPEN trial compared with the most recently completed clinical trials with this regimen by the Children’s Oncology Group

SIOPEN trial data “confirm the importance of myeloablative consolidation” in patients with high-risk neuroblastoma, even as she indicated that all steps of treatment, including the induction regimen, need further refinement to improve rates of cure. Despite very encouraging cure rates in other forms of neuroblastoma, trials in high-risk forms, which account for about 50% of cases, are still focused on improving EFS rates at three years, whereas the real goal is improving OS rates at five years and beyond.

—Ted Bosworth Drs. Ladenstein and Park have no relevant disclosures.

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

SOLID TUMORS

Clinical Oncology News • August 2011

5

Breast

continued from page 1 

By far the most encouraging results came from a Phase II, randomized, placebo-controlled study of AstraZeneca’s olaparib in 265 women with relapsed, platinum-sensitive serous ovarian cancer with and without BRCA1/2 mutations (abstract 5003). Patients were randomized to the investigational oral PARP (poly [ADP-ribose] polymerase) inhibitor or placebo. Patients receiving olaparib almost doubled their progressionfree survival (PFS): 8.4 compared with 4.3 months in those taking placebo. This translated to a 65% reduction in the hazard ratio (HR, 0.35; P<0.00001).

Although adverse events were more common with the PARP inhibitor—nausea being the most common—overall tolerability was good, according to lead investigator Jonathan Ledermann, MD, consultant in medical oncology at University College London Hospitals, and professor of medical oncology at University College London.

Barbara Goff, MD, director of gynecologic oncology at the University of Washington and the Seattle Cancer Care Alliance, was delighted by the results. “What was exciting to me is that the women in this study didn’t necessarily have BRCA mutations. They had high-grade serous tumors and were platinum-sensitive—two things that we have thought would signal response to PARP inhibitors,” she said.

Dr. Goff noted that there has long been a need for a targeted agent to use as maintenance therapy in patients with recurrent ovarian cancer. “Most women with advanced-stage ovarian cancer are going to recur, so to have agents that can keep people from progressing and developing symptoms is important,” she said. “Until recently, all we’ve had is bevacizumab [Avastin, Genentech], but it’s expensive, and there are significant toxicities.

These results open up an oral alternative as a maintenance therapy that is relatively nontoxic.” (Bevacizumab is not approved yet for ovarian cancer, but some doctors have been using it off label.)

Some studies have examined the use of paclitaxel as a maintenance therapy for ovarian cancer, and it has been found to improve PFS but not overall survival (OS). And paclitaxel, too, is associated with significant toxicities—including hair loss and neuropathy—and requires monthly infusions. “Who wants to be coming in and getting cytotoxic chemotherapy once a month?” Dr. Goff asked.

“Ovarian cancer is often a chronic disease, so we need to find agents that keep the disease from growing and are relatively nontoxic. Olaparib looks like it could be one of those agents.”

The news from a Phase III trial of a different PARP inhibitor, iniparib, in metastatic triple-negative breast cancer

“The olaparib data, this single-agent maintenance trial, really opens up the field … This is major, exciting news.”

—Ursula Matulonis, MD

(TNBC), was not nearly so encouraging.

Despite promising results in the Phase II setting reported earlier this year (N Engl J Med 2011;364:205-214, PMID: 21208101), a Phase III trial showed the drug yielded only a one-month improvement in PFS that was not statistically significant (abstract 1007). (The study was supported by BiPar Sciences, now owned

by Sanofi-aventis.)

The trial involved 519 women, each treated with two or fewer regimens for metastatic disease. All patients received gemcitabine and carboplatin and were randomized to iniparib or placebo.

Patients in the iniparib arm had a median PFS of 5.1 months, compared with 4.1 months in the placebo group (P=0.027).

Median OS was 11.8 months in patients on iniparib and 11.1 months in the placebo arm (P=0.28).

“These results were definitely disappointing,” said Julie Gralow, MD, director of breast medical oncology at the University of Washington and the Seattle Cancer Care Alliance. “This shows you why we do Phase III trials.”

But the results do not necessarily mean that PARP inhibitors don’t work in TNBC. “We can say that iniparib doesn’t work in this particular setting,” said Alex Adjei, MD, PhD, professor and chair of the Department of Medicine and senior vice president for clinical research at Roswell Park Cancer Institute, in Buffalo, N.Y. “There are two issues that both may be playing a part here. First, the really promising data with the PARP inhibitors that we have had was really in patients with

Placebo Olaparib

10

8.4

8

PFS, mo

PARP

6 4.3

4 2 0

Figure. PFS in patients with platinum-sensitive ovarian cancer.

BRCA1/2 mutations. In this trial, they tried to broaden this idea a little bit into triple-negative, and said that these cancers are sort of like BRCA1 cancers, but that’s not necessarily so.” Some TNBC patients may be similar to BRCA1 patients, while others may not have the DNA deficiencies associated with the PARP inhibitor response.

In her talk, lead investigator of the study, Joyce O’Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research, Baylor Sammons Cancer Center, and co-chair, Breast Cancer Research, US Oncology, both in Dallas, also pointed out that iniparib might not be a true PARP inhibitor. Indeed, as Robert Nagourney, MD, medical and laboratory director at Rational Therapeutics, in Long Beach, Calif., pointed out in his blog, a full dose of a true PARP inhibitor combined with carboplatin and gemcitabine would likely yield intolerable toxicities.

The Phase I results, in retrospect, provide a clue to this, noted Dr. Adjei. “This is a drug where the single-agent Phase I study was really benign. There were virtually no toxicities. To reach their highest tolerable dose, they had to use pharmacokinetics because there were so few toxicities. That’s very unusual.”

Dr. Gralow agreed.

“We need to separate iniparib out from the other drugs that are true PARP inhibitors,” he said. “Iniparib definitely has inhibition Scan for abstract of DNA repair, a minor 5003. See page 8. part of which is PARP. We didn’t understand that even a couple of years ago. We have to be careful about what we say this drug does.”

More work needs to be done in TNBC to determine if there is a population of patients who will respond to a PARP inhibitor that has true PARP inhibition at physiologic doses. “Is there a subpopulation in triple-negative that will have single-agent responses? Or do you have to augment their activity with either chemo or other targeted therapies aimed at other pathways besides DNA repair?” asked Ursula Matulonis, MD, director and program leader of medical gynecologic oncology at DanaFarber Cancer Institute, in Boston. “All this is still unknown.”

Dr. Gralow drew parallels with the groundbreaking targeted breast cancer agent trastuzumab (Herceptin, Genentech). “If you look at the modeling, if we’d tested trastuzumab in the general breast cancer population, even though 20% to 25% of women with breast cancer express HER2, it never would have shown a benefit.”

According to Dr. Matulonis, the olaparib results in ovarian cancer should be getting much more attention. “To date, the ability of a true PARP inhibitor to shrink tumors and kill cancer cells has been shown predominantly in germline BRCA carriers,” she said. “The olaparib data, this single-agent maintenance trial, really opens up the field to say that we can use these drugs not only in women with BRCA mutations, but in those with highgrade serous mutations regardless of if they have the [BRCA] mutations as well.

This is major, exciting news.”

—Gina Shaw

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

Beginning with this issue and continuing on a monthly basis, Clinical Oncology News will highlight key studies from the journals to help you stay up to date.

We hope you find this a useful tool.

See pages 16, 17, 24 and 28.

SOLID TUMORS

Clinical Oncology News • August 2011

Breast

What Happened at the FDA Avastin Meeting?

In late June, the FDA’s Oncologic Drugs Advisory Committee (ODAC) gave a unanimous thumbs down to bevacizumab’s metastatic breast cancer (MBC) indication.

The vote followed a two-day hearing in which patients, doctors, Genentech representatives and FDA officials offered testimony as to whether the MBC indication for bevacizumab (Avastin, Genentech) should be removed or left intact.

Patients, some breaking into tears during their testimony, gave impassioned speeches as to the benefits of the drug. FDA and Genentech representatives presented copious slides discussing progression-free survival (PFS) and overall survival (OS) benefits in various trials.

At the end of the two-day hearing, the ODAC was asked to vote on several convolutedly written questions. 1) Do the AVADO and RIBBON trials fail to verify the clinical benefit of Avastin for the breast cancer indication for which it was approved? 2a) Does the available evidence on Avastin demonstrate that the drug has not been shown to be safe for the breast cancer indication for which it was approved? 2b) Does the available evidence on Avastin demonstrate that the drug has not been shown to be safe for the breast cancer indication for which it was approved, in that Avastin has not been shown to present a clinical benefit that justifies the risks associated with use of the product for this indication? The ODAC was unanimous in voting yes on all three questions.

The ODAC also voted on a fourth question: If the commissioner agrees with the grounds for withdrawal set out in issue 1, issue 2a or issue 2b, should the FDA nevertheless continue the approval of the breast cancer indication while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit? The committee unanimously voted no.

“I think what it gets down to here is that if we don’t think it’s effective, then we can’t tolerate any toxicity from it,” said ODAC member Frank Balis, MD, director of oncology research at the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia.

To date, no trial has shown that bevacizumab improves OS in MBC. Although the committee members admitted that the 5.5-month improvement in PFS seen in the E2100 trial was impressive, they thought this result represented a “random high” because data from five well-controlled trials (seven comparisons), did not show anywhere near this magnitude of benefit (Figure).

They also pointed out that there were no data showing that the drug improved

quality of life, so the value of increased PFS was unclear.

Additionally, data from a recent Phase II study did not bolster Genentech’s case.

In this trial, 282 patients with untreated HER2-negative MBC were randomly assigned in a 1:1:1 ratio to paclitaxel plus either motesanib (Amgen), placebo or bevacizumab. The overall response rate (ORR) in the bevacizumab group was similar to that in the motesanib group, which did not differ significantly from the placebo group (Lancet Oncol 2011;12:360-376, PMID: 21429799).

“I think the label should reflect the current understanding of the benefit– risk profile and that benefit–risk profile is not favorable right now,” said ODAC member Brent Logan, PhD, associate professor of biostatistics at the Medical College of Wisconsin, in Milwaukee. Although ODAC members agreed that the drug’s safety profile has not changed, they argued that the risks were acceptable in cancers such as colon cancer because the benefits outweighed the risks, but this wasn’t the case with MBC. In MBC, the limited effects on PFS and ORR do not outweigh the serious and potentially fatal risks, such as hemorrhage or gastrointestinal perforation, or ongoing risks for new or worsening hypertension or for glomerular injury manifesting as proteinuria, argued the members.

Among the many arguments that Genentech put forth in favor of keeping the breast cancer indication was that AVADO and RIBBON-1 merely suggest that bevacizumab’s therapeutic impact may vary depending on its chemotherapy partner. Genentech representatives proposed launching a doubleblind, randomized trial that incorporates a biomarker component to identify patients more likely to derive benefit from the bevacizumab-paclitaxel combination. Enrollment for this Phase III trial would begin in 2012, they said, with an interim analysis at 3.5 years to determine futility, and a final analysis at roughly 4.5 years. They asked that the breast cancer indication be maintained in the meantime.

The company argued that drugs that have been approved for MBC do not meet the standard that the FDA is using for bevacizumab. The agency has accepted PFS and time-to-progression (TTP) end points as the basis for drug approvals in MBC without requiring a demonstration of OS benefit. Gemcitabine, argued Genentech, in particular does not meet the criteria that the FDA is now setting forth. Gemcitabine was approved based on TTP data, and mature data showed that the drug’s effect on OS was not statistically significant. The company also argued that detecting improvements in OS in the first-line setting of MBC is difficult, because subsequent lines of therapy may obscure the effect of a treatment tested in a clinical trial.

At the meeting, Lee Pai-Scherf, MD, medical officer, Office of Oncology

‘There is nothing we can hang our hat on in these studies that would make me feel comfortable continuing to expose a lot of patients to risk without a clear benefit.’

—Michael Skeres, MD

6 5

PFS, mo

6

4 3 2 1 0 E2100

AVADO 7.5

AVADO 15.0

RIBBON 1 T/A

RIBBON 1 Cap

AVF2119g

Trial

Figure. Absolute difference in median PFS for all trials.

RIBBON2

Drug Products, FDA’s Center for Drug Evaluation and Research, shared several concerns that the E2100 study had shortcomings and inconsistencies such as missing scans and data. Genentech pointed out that in the FDA’s 2007 medical review of lapatinib (Tykerb, GlaxoSmithKline), the missing rate of scans was 10%, exactly the same as in the E2100 trial.

Patricia Keegan, MD, director of the Division of Biologic Oncology Products at FDA’s Office of Oncology Drug Products, said that Genentech had not supplied any evidence that Avastin’s efficacy depends on the chemotherapy partner or duration of therapy. They had not provided data on the synergism between bevacizumab and paclitaxel, pharmacokinetic interactions between bevacizumab and other chemotherapies, or antagonism between bevacizumab and other chemotherapies.

Most of the patients and doctors who presented public testimony spoke in favor of keeping the drug available for patients with MBC, but a handful spoke in support of the indication’s withdrawal. “[The drug] does not extend life,” testified Christine Brunswick of the National Breast Cancer Coalition.

“The drug does raise false expectations and does detract from focusing on other research that may produce effective and lifesaving drugs.” At times, emotions ran high. Kimberly Jewitt, a breast cancer survivor who testified after Ms. Brunswick, stepped to the podium enraged. “I am completely disgusted to have to follow something like that,” said Ms. Jewitt, and then went on to testify as to how the drug benefited her.

Joyce O’Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research, Baylor Sammons Cancer Center, and co-chair, Breast Cancer Research, US Oncology, both in Dallas, testified in favor of keeping the indication. “I call on the FDA to work with the sponsor to keep Avastin/paclitaxel available as an approved option, even by limiting the indication to patients with metastatic triple-negative and aggressive ER [estrogen receptor]-positive breast cancer whom their oncologists believe need combination therapy, while the confirmatory trial is being done,” she said. Dr. O’Shaughnessy, a paid consultant for Genentech, pointed out that triple-negative MBC is highly symptomatic with a median survival of 12 to 18 months and has few known effective treatment options. A pooled analysis of first-line MBC trials showed a median PFS difference of 2.7 months with a hazard ratio of 0.63.

Although a couple of ODAC members appeared to be possibly leaning toward an affirmative answer to the last

SOLID TUMORS

Clinical Oncology News • August 2011

Breast

question—keeping the indication intact until a new trial was completed—in the end they voted unanimously to pull the indication. “It’s very difficult in the absence of clear information that indicates that a subset of patients is benefiting. Intuitively, one might think patients with bulky disease and symptoms would be most likely to benefit, [but] maybe they would do worse because they would have the disease plus the serious adverse events to deal with,” said ODAC member Ralph Freedman, MD, PhD, clinical professor in the Department of Gynecologic Oncology at the University of Texas, Houston. “The agency has to look at protecting a larger number of patients.

Sometimes they have to make a decision that doesn’t favor individual patients, but is on the basis of a whole.”

ODAC member Michael Skeres, MD, seemed a bit more pessimistic about finding a subgroup in which the drug worked. “We tried to slice this pie in

lot of different ways, to try to find some kind of benefit for this drug in combination with chemotherapy for a desperate breast cancer population,” he said. “No matter which way we look at it … looking for data about subgroups, all we are left with are crumbs. There is nothing we can hang our hat on in these studies that would make me feel comfortable continuing to expose a lot of patients to risk without a clear benefit.” Dr. Skeres is associate professor of medicine in the Department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic Taussig Cancer Institute, in Ohio.

Executive vice president of Genentech, Hal Barron, MD, said the company will proceed with the Phase III trial they planned whether or not the FDA follows the advice of ODAC and withdraws the breast cancer indication. ODAC member Wyndham Wilson, MD, PhD, chief of the Lymphoma Therapeutics Section at the National Cancer Institute, encouraged the company “to do this follow-up trial as quickly as possible.”

At press time, the FDA had not announced whether it would follow ODAC’s advice.

—Kate O’Rourke

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A Randomized Phase II Trial for Newly Diagnosed Glioblastoma Patients: Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized, multicenter, open-label, controlled, phase II study investigating two cilengitide regimens in combination with standard treatment (TMZ with concomitant RT, followed by TMZ) versus standard therapy alone MAIN INCLUSION CRITERIA Newly diagnosed supratentorial glioblastoma (WHO grade IV) Unmethylated MGMT gene promoter status ECOG PS 0-1 Baseline Gd-MRI Stable or decreasing dose of steroids (for 5 days)

Mark Neufeld, Associate Director, Project Management

McMahon Publishing Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

MAIN EXCLUSION CRITERIA Prior anti-angiogenic therapy Investigational agents within 30 days Chemotherapy within 5 years Prior cranial radiotherapy Placement of Gliadel® wafer Significant hepatic or renal impairment Coagulation disorder, myocardial insufficiency, peptic ulcer or another malignancy

MGMT: O6-methylguanine–DNA methyltransferase; RT: radiotherapy; TMZ: temozolomide Cilengitide (EMD 121974) currently is under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proved to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the CORE trial Please call 1-800-507-5284 or refer to ClinicalTrials.gov for more information (http://www.clinicaltrials.gov/ct2/show/NCT00813943) The CORE study is in collaboration with the Canadian Brain Tumour Consortium (CBTC).

101108 - 115024

7

SOLID TUMORS

Clinical Oncology News • August 2011

Sarcoma

Pazopanib Improves PFS in Advanced Sarcoma Chicago—Pazopanib increased progression-free survival (PFS) by about three months in treatment-experienced patients with advanced soft tissue sarcoma, at the interim analysis of a multinational Phase III study. The improvement in PFS, the primary end point, was accompanied by a promising but nonsignificant improvement in overall survival (OS).

“After decades of chemotherapy, we now have a new drug in soft tissue sarcoma with an important benefit not restricted to a rare subtype,” said Winette van der Graaf, MD, head of the Department of Medical Oncology, Radboud University Medical Center, in Nijmegen, The Netherlands. Providing these data in a latebreaker presentation at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO), Dr. van der Graaf reported that the almost threefold increase in PFS in patients on this agent was accompanied by “manageable” adverse events (LBA10002).

Based on the study, GlaxoSmithKline, the maker of pazopanib (Votrient), has submitted a new drug application to the FDA to expand the drug’s indications.

In the study, 369 patients with advanced and progressive soft tissue sarcoma were randomized to 800 mg of pazopanib or placebo once daily. Pazopanib is a multikinase inhibitor of several angiogenic pathways, including those involving vascular endothelial growth factor, plateletderived growth factor and c-Kit. Although no previous exposure to anti-angiogenesis therapies was permitted, patients had taken up to four lines of chemotherapy. Prior exposure to anthracyclines was an entry criterion. Patients were also required to be older than 18 years and have a performance status of 0 or 1.

The most common soft tissue sarcomas treated in this study were leiomyosarcoma (41%) and synovial sarcoma (11%), but a wide range of rarer types, such as fibroblastic and fibrohistiocytic sarcomas were represented. The trial excluded patients with certain sarcomas, including adipocytic malignancies, Ewing sarcoma, osteosarcoma, gastrointestinal stromal tumors and mesotheliomas.

After a median follow-up of 15 months, the improvement in median PFS in patients on pazopanib compared with placebo was approximately three months (4.6 vs. 1.5 months), yielding a hazard ratio (HR) of 0.31 (95% confidence interval [CI], 0.24-0.40; P<0.0001) (Figure).

When patients were stratified by those with leiomyosarcomas, synovial sarcomas or other types of sarcomas, the relative advantage of pazopanib for PFS remained consistent. The median OS was improved by approximately 1.5 months (11.9 vs. 10.4), but the HR of 0.88 has not reached statistical significance in followup to date (P=0.1782).

Clinical benefits were largely driven by pazopanib’s ability to cause stabilization

of disease. Although the only partial responses occurred in the pazopanib arm (6% vs. 0%) and there were no complete responses in either arm, 67% of those receiving pazopanib compared with 38% of those randomized to placebo achieved stable disease. Treatment duration was twice as long in patients receiving pazopanib as in those receiving placebo (16.4 vs. 8.1 weeks). Although dose reductions were required in 37% of those randomized to pazopanib, the dose intensity in this arm still reached 96.3%.

Therapy was halted because of disease progression in 70% of patients receiving pazopanib compared with 90% of those receiving placebo, and treatment was stopped because of toxicity in 14% and 1% of patients, respectively.

in pazopanib-treated patients included diarrhea (5% vs. 1%) and hypertension (7% vs. 3%). Weight loss of any grade was also common in both groups, but more so in the pazopanib group (48% vs. 20%).

Cardiovascular function was monitored closely, and although rates were higher with pazopanib (10% vs. 5%), the depression in left ventricular ejection fraction (LVEF) in patients receiving pazopanib was generally reversible after therapy discontinuation. Pazopanib was also associated with higher rates of venous thromboembolism (7% vs. 3%) and pneumothorax (3% vs. none), with the latter thought to occur as a result of necrosis of pleural lesions.

After patients left the study, subsequent treatments were common,

‘After decades of chemotherapy, we now have a new drug in soft tissue sarcoma with an important benefit not restricted to a rare subtype.’

—Winette van der Graaf, MD

Fatigue was the most common side effect in both arms of the study, reported by 65% of those receiving pazopanib and 49% of those receiving placebo. Grade 3 or higher fatigue was substantially more common for those receiving pazopanib (17% vs. 6%). Other grade 3 or higher adverse events that were more common

including radiotherapy, surgery and novel agents, such as sorafenib (Nexavar, Bayer). These treatments may have obscured the OS benefit of pazopanib in follow-up so far, but survival data are incomplete. The investigators did not present data on quality of life.

The ASCO-invited discussant,

Placebo Pazopanib

5

4.6

4

Survival, mo

8

3 2

1.5

1 0

Figure. Median progression-free survival in advanced sarcoma.

Shreyaskumar Patel, MD, medical director of the Sarcoma Center, University of Texas MD Anderson Cancer Center, in Houston, pointed out that the study has many strengths, including its size, and the data show that pazopanib “clearly has a defined level of efficacy” that might be clinically meaningful to both patients and physicians. Nevertheless, Dr. Patel said that it is not yet clear whether pazopanib is superior to other drugs in the same class, such as brivanib (Bristol-Myers Squibb), which also improved PFS significantly in a multicenter trial presented in the same session as pazopanib (abstract 1000). This trial, conducted in 251 heavily pretreated sarcoma patients with unresectable malignancies, was also promising, although it was a Phase II investigation. However, Dr. Patel indicated that there are numerous other novel therapies being evaluated for sarcoma. He cautioned that one reason an improvement in OS has not yet been seen with pazopanib could be that 45% of patients had only one line of previous therapy, permitting subsequent regimens to dilute any survival advantage that might have been seen in a population with more advanced disease.

—Ted Bosworth Drs. van der Graaf and Patel report no relevant conflicts of interest. The study was sponsored by GlaxoSmithKline.

Look for 2-D Bar Codes in ClinOnc 1. Get the FREE Microsoft Tag Reader application through your smartphone browser by going to http://gettag.mobi and follow the steps to download.

(There may be a charge from your wireless provider for the data services.)

our educational review on:

2. Open the Tag Reader and find the ClinOnc bar-code image in this publication.

Soft Tissue Sarcomas of the Extremities and Trunk: A Comprehensive Review

3. Let the Tag Reader focus on the bar-code image to instantly access related materials and/or Web sites.

…. in the September issue.

SOLID TUMORS

Clinical Oncology News • August 2011

Prostate

ABIRATERONE

Placebo Abiraterone

continued from page 1 

P=0.0006

301

300

Days, no

who had progressed after treatment with docetaxel. There were equally significant improvements in all of the secondary end points, such as prostate-specific antigen (PSA) response rate, time to PSA progression and progressionfree survival (PFS), but the doubling of the time to SREs and the significant protection from pain progression may be at least as important from the patient’s perspective.

“Clinical benefit of abiraterone acetate in the treatment of bone metastases [in patients with mCRPC] crosses all dimensions. It improves pain palliation, it delays pain progression, it delays time to SRE, and the effect is sustained over all treatment cycles,” reported Christopher J. Logothetis, MD, chair, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. Presenting the pain control results from COUAA-301 at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Logothetis said these data confirm “meaningful improvement in symptom-free survival, in addition to the improvement in overall survival.”

In this study (abstract 5420), 1,195 patients with mCRPC who had progressed after previous treatment with docetaxel and had an Eastern Cooperative Oncology Group (ECOG) status score of 2 or lower were randomized in a 2:1 ratio to 1 g of abiraterone acetate or placebo daily. Both groups received 5 mg of prednisone twice daily. Abiraterone acetate, a prodrug of abiraterone, blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis, which, in turn, blocks androgen synthesis by the adrenal glands, testes and within the prostate tumor.

After a median follow-up of 12.8 months, OS, the primary end point, was 14.8 months in the abiraterone group and 10.8 months in the placebo group, generating a 35% relative improvement for the active therapy (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.54-0.77; P<0.001). These results were published in The New England Journal of Medicine just prior to the ASCO meeting (2011;364:19952005, PMID: 21612468). The PFS was 5.6 months in the abiraterone group compared with 3.6 months in the placebo group (P<0.001). PSA response rate was 29% in the abiraterone group compared with 6% in the placebo group (P<0.001). Time to PSA progression was 10.2 in the abiraterone group compared with 6.6 months in the placebo group (P<0.001).

400

200 150

100

0

Figure. Time to skeletal-related events.

The drug was considered even more impressive, however, when investigators dissected abiraterone’s ability to relieve the burden of symptomatic metastases, particularly bone pain.

One of the most impressive results was the doubling of time to SRE, defined as pathologic fracture, spinal cord compression or palliative radiation or surgery for bone symptoms, which was a median of 301 days in the abiraterone group compared with 150 days in the placebo group (P=0.0006) (Figure).

According to Dr. Logothetis, overall pain, measured in several ways, such as progression of intensity or the interference that pain imposed on daily activities, also was highly significantly less on abiraterone. Moreover, Dr. Logothetis said, actual symptomatic benefit in patients who received a full course of therapy was likely to have been even better than those reflected in this intent-to-treat analysis. A full course of

treatment costs $40,000.

The prostate cancer expert invited to discuss the study at ASCO also emphasized the significance of these pain results, which, although preplanned, were not even formal secondary end points. Although an improvement in survival is generally required in oncology before a new treatment is considered practice-changing, the quality of life in patients with prostate cancer and bone pain deserves attention, he said.

“Not only were they palliated, they were palliated more quickly and they were palliated more fully,” said Michael J. Morris, MD, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York City. “Abiraterone and prednisone do appear to have achieved, or at least preliminarily to have achieved, the hat trick of oncology in prostate cancer. It improved how patients survived, it improved how patients feel, and it improved how patients function.”

The benefit of abiraterone is of interest when compared with the results of another Phase III study that reported the combination of a bisphosphonate plus docetaxel in the management of bone metastases in prostate cancer. In this study (ASCO abstract 4518), 592 patients with mCRPC with bone metastases were randomized to receive or not to receive the bisphosphonate risedronate (Actonel, Warner Chilcott) with an every-three-week cycle of docetaxel and prednisone. Not surprisingly, there were no significant differences in time to progression or PSA responses over a median 37-month follow-up, but the addition of risedronate did not result in significant benefit with respect

‘Abiraterone and prednisone do appear to have achieved, or at least preliminarily to have achieved, the hat trick of oncology in prostate cancer.

It improved how patients survived, it improved how patients feel and it improved how patients function.’

to OS (19.7 vs. 18 months; P=0.6) and bone-related outcomes.

“A third-generation bisphosphonate did not proScan for abstract vide any addition- 4520; instructions al benefit in the page 8. setting of an effective first-line regimen of docetaxel and prednisone,” said Hielke J. Meulenbeld, MD, Department of Medical Oncology, Erasmus University, Rotterdam, The Netherlands. Despite the appealing rationale for this combination and some synergy observed between docetaxel and bisphosphonates in experimental models, this strategy was disappointing.

Denosumab (Prolia, Amgen) and zoledronic acid (Zometa, Novartis) are two other agents approved for the treatment of solid tumors for the control of SREs. At the ASCO meeting, Neil D. Shore, MD, director, Carolina Urologic Research Center, Myrtle Beach, S.C., presented new data from a Phase III study that had previously found denosumab to be superior to zoledronic acid for delaying and preventing SREs in patients with bone metastases and mCRPC. A subgroup analysis found that in asymptomatic patients with no prior SREs and no pain or mild pain, the advantage remained highly significant (HR, 0.88; P=0.011 vs. HR, 0.82; P=0.008 for the overall population). The large trial of 1,901 patients did not include OS data (abstract 4533). Studies investigating combinations with abiraterone would be of interest.

—Ted Bosworth Dr. Logothetis disclosed he is a consultant for and receives research funding from Cougar Biotechnology.

Drs. Morris and Meulenbeld reported no relevant disclosures.

Dr. Shore receives honoraria and research funding from Amgen and is a consultant for the company.

— Michael J. Morris, MD

Article Reprints Reprints of Clinical Oncology News articles are available.

Call Julianna Dawson at (212) 957-5300 x271.

Reprints can be ordered in black & white or 4-color.

9

Sponsored by Novartis Pharmaceuticals Corporation

A 1-log Increase in BCR-ABL With a Loss of Major Molecular Response: A Case Discussion Michael W. Deininger, MD, PhD Chief of Hematology and Hematologic Malignancies University of Utah Huntsman Cancer Institute Salt Lake City, Utah

Introduction Patients with Philadelphia chromosome– positive (Ph+) chronic myelogenous leukemia in the chronic phase (CML-CP) require both strict treatment regimens and careful attention to the level of response. Physicians treating such patients must evaluate the patient’s response at various time intervals to note signs of relapse.

The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have guidelines for monitoring patients following treatment

initiation (Figure 1).1,2 After initiating therapy, patients newly diagnosed with Ph+ CML should be evaluated with complete blood count (CBC) to assess the hematologic response to treatment.

Cytogenetic testing is the traditional means for monitoring CML treatment response, and bone marrow aspiration with cytogenetics is recommended after 3, 6, and 12 months of therapy or until a complete cytogenetic response (CCyR) is documented.

The hallmark of Ph+ CML is a myeloid cell population with an abnormally shortened chromosome 22, produced by a genetic translocation with chromosome 9, resulting in the abnormal Ph chromosome.1 The Ph chromosome can be detected microscopically in dividing cells during metaphase, and a CCyR is indicated by an absence of Ph+ metaphases. A partial cytogenetic response (PCyR) indicates that 1% to 34% of metaphase cells are still Ph+.

An alternative assay for the Ph chromosome, fluorescence in situ hybridization (FISH), may be performed on either peripheral blood

or bone marrow. FISH examines many more cells than conventional cytogenetics, and interphase FISH is applicable to nondividing cells. It is more sensitive than conventional cytogenetic testing, but has a false-positive rate of 1% to 10%.1 At 3-month intervals, real-time quantitative polymerase chain reaction (RQPCR) monitoring is recommended while the patient is responding to therapy. The RQ-PCR assay is the most sensitive test of treatment response. It evaluates the levels of BCR-ABL transcripts,1 which encode a mutant, constitutively active, tyrosine kinase fusion protein resulting from the Ph translocation. The Bcr-Abl protein is the foundation of Ph+ CML. In the RQ-PCR assay, BCR-ABL RNA generally is compared with that of a common control gene so that the values are comparable among samples containing different amounts of RNA.2 The resulting ratio is expressed as a percentage of a reference baseline that was initially derived from a cohort of newly diagnosed, untreated patients. Although different laboratories use

Diagnostic Workup CBC, platelets

Bone marrow aspirate and biopsy for morphology and cytogenetics

RQ-PCR

3 months CBC, platelets

Bone marrow cytogenetics

RQ-PCR

6 months Bone marrow cytogenetics

RQ-PCR

12 months Bone marrow cytogenetics if no CCyR at 6 months

RQ-PCR

18 months Bone marrow cytogenetics if no CCyR at 12 months

Figure 1. Patient-monitoring milestones in Ph+ CML. CBC, complete blood count; CCyR, complete cytogenetic response; RQ-PCR, real-time quantitative polymerase chain reaction Adapted from references 1 and 2.

10

CLINICAL ONCOLOGY NEWS • AuGuSt 2011

RQ-PCR

different technologies to measure BCR-ABL, the results can be normalized to a unified scale with the help of a correction factor.

This unified scale is called the international scale (IS). Reductions in the BCR-ABL/control gene ratio are expressed as a percentage of the IS standardized baseline, which is defined as 100% IS.3 A value of 0.1% IS (equivalent to a 3-log reduction from the standardized baseline) is referred to as a major molecular response (MMR).

Here I’ll review treatment-monitoring guidelines for patients with Ph+ CML-CP using a recent case. I’ll also discuss the possibility of molecular response as a marker for patient outcomes.

Case Presentation and Diagnosis A 45-year-old man presents to his primary care physician with a 4-month history of reduced appetite with abdominal fullness and some night sweats. He has had unintentional weight loss equivalent to 10% of his total body weight. His past medical history includes hypertension, which was first diagnosed 5 years ago. His blood pressure was initially managed through lifestyle changes, but this ultimately proved inadequate. His physician then prescribed approved therapies for hypertension. The patient’s family history notably includes cardiovascular disease, but is free of cancer or hematologic disorders. He is the oldest of 3 brothers, is married, and has 2 healthy children.

The physician notes regular bowel sounds on physical examination, and the patient’s liver is not palpable. The tip of the spleen is felt 12 cm below the left costal margin in the midclavicular line. There are no other abdominal masses, but several nontender lymph nodes in the neck, less than 1x1x1 cm in diameter, are palpable bilaterally. The patient’s heart rhythm is regular; S1/2 is present, and there are no murmurs or rubs.

The physician observes reduced breath sounds in the left lower lung. The patient’s extremities, skin, and gross neurologic examination are all unremarkable and vital signs are within normal limits.

A CBC and differential were then ordered. Notably, the patient’s hemoglobin level is 10.8 g/dL, and his white blood cell count is 245,000/mL. The differential reports 30% segmented neutrophils, 20% band neutrophils, 15% metamyelocytes and myelocytes, 11% promyelocytes, 9% basophils, 6% myeloblasts, 5% monocytes, and 4% lymphocytes.

The physician refers the patient to a hematologic oncology clinic, where a bone marrow aspiration is performed. This procedure

Sponsored by Novartis Pharmaceuticals Corporation

the Science Behind PoSitive Patient outcomeS

Table. European LeukemiaNet Treatment Response Criteria

Optimal

Suboptimal

Failure

3 months

CHR + CyR

CHR

<CHR

6 months

PCyR

<PCyR

No CyR

12 months

CCyR

PCyR

<PCyR

18 months

MMR

<MMR

<CCyR

Anytime

Stable or improving MMR

Loss of MMR, mutations

Loss of CCyR or CHR, mutations

CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; MMR, major molecular response; PCyR, partial cytogenetic response Adapted from reference 2.

reveals trilineage hyperplasia with 11% basophils and 6% myeloblasts. There is mild to moderate reticulin fibrosis. Bone marrow cytogenetics show that all metaphases (20 of 20) are Ph+. Additionally, FISH of the peripheral blood finds that 191 of 200 (95.5%) cells examined are Ph+. Finally, RQPCR shows a BCR-ABL/ABL transcript ratio equivalent to 135% of standardized baseline on the IS.

The clinic makes a diagnosis of Ph+ CML-CP with a high-risk Sokal score. Treatment is initiated for Ph+ CML.

Treatment and Follow-up After 3 months, the patient shows a complete hematologic response, with normalization of blood counts. At 6 months, the patient displays a PCyR (25% of bone

10-fold

Difference From Reference Lab Before IS Conversion

5-fold 3-fold 1-fold -3-fold -5-fold

• Laboratories analyzing the same samples arrive at different valuesa

-10-fold A B C D E F G H I

J K L M N O P Q R S

Laboratory 10-fold

Difference From Reference Lab After IS Conversion

5-fold 3-fold 1-fold -3-fold -5-fold

• Conversion to IS makes results from different laboratories comparable

-10-fold A B C D E F G H I

J K L M N O P Q R S

Laboratory

Figure 2. Conversion of RQ-PCR results to IS allows comparison of results between laboratories.

IS, international scale; RQ-PCR, real-time quantitative polymerase chain reaction Results differ because of use of different protocols, assays, control genes, and standardized baselines.

Adapted from reference 6. a

marrow Ph+ metaphases). Furthermore, RQ-PCR at 6 months finds that BCR-ABL transcripts have declined 1 log from standardized baseline, or 10% IS. At 12 months, the patient achieves CCyR with a 2-log reduction from standardized baseline in BCR-ABL (1% IS). However, there still is no MMR (or a 3-log BCR-ABL reduction from standardized baseline to 0.1% IS) at 18 months. CCyR is maintained at this time point.

The patient undergoes another RQ-PCR after 3 months and this time achieves an MMR. He is scheduled to undergo followup testing for BCR-ABL levels every 6 months. At 27 months, RQ-PCR detects a 1-log increase in BCR-ABL RNA with a loss of MMR. At this point, it came to the physician’s attention that the patient had switched laboratories because his insurance company changed laboratory service providers. The RQ-PCR results were not reported using the IS; therefore, they were not comparable to the previous RQ-PCR results for this patient.

Importance of Monitoring BCR-ABL Levels The NCCN and ELN guidelines both contain response milestones that establish criteria for evaluating treatment response (Table).

These guidelines are similar, but unlike the ELN, the NCCN does not specifically categorize responses as optimal, suboptimal, or failing.1 A notable difference in the guidelines is that ELN has revised its optimal response criteria to include achievement of an MMR at month 18.2 In the aforementioned case, the patient did not achieve an MMR until 21 months after initiating treatment. This is important because patients who achieve an earlier molecular response may have a more durable CCyR.1 There also may be a correlation between earlier decreases in BCR-ABL levels and improved outcome.4 In this case, the patient experienced a further rise in BCR-ABL levels after achieving MMR. There are several

The International Scale: Comparison of Results Between Laboratories The use of an IS to standardize molecular monitoring by RQ-PCR allows for comparison of molecular responses from different laboratories, which is otherwise not possible because of interlaboratory differences in assays and reporting methods. This scale, aimed at standardizing RQ-PCR testing and reporting, was designed after a National Institutes of Health consensus meeting held in late 2005.5 A set of reference standards is used to determine a conversion factor, which is then used to convert the RQ-PCR results of local, individual laboratories to the IS. Figure 2 summarizes an international study that illustrates the utility of the IS.6 In this study, 19 laboratories analyzed the same sample and showed varying RQ-PCR results, ranging from 7.2-fold lower than to 8.1-fold higher than results from a reference laboratory. After converting to the IS, the results from the laboratories in this study were in agreement with the results from the reference laboratory (±1.2-fold difference).

In the case of this patient, the new laboratory had not undergone the process of calibration with the reference laboratory to develop a conversion factor and report results using the IS. Because RQ-PCR from the first and second laboratories cannot be compared, it is not possible to say whether the apparent increase in BCR-ABL level at 27 months represented a loss of response or a laboratory difference. A repeat RQ-PCR by a laboratory that uses the IS would determine the patient’s true status.

References 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Chronic Myelogenous Leukemia. Version 2.2011.

2. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051.

3. Hughes tP, Branford S. Monitoring disease response to tyrosine kinase inhibitor therapy in CML. Hematology Am Soc Hematol Educ Program.

2009:477-487.

4. Radich JP. How I monitor residual disease in chronic myeloid leukemia. Blood. 2009;114(16):3376-3381.

5. Central European Leukemia Study Group. CML-InfoOngoing Management. http://www.cml-info.com/de/ healthcare-professionals/about-cml/ongoingmanagement.html. Accessed April 7, 2011.

6. Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials.

Blood. 2008;112(8):3330-3338.

CLINICAL ONCOLOGY NEWS • AuGuSt 2011

11

CDE-1017504

Milestone

potential causes for a rise in BCR-ABL levels after an initial response, including sampling error, laboratory variability, natural fluctuations in BCR-ABL levels, a loss of response to treatment, and poor compliance.

BB1010

Response Definition and Criteria from the ELN

12

PRN

Clinical Oncology News • August 2011

Community Oncology

Clinical Conundrums A Quiz for the Community Oncologist QUESTIONS

1.

A 45-year-old African American woman with metastatic triple-negative breast cancer (TNBC) is referred to you for a discussion about further treatment options. You note that she has progressed on an anthracycline-based regimen and is eligible for an ongoing Phase III clinical trial that includes a combination therapy of gemcitabine and carboplatin with or without the PARP-1 inhibitor iniparib (BiPar). The patient is a nurse and asks you to explain the rationale behind this particular combination for metastatic TNBC. All of the following statements are correct except: a. Preclinical studies have shown that combining PARP-1 inhibitors with platinum-based therapy potentiates chemotherapeutic cytotoxicity. b. A randomized Phase II study with a similar combination demonstrated significant improvement in response rate and progression-free survival (PFS). c. Several studies have demonstrated a decrease or loss of BRCA1 expression in sporadic TNBC. d. Studies have suggested that TNBC shares clinical and pathologic features with hereditary BRCA1-related breast cancer. e. There is no standard of care for TNBC, and therefore this Phase III clinical trial is the best therapeutic approach for this patient.

2.

A 35-year-old man presents with non-bulky, right anterior cervical and mediastinal lymphadenopathy.

Scans confirm these findings. He has 2 sites of disease involvement. The excisional biopsy of the cervical lymph node reveals nodular-sclerosis Hodgkin’s lymphoma. The bone marrow biopsy is negative for involvement with lymphoma cells. Laboratory test reveals normal complete blood cell count (CBC) and an erythrocyte sedimentation rate (ESR) of 8. Baseline cardiac and pulmonary function tests are normal, and the patient has stage II disease without B symptoms. Following accurate prognostic risk assessment and discussion about its implications, you inform him about a randomized study recently published in the New England Journal of Medicine by Engert et al. (HD10 trial) on early-stage Hodgkin’s lymphoma.

In view of the HD10 trial results, which of the following would be the best treatment option for this patient? a. 2 cycles of ABVD, followed by 20 Gy IFRT b. 2 cycles of ABVD, followed by 30 Gy IFRT c. 4 cycles of ABVD, followed by 30 Gy IFRT d. 4 cycles of ABVD, followed by 20 Gy IFRT

3.

A 36-year-old man is diagnosed with grade 2 follicular lymphoma.

The patient asks you to explain the relevance of t(14;18) detected in the supraclavicular biopsy specimen. All of the following statements are correct about t(14;18) except: a. The B cell lymphoma-2 (BCL2) gene on chromosome 18q is translocated to the constitutively expressed

immunoglobulin heavy chain gene on chromosome 14q. b. t(14;18) is detected in 80% to 90% of patients with follicular lymphoma. c. The BCL2 gene on chromosome 14q is juxtaposed to the constitutively expressed immunoglobulin heavy chain gene on chromosome 18q. d. The t(14;18) translocation causes overexpresssion of BCL2 gene resulting in resistance to apoptosis.

4.

Azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Eisai) are FDA-approved drugs to treat certain subgroups of patients with myelodysplastic syndrome (MDS). These drugs were developed based on the observation that the promoter regions of tumor suppressor gene(s) are inhibited by which of the following proposed mechanisms? a. Hypermethylation b. Hypomethylation

5.

A 60-year-old woman presents with a productive cough that has not responded to antibiotic therapy. She smoked 2 packs of cigarettes per day for the past 40 years. A computed tomography (CT) scan of her chest revealed a 6-cm left upper lobe mass without lymphadenopathy. She underwent a successful left upper lobectomy. Pathology revealed a 7.1-cm squamous cell carcinoma with negative hilar and mediastinal lymph nodes. The surgical margins were negative. Postoperatively, she recovered well and has ECOG performance status of 0-1. Which of the following is the best management strategy at this time? a. Observation alone with close surveillance b. Postoperative chemotherapy followed by radiation therapy to the surgical bed c. Postoperative radiation therapy d. Postoperative chemotherapy

Prepared by

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

6.

The patient in question 5 returns to you approximately 3 months after completion of recommended therapy.

She has no evidence of disease and has quit smoking. Her husband, who has a 20 pack-year smoking history, requests that you comment on some sort of screening method for lung cancer. All of the following statements about screening for lung cancer are correct except: a. Screening with low-dose CT can result in false-positive results showing benign nodules and can lead to unnecessary thoracotomies. b. Screening for lung cancer using lowdose CT has resulted in a significantly higher detection rate of non-small cell lung cancer. c. Implementing lung cancer prevention strategies is likely to have a far greater impact on lung cancer mortality than screening. d. Randomized studies favor routine use of CT scans for early lung cancer detection in the general population.

7.

Cigarette smoking is a risk factor for all of the following cancers except: a. Breast cancer b. Bladder cancer c. Esophageal cancer d. Pancreatic cancer e. Acute myeloid leukemia f. Gastric cancer

SUPPORTIVE CARE Pain

Cancer Patients Can Be Drug Abusers Too Salt Lake City—Managing cancer pain in the outpatient setting can be very challenging, particularly if a patient is at high risk for drug abuse.

“Cancer patients can be drug abusers too,” said David Craig, PharmD, director of the Pain and Palliative Care Pharmacist Residency Program at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla. “Just because they have a cancer diagnosis does not mean that they will not abuse the drugs we give them to treat their pain.”

Assessing their degree of risk for drug abuse is the first step in managing these patients, Dr. Craig said at the annual

meeting of the Hematology/Oncology Pharmacy Association.

As an example of this type of patient, Dr. Craig presented the case of a 37-yearold man with a history of squamous cell carcinoma of the glottis who had received radiation and chemotherapy followed by a total laryngectomy and a gastric feeding tube. This patient had a history of heroin addiction and had completed a rehabilitation program with methadone. The decision was made to treat the patient’s pain

with methadone and oxycodone, with adjuvant pregabalin (Lyrica, Pfizer). The methadone caused a prolongation of his QT interval but his other laboratory values remained within normal ranges.

Caveats for Methadone “Methadone can cause QT prolongation and it is important to monitor patients for this,” Dr. Craig said. “Also, if you are going to use intravenous methadone for an extended period of time, use the formulation that is free of preservatives, because the intravenous formulation can cause more QT prolongation.”

Other methadone “pearls” include performing an electrocardiogram at baseline

for high-risk patients, such as those at risk for torsades de pointes, patients using concomitant QT-prolonging drugs or other drugs that may have significant interactions with methadone, patients on oral doses exceeding 100 mg per day and patients with electrolyte abnormalities. Monitoring should be done more frequently if the patient’s current QTc is greater than 450 ms but less than 500 ms, and if the QTc is greater than 500 ms, “watch out!” Dr. Craig warned.

The squamous cell cancer patient continued to report that his pain was at 9 out of 10, describing it as “sharp,” “stabbing,” “burning” and “constant,” despite the methadone, oxycodone and pregabalin

PRN

Clinical Oncology News • August 2011

Community Oncology

ANSWERS

but only in a high-risk population. A number of clinical and nonclinical issues need to be addressed prior to broad application of lung cancer screening in routine clinical practice. Presently, routine screening for detection of early lung cancer is not recommended. The most effective way for smokers to improve their health and prevent lung cancer is to stop smoking. The patient’s husband should be encouraged to see a family physician for smoking cessation counseling.

1.

The answer is E. This might have been a good clinical trial for this type of patient population, but the accrual to this trial is completed (NCT01045304) and the preliminary results did not meet the pre-specified criteria for significance for co-primary end points of overall survival (OS) and PFS with triple therapy. Nevertheless, it is important to be aware of the current scientific and clinical data forming the basis of this type of therapy. Practitioners should have a detailed discussion with their patients about this and any other therapy being considered, so that patients and their caregivers can make a confident and well-informed decision.

O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer. J Clin Oncol. 2011;29(suppl): Abstract 1007.

O’Shaughnessy J, Osborne C, Pippen JE, et al.

Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205-214, PMID: 21208101.

Foulkes WD, Smith IE, et al. Triple-negative breast cancer. N Engl J Med. 2010;363():1938-1948, PMID: 21067385.

2.

The answer is A. The HD10 trial showed that in patients with favorable (non-bulky mediastinal lymphadenopathy, lymph node size <10 cm, ESR <50, <3 sites of disease, and no B symptoms), early-stage Hodgkin’s lymphoma, treatment with 2 cycles of ABVD followed by 20 Gy of involvedfield radiation therapy is as effective as options b, c, and d.

Engert A, Plutschow A, Eich HT, et al.

Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652, PMID: 20818855.

3.

The answer is C.

Leich E, Salaverria I, Bea S, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114(4):826, PMID: 19471018.

Rowley JD. Chromosome studies in the nonHodgkin’s lymphomas: the role of the 14;18 translocation. J Clin Oncol. 1988;6(5):919, PMID: 3284977.

4.

The answer is A. Hypermethylation of the promoter region of tumor suppressor gene(s) is believed to cause gene silencing and appears to have an important role in epigenetic modulation in many cancers, especially MDS. Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov.

2006;5(2):37-50, PMID: 16485345.

5.

The answer is D. This patient has stage IIB (T3N0) squamous cell cancer. There is a definitive role for adjuvant platinum-based doublet therapy. The Adjuvant Navelbine International Trialist Association (ANITA) and International Adjuvant Lung Cancer Trial (IALT) studies demonstrated that platinum-based doublet therapy can

increase survival in this patient population. Postoperative radiotherapy is not a standard of care in this particular situation. The PORT Meta-analysis Trialists Group demonstrated a detrimental effect of postoperative radiotherapy in patients with early-stage, completely resected non-small cell lung cancer.

Arriagada R, Dunant A, Pignon JP, et al. Longterm results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol. 2010;28(1):35, PMID: 19933916.

Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.

Lancet Oncol. 2006;7(9):719, PMID: 16945766.

[No authors listed] Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials.

PORT Meta-analysis Trialists Group. Lancet.

1998;352(9124):257-263, PMID: 9690404.

6.

The answer is D. Issues related to lung cancer screening are rapidly evolving. A recent randomized study showed reduced lung cancer mortality associated with low-dose CT screening

[No authors listed] Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 June 29 [Epub ahead of print], PMID: 21714641.

Gopal M, Abdullah SE, Grady JJ, et al. Screening for lung cancer with low-dose computed tomography: a systematic review and meta-analysis of the baseline findings of randomized controlled trials.

J Thorac Oncol. 2010;5(8):1233, PMID 20548246.

Welch HG, Woloshin S, Schwartz LM, et al.

Overstating the evidence for lung cancer screening: the International Early Lung Cancer Action Program (I-ELCAP) study. Arch Intern Med. 2007;167(21):2289, PMID: 18039986.

[No authors listed] A clinical practice guideline for treating tobacco use and dependence: A US Public Health Service report. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives. JAMA. 2000;283(24):3244, PMID: 10866874.

7.

The answer is A. The relationship between cigarette smoking and the development of breast cancer is controversial.

Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence.

J Natl Cancer Inst. 2004;96:99, PMID: 14734699.

Do you have feedback on this quiz?

Please send comments to

korourke@mcmahonmed.com.

SUPPORTIVE CARE Pain

regimen, and he requested oxycodone CR. “This patient was really challenging,” Dr. Craig noted. “Sometimes, despite what you do, patients will not respond.

I could have jacked the dose of methadone up to 1,000 mg and probably nothing would have happened.”

Assessing Risk for Abuse It is important to stratify patients’ risk for abusing drugs, Dr. Craig said. Clinicians have a choice of three assessment tools that can help: the Opioid Risk Tool (ORT), the Current Opioid Misuse Measure (COMM), and the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R).

The ORT is a five-question screening tool that can predict opioid-related aberrant behavior (Pain Med 2005;6:432-442).

It uses the following factors to gauge risk: • Family history of substance abuse • Personal history of substance abuse

• Age (16-45 years) • History of preadolescent sexual abuse (women only) • Psychological illness “Younger age is more predictive of substance abuse potential. A history of preadolescent sexual abuse accounts for 4 points but only in females,” Dr. Craig said. “A total score of 0 to 3 indicates low risk, 4 to 7 is moderate risk and greater than 8 is high risk.”

The COMM assessment tool (http:// www.painedu.org) uses more subjective questions and is a 17-item, 5-point Likert scale questionnaire. The test is quick and easy to administer, has been validated in approximately 500 patients, and is ideal for documenting decisions about the level of monitoring planned for a particular patient or justifying referrals to a specialty pain clinic.

The COMM evaluates behaviors in the past 30 days and is scored by adding the

sum of responses of patients to questions, where 0 equals “never” and 4 equals “very often.” A score of 9 or higher is considered a positive score. “The COMM is useful for screening and telling us how aggressive we have to be,” Dr. Craig said.

The SOAPP-R (http://www.painedu.org) is similar to the COMM, but is more cumbersome to use. It consists of a 24-item questionnaire on a 5-point Likert scale, and a score of 18 or higher is considered high risk, a score between 10 and 21 is moderate risk and a score of less than 9 is low risk.

“Patients with active substance abuse are very challenging to treat, and so are patients with psychiatric illnesses,” Dr. Craig said. “We have to treat their cancer pain, but we cannot give them a free ticket to all of the drugs they want simply because they have cancer.”

He added, “The health care system discriminates against patients with

noncancer pain. If the patient has cancer pain, it’s ‘come right in, we’re going to treat you right away.’ There is a big disconnect and I see this a lot.”

Lee Kral, PharmD, BCPS, adjunct assistant professor at the University of Iowa Hospitals and Clinics Center for Pain Medicine, in Iowa City, said she would agree with all of Dr. Craig’s comments.

She noted that health care providers can feel caught between the empathy they have for the patient and the need to prevent abuse and diversion, she added.

Dr. Kral admitted that she finds herself spending more time talking to oncologists about opioid screening tools, urine drug screens, and opioid consent and management agreements. “This is something most of them never thought they would have to deal with, but it is becoming ever more a part of their daily practice,” she said.

—Fran Lowry

13

14

CLINICAL TRIALS

Clinical Oncology News • August 2011

Informed Consent

‘UNREALISTIC’ continued from page 1 

regarding their own favorable outcome.1 These researchers apparently feel such optimism poses a serious problem, with one member of this community of scholars being quoted as remarking, “We just need to realize that not all optimism is ethically benign.”2 There is truly much to question in such assertions, beginning with the fundamental legitimacy of any expert’s claim that an individual cancer patient’s positive/optimistic attitude in the face of progressive cancer is unrealistic and potentially harmful. But the point of this commentary is not to inquire as to the authority and expertise of those who feel justified to make such sweeping claims (although this is surely a matter worthy of future frank discussion), but rather to point out the serious factual errors underlying their basic assumptions.

For it would appear that those who support the concept of unrealistic optimism, or its sister term therapeutic misconception, have not kept up with the oncology literature dealing with earlyphase clinical trials. A large and rapidly growing number of excellent studies have clearly documented the quite realistic potential for unquestionable direct clinical benefit associated with participation in these trials, with both older (eg, Phase 1 trial of cisplatin involving patients with germ-cell tumors3) and more recent examples (eg, imatinib in chronic myelocytic leukemia4) demonstrating genuinely impressive outcomes.

For example, in the considerable number of Phase I trials conducted under the auspices of the National Cancer

Institute, the overall objective response rate was 10.6%, and it increased to 17.8% if at least one drug in a combination regimen had previously been approved by the FDA for some clinical indication.5 Similar results have been reported by other Phase I trial groups.6,7 One must seriously challenge the assertion that a patient who accepts a 1-in-10 chance of objective tumor shrinkage (which may equate to an even greater opportunity for symptomatic benefit with respect to reduction in pain, etc) is exhibiting a mental state of unrealistic optimism.

And it would not be possible to provide a more poignant example of the remarkable disconnection between the rhetoric of unrealistic optimism and the increasingly common scenario of clinical benefit in early cancer drug development than to comment on the specific disease setting described in an unbalanced and highly biased commentary in The New York Times that attempted to hype the so-called research findings in this area.2 The physician-writer describes her personal experience during medical training dealing with a young mother with widely metastatic melanoma, who was about to enter her third clinical trial. The clear implication of this description was that this woman was experiencing unrealistic optimism in agreeing to go through “another futile attempt” to treat her cancer.

Yet, if this specific woman’s cancer had been found to have a mutated and activated BRAF, she might have entered the early-phase trial employing PLX4032, in

which more than threefourths of the treated patients experienced measurable tumor regressions.8 Perhaps someone can explain what is so unrealistic about the belief of a patient with advanced cancer that, perhaps— just perhaps—the trial she or he is entering may have such an overall outcome for the treated population, and that he or she may personally experience a meaningful degree of clinical benefit?

It is relevant to distinguish between patients who are appropriate candidates for participation in an early-phase clinical trial who firmly believe they will attain clinical benefit and individuals unable to understand that a particular investigative strategy may be harmful in their specific condition (eg, serious cancer-related or comorbid hepatic or renal dysfunction). Furthermore, treatment in an early-phase clinical trial may realistically be inappropriate for a particular patient if it mandates an “unrealistic commitment” (eg, requirement for daily clinic visits in a nonambulatory individual who lives a long distance from the research center and who has inadequate family support to permit participation).

In summary, while it is reasonable to speculate that some ethicists may elect to employ the term unrealistic optimism (as they have used the term therapeutic misconception), in future discussions of the adequacy of the process of informed consent involving early-phase cancer trials, it is essential that the validity and relevance of this basic concept in this specific clinical arena be fully and

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Cancer Treatment Centers of America Eastern Regional Medical Center Philadelphia, PA

openly discussed, and ultimately vigorously challenged.

References 1. Jansen LA, Appelbaum PS, Klein WM, et al.

Unrealistic optimism in early-phase oncology trials. IRB. 2011;33(1):1-8.

2. Chen PW. When optimism is unrealistic.

The New York Times. March 3, 2011.

3. Higby DJ, Wallace HJJ, Albert DJ, Holland JF. Diaminodichloroplatinum: A phase 1 study showing responses in testicular and other tumors. Cancer. 1974;33(5):1219-1225.

4. Druker BJ, Talpaz M, Resta DJ, et al.

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037.

5. Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med. 2005;352(9):895-904.

6. Arkenau HT, Olmos D, Ang JE, de Bono J, Judson I, Kaye S. Clinical outcomes and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden experience. Br J Cancer.

2008;98(6):1029-1033.

7. Moroney J, Wheler J, Hong D, et al. Phase I clinical trials in 85 patients with gynecologic cancer: the M.D. Anderson Cancer Center experience. Gynecol Oncol.

2010;117(3):467-472.

8. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF results in tumor regression in metastatic melanoma.

N Engl J Med. 2010;363(9):809-819.

Race Examined as Factor in Patient Recruitment for Clinical Trials Carmen R. Green, MD, believes in the “science of inclusion.” That’s why Dr. Green, a researcher at the University of Michigan, and her team in Ann Arbor are exploring the reasons why blacks are less likely to participate in clinical research.

“In order to meet the medical needs of an increasingly diverse society, we need to be able to assess its needs and differences,” noted Dr. Green, professor of anesthesiology and obstetrics and gynecology. “In general, clinical study populations do not include a representative sample, one that is truly generalizable and that mirrors the population of society as a whole. We need to explore this more and look at how we recruit for studies, and how we get potential participants the information they need to understand the purpose of medical research and how it changes lives.”

Dr. Green’s research in this area

includes a study published in the May 1 issue of the journal Cancer that assessed chronic cancer-related pain and its impact on patient quality of life in

‘For people of color, there is a history of distrust and of not being treated equally in terms of access to care and quality of care.’

—Carmen R. Green, MD

diverse populations (2011;117:1994-2003, PMID: 21509777). Even more recently, she and her team presented a poster at the 2011 annual meeting of the American

Pain Society in May, that examined outcomes for passive and active recruitment approaches for black participants in a survey study of cancer survivors.

Using Michigan’s cancer registry, the researchers invited 949 (499 black and 450 white) cancer survivors to participate in the survey study. Each subject was sent up to three letters, by mail, using last-known addresses recorded in the registry. Cancer survivors who returned “willing to participate” responses then were notified to the study team and actively recruited. Black cancer survivors in the state registry were significantly more likely to have died (14.0% vs. 7.3%) or moved (14.2% vs. 6.2%). In addition, although blacks were less likely to officially refuse to participate in the survey study, they also were less likely to agree to participate;

CLINICAL TRIALS

Clinical Oncology News • August 2011

Table 1. Response to Registry Invitation Whites

Blacks

Number of people eligible for study

357

313

Agreed to participate

44.3%

33.5%

Actively refused

24.1%

14.1%

Passive refusal

31.7%

52.4%

Table 2. Response Of Those Who Expressed Interest Whites

Blacks

Number of interested people

158

105

Completed surveys

86.7%

59.0%

Refused

8.9%

13.3%

Passive refusal

5.7%

26.7%

that is, they were more likely to passively refuse (Tables).

“For people of color, there is a history of distrust and of not being treated equally in terms of access to care and quality of care,” Dr. Green said. “Disparities exist because of historical and current perspectives. This may make us uncomfortable, but we need to explore it more. Our research is focused on an area that is understudied.”

Dr. Green and her team plan to expand their research to assess the prevalence of cancer-related chronic pain in the general population and to explore differences in relation to race and gender. Their work will attempt to determine the reasons behind the higher rates of mortality and morbidity among blacks with cancer and cancerrelated chronic pain.

“This is a very important study, reinforcing the sad but true fact of underrepresentation of African-Americans— among other minorities and vulnerable populations—in many types of important research studies, including pain and palliative care research,” said Perry G. Fine, MD, professor of anesthesiology at the Pain Research Center in the University of Utah School of Medicine, in Salt Lake City. Dr. Fine is a noted pain researcher who was not involved in the University of Michigan studies.

“The reasons are complex and deeply embedded in what have become problematic cultural norms, within both research establishments and the patient/ subject populations themselves,” he

‘This is a very important study, reinforcing the sad but true fact of under-representation of African-Americans—among other minorities and vulnerable populations—in many types of important research studies, including pain and palliative care research.’

—Perry Fine, MD

added. “Dr. Green continues to be an important researcher in this area of disparities, and her conclusions need to be widely disseminated and seriously

considered in order to improve pain care and research.”

For now, Dr. Green hopes pain specialists and primary care physicians treating

patients with chronic pain consider racial disparities when providing care, particularly when it comes to patient– physician communication. “How do you listen to someone? What are our stereotypes of others? We all have them,” she said. “But how do we get by them? How do you build trust in these relationships?

Ultimately, that is the key question we need to answer.”

—Brian P. Dunleavy Drs. Green and Fine reported no relevant conflicts of interest.

15

16

NEWS FROM THE JOURNALS

Clinical Oncology News • August 2011

Triptorelin Can Prevent Early Menopause in Breast Cancer Patients From JAMA

A

dding the gonadotropin-releasing hormone (GnRH) analog triptorelin to chemotherapy reduces the incidence of chemotherapy-induced early menopause in premenopausal women treated for breast cancer, according to a new study.

Recognizing the significant problem early menopause causes in younger patients with breast cancer and the lack of standard strategies for addressing chemotherapy-induced ovarian failure in this patient population, the investigators evaluated a regimen using triptorelin to temporarily suppress ovarian function during chemotherapy to protect against early menopause.

The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients— Gruppo Italiano Mammella 6) investigators conducted a randomized, open-label, parallel, Phase III study of 281 premenopausal women with stage I to III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy (JAMA 2011;306:269-276, PMID: 21771987). The patients were randomized to receive chemotherapy alone (n=133) or chemotherapy plus 3.75 mg triptorelin, administered intramuscularly at least one week prior to the start of chemotherapy and then every four weeks during the chemotherapy regimen (n=148). The clinical presentations and tumor characteristics of both groups were similar.

One year after the final chemotherapy cycle, the intention-to-treat analysis found that the rate of early menopause —defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol one year after the last cycle of

chemotherapy—was 8.9% in the chemotherapy plus triptorelin group and 25.9% in the chemotherapy-only cohort. The odds ratio (OR) for treatment-related early menopause was found to be 0.28 (95% confidence interval, 0.14-0.59; P<0.001).

The number needed to treat was six.

The investigators concluded that temporarily suppressing ovarian function with triptorelin during chemotherapy for early-stage breast cancer reduced the incidence of chemotherapy-induced early menopause, a distressing consequence of chemotherapy for significant numbers of patients. Premature menopause in these women has several significant consequences, including sexual dysfunction, vasomotor symptoms and infertility, the latter of which is especially concerning to younger patients and affects treatment decisions in about 30% of cases.

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

“This is the largest randomized prospective trial to date examining the impact of temporary ovarian suppression with a GnRH analog (in this case, triptorelin) on ‘early menopause’ among premenopausal women receiving adjuvant chemotherapy (with/without tamoxifen, as appropriate, and with extended ovarian suppression for those women who regained ovarian function during the first year after chemotherapy) for early-stage breast cancer. A lot of qualifications and conditions, you’ll note. The definition of

‘early menopause’ for these patients was ‘no resumption of menses and postmenopausal levels of follicle-stimulating hormone (FSH) and estradiol one year after the last cycle of chemotherapy.’

By this definition, the rate of early menopause was 26% in the chemotherapy-alone group versus 9% in the chemotherapy plus triptorelin group (OR, 0.28; P<0.001). Fully 25% of chemotherapy-treated patients and 29% of chemotherapy plus triptorelin–treated patients maintained premenopausal levels of estradiol and FSH, despite amenorrhea.

The difference in resumption on menses at one year, regardless of hormone levels, was 49.6% in the chemotherapyalone group versus 63.3% in the chemotherapy plus triptorelin group (P=0.03).

At last follow-up, one full-term pregnancy occurred in the chemotherapy-alone group, and three pregnancies occurred in the chemotherapy plus triptorelin group (one full-term, one premature delivery, one elective abortion).

Most women would be motivated toward a strategy to preserve ovarian function as a means to preserve ovarian reserve and fertility. This work does not demonstrate that potential, and indeed, the authors and the editorial both point out that embryo cryopreservation via in vitro fertilization and oocyte or ovarian tissue cryopreservation are more robustly studied. Other reasons for pursuing a strategy to preserve ovarian function could conceivably relate to the desire to reduce or delay menopausal symptoms and/or the consequences of estrogen deprivation (e.g., hot flashes, vaginal dryness, mood changes, decreased libido, cognitive dysfunction, and accelerated loss of bone density). These issues were not reported on in the present study.

The authors point to a prior published report from Petrek et al. that ‘most who do not resume menstruating in the first year after the end of chemotherapy are likely to lose their ovarian function completely and permanently.’ This is a bit of an overstatement, because many such women will regain ovarian function, and this is determined by age, chemotherapy regimen, the use of tamoxifen, and other factors; thus the definition of the main outcome measure is problematic. Finally, and notably, the decision to employ 2 additional years of triptorelin in women who resumed menses or estradiol levels back into the premenopausal range confounds the ability to assess the impact of the primary intervention (triptorelin during chemotherapy) for the hormonesensitive (ER+) subgroup.

The authors noted that the greatest impact for triptorelin in preserving ovarian function was in the ER-negative subset. This is perhaps fortuitous, given the theoretical concern that coadministration of LHRH analog during chemotherapy might serve to make cells less sensitive to the chemotherapy.

Despite the limitations mentioned, these data, taken together with the larger body of evidence in this field, will serve to motivate a discussion of the possible use of this strategy in selected premenopausal patients with hormone receptor– negative breast cancer; any decision to employ this strategy would be informed by a clear understanding of the goals and expectations of the patient upon the various outcomes mentioned above. For me, the use of an LHRH analog to preserve ovarian function does not equate with its use to preserve fertility, nor would it replace the role of fertility preservation interventions prior to the first drop of chemotherapy.”

CALBG Team Clarifies Prognostic Value of Some Biomarkers in CRC From Journal of Clinical Oncology

M

ismatch repair deficiency (MMRD) is associated with a better prognosis in stage II and III colorectal cancer (CRC), whereas loss of heterozygosity at chromosome 18q (18qLOH) was not prognostic for patients with stage II disease, nor was it associated with differences in outcome when patients with stage II and III disease were considered together, according to a recent report from the Cancer and Leukemia Group B (CALGB).

This analysis of two randomized clinical trials of adjuvant therapy in patients with stage II (CALGB 9581) and stage III colon cancer (89803) sought to identify the potential role

of two genomic defects, MMR-D and 18qLOH that could identify risk for recurrence in patients with stage II or III CRC (J Clin Oncol July 11, 2011, doi: 10.1200/JCO.2010.33.0092). The investigators explored MMR-D, which typically results from methylation-associated silencing of the MLH-1 gene in patients with sporadic CRC, and whose presence is believed to indicate lessaggressive disease; and chromosomal instability (CIN), in which chromatids segregate during mitosis incorrectly, causing allelic loss at multiple tumor suppressor loci, resulting in a reduction in overall survival (OS). The investigators focused on CIN causing 18qLOH. CALGB protocols 9581 and 89803

included prospective analyses on the relationship between these two specific markers and treatment outcomes. The two trials included 1,852 (62%) of the patients for MMR-D and 955 (32%) for 18qLOH (this group did not include those who were MMR-deficient).

As has been previously reported, a higher proportion of stage II tumors were MMR-deficient compared with stage III tumors (21.3% vs. 14.4%; P<0.001) and were intact at 18q (24.2% vs. 15.1%; P=0.001). Patients shown to have MMR-D experienced improved five-year disease-free survival (DFS; 0.76 vs. 0.67; P<0.001) and OS (0.81 vs.

0.78; P=0.029) compared with those without MMR-D. The investigators also combined

MMR-deficient and 18q-intact patient cases and studied differences in outcome between these patients and those whose tumors had 18qLOH. Their analysis showed significantly worse fiveyear DFS and OS in patients whose tumors demonstrated 18qLOH. In the combined cohort of stage II and III patients, patients with 18qLOH experienced worse five-year DFS (0.65 vs.

0.75; P=0.021) and OS (0.77 vs. 0.81; P=0.002) than those with intact 18q. In patients with intact MMR tumors, the status of 18q did not affect outcomes; five-year DFS for patients with intact 18q versus 18qLOH tumors was comparable (0.74 vs. 0.65; P=0.18), as was OS (0.81 vs. 0.77; P=0.18).

“This study has important clinical

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ANDREW J. ARMSTRONG, MD, SCM Assistant Professor of Medicine and Surgery Duke Cancer Institute and the Duke Prostate Center Duke University Durham, North Carolina

I

n the past year, great strides have been made in identifying effective, new

therapies for men with advanced castration-resistant prostate cancer (CRPC).

Three novel agents (sipuleucel-T, cabazitaxel, and abiraterone acetate) have

been shown to improve overall survival (OS) in these patients, while another

agent (denosumab) has been shown to result in a significant delay in skeletalrelated events (SRE) in men with castration-resistant bone metastases.

Despite these advances, approximately 30,000 men still die of advanced prostate cancer in the United States each year,1 making it the second most common cause of cancer-related death among American men. Therefore, additional treatments are needed and available therapies need to be optimized. This review discusses the range of novel agents that are newly approved or expected to be approved soon for the management of metastatic CRPC (Figure 1) and highlights emerging agents that have shown promise and are in Phase III clinical development (Table 1).

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Newly Approved Agents: Where Do They Fit In? SIPULEUCEL-T Cancer immunotherapy refers to approaches that attempt to treat cancer by activating an immune response against malignant cells while overcoming tumor-induced tolerance, a major resistance mechanism (Figure 2). Prostate cancer may be an ideal target for immunologic attack because it produces several tissuespecific proteins that may serve as tumor antigens, such

C L I N I C A L O N CO LO GY

NEWS â&#x20AC;˘ AUGUST 2011

1

Non-metastatic hormoneresponsive prostate cancer Non-metastatic CRPC Clinically localized prostate cancer

Biochemically relapsed prostate cancer

(Prostatectomy Radiation Âą ADT Brachytherapy Primary ADT Active surveillance)

(Salvage radiation)

Supportive Care

Metastatic hormone-responsive prostate cancer

Metastatic CRPC

Chemotherapyrefractory CRPC

Observation â&#x17E;&#x17E; ADT

Zoledronic acid or denosumab

Docetaxelprednisone

Abiraterone, cabazitaxel, mitoxantrone

Sipuleucel-T

= Standard of care

Secondary/tertiary hormonal therapies (anti-androgens, ketoconazole, steroids, estrogens)

= Speculative MDV3100, orteronel, ipilimumab, abiraterone

Figure 1. The treatment landscape for prostate cancer in 2011.

ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer

as prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) (Figure 3). This notion has been applied to the development of sipuleucel-T (Provenge, Dendreon), an autologous PAP-loaded dendritic cell immunotherapy.2 During treatment with sipuleucel-T, a patientâ&#x20AC;&#x2122;s own antigen-presenting cells are collected by leukapheresis and co-incubated with a fusion protein containing PAP linked to granulocyte macrophage colony-stimulating factor (GM-CSF). After this fusion protein is cultured with the antigen-presenting cells, the primed immunotherapy is reinfused into the patient, activating T cells via major histocompatibility complex class I and class II molecules and resulting in a PAPspecific antitumor attack.3 Several early-phase clinical trials using this immunotherapy have demonstrated the safety of this personalized cellular product and have hinted at the potential ability to improve outcomes. Two small, randomized Phase II trials powered to detect a progression-free survival (PFS) advantage failed in their primary end point but showed that sipuleucel-T resulted in a significant 4- to 5-month survival

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advantage over placebo.4,5 Adverse events (AEs) with sipuleucel-T are generally mild and include fever, chills/ sweats, myalgia, and headache. These usually occur during or shortly after infusion of the immunotherapy.

To definitively evaluate the effect of sipuleucel-T on survival, the pivotal multicenter Phase III IMPACT trial was conducted in men with asymptomatic or minimally symptomatic metastatic CRPC,6 leading to the FDA approval of this agent in April 2010. In this double-blind, placebo-controlled trial, 512 patients were randomized (2:1) to sipuleucel-T or placebo, and the study was powered to detect an OS advantage. Notably, this study did not enroll men with visceral metastases or those taking narcotics for cancer pain, and most patients (85%) were chemotherapy-naive. Impressively, median OS was 25.8 months in the sipuleucel-T group versus 21.7 months in the placebo group (hazard ratio [HR], 0.78; P=0.03), despite 64% of patients on placebo crossing over to receive salvage sipuleucel-T. In the subset of patients with prior chemotherapy exposure, OS trended in favor of sipuleucel-T, but this effect was not statistically significant. Therefore, although this immunotherapy is

approved for all patients with asymptomatic or minimally symptomatic CRPC, it likely will have its largest impact in the pre-chemotherapy setting.

Similar to previous studies with sipuleucel-T, the IMPACT study found no difference in PFS or PSA/radiographic response rates between the 2 treatment arms. Some investigators attribute the discordance between PFS and OS to a possible class effect of immunotherapy agents, relating to their mechanism of action, which is distinct from that of cytotoxic therapies. To this end, a similar phenomenon has been observed in a study using a PSA-directed poxviral-based immunotherapy product (ProstVac-VF) in men with metastatic CRPC.7 Problematic end points such as PFS in CRPC (which may be confounded by bone scan flare or delayed-onset effects) may be better addressed by revised guidelines using outcomes that are tailored to immunologic agents.8

CABAZITAXEL WITH PREDNISONE Cabazitaxel (Jevtana, Sanofi-aventis) is a novel tubulin-binding taxane that differs from docetaxel and paclitaxel because of its poor affinity for P-glycoprotein, the adenosine triphosphate–dependent drug efflux pump.9 In preclinical studies using cancer cell lines and mouse xenograft models, cabazitaxel was shown to be active against both docetaxel-sensitive tumors as well as those with primary or acquired docetaxel resistance.10 The first hint of cabazitaxel’s safety and efficacy in men with prostate cancer came during Phase I testing, during which cabazitaxel was administered by IV infusion every 3 weeks at escalating doses of 10 to 25 mg/m2.11 In that study, the principal dose-limiting toxicity was neutropenia. Given the lack of cross-resistance to this agent with docetaxel and early reports of responses in men with CRPC during this Phase I trial, a Phase III trial was launched to evaluate efficacy.

The pivotal Phase III TROPIC trial definitively evaluated the safety and efficacy of cabazitaxel in 755 men with metastatic CRPC who had progressed during or after docetaxel-based chemotherapy.12 Of these, 377 patients were randomized to receive mitoxantrone 12 mg/m2 IV every 3 weeks (with oral prednisone 10 mg daily) and 378 patients were assigned to receive cabazitaxel 25 mg/m2 IV every 3 weeks (plus prednisone). This study was the basis for the FDA’s approval of cabazitaxel with prednisone for the second-line treatment of docetaxelrefractory metastatic CRPC in June 2010.

After a median follow-up of 12.8 months, OS in men receiving cabazitaxel was 15.1 months compared with 12.7 months in men receiving mitoxantrone (HR, 0.70; P<0.0001).12 Compared with mitoxantrone, cabazitaxel also significantly lengthened PFS (2.8 vs 1.4 months; P<0.0001), extended the time to PSA progression (6.4 vs 3.1 months; P=0.001), increased radiographic tumor

response rates (14.4% vs 4.4%; P=0.0005), and increased PSA response rates (39.2% vs 17.8%; P=0.0002). There were no differences between the 2 treatment arms with respect to pain responses or time to pain progression.

In subset analyses, the survival advantage of cabazitaxel persisted regardless of whether patients had measurable disease or pain or whether progression had occurred during docetaxel therapy or following a treatment holiday. In addition, cabazitaxel’s survival benefit was most pronounced for men with Eastern Cooperative Oncology Group performance status 0 to 1 (vs 2) and for patients with disease progression less than 3 months after docetaxel initiation (vs 3 or more months after docetaxel initiation).12 The last observation implies that cabazitaxel may be effective even in men with truly docetaxel-refractory disease.

The most common serious AEs related to cabazitaxel were hematologic, including grade 3 or higher neutropenia in 82% of patients (febrile neutropenia in 8%).12 This degree of myelosuppression begs the question of whether a lower dose of cabazitaxel (eg, 20 mg/m2) may have been more appropriate, and a randomized trial comparing the safety and efficacy of these 2 doses (25 vs 20 mg/m2) is being conducted.

Use of growth factor support should be strongly considered, as recommended in several national guidelines.13 Nonhematologic toxicities included grade 3 or higher diarrhea (6%) and grade 3 or higher fatigue (5%). Although peripheral neuropathy (all grades) was observed in 14% of patients receiving cabazitaxel, only 1% developed grade 3 neuropathy.

ABIRATERONE ACETATE WITH PREDNISONE Ectopic (adrenal, intratumoral, paracrine) androgen production in the setting of gonadal ablative therapies represents an important resistance mechanism in CRPC (Figure 2). Abiraterone acetate (Zytiga, Centocor Ortho Biotech) is a potent, selective, and irreversible oral inhibitor of the steroidogenic enzyme CYP17, blocking 17α-hydroxylase and C17,20-lyase activity.14 As a result, extragonadal androgen production is impaired through the inability to convert pregnenolone to dihydroepiandrostenedione and progesterone to androstenedione. In an initial Phase I study in men with chemotherapy-naive CRPC, the primary toxicities of abiraterone (hypertension, hypokalemia, and peripheral edema) were related to a syndrome of secondary mineralocorticoid excess due to feedback upregulation of mineralocorticoid synthesis and were largely reversible with administration of an aldosterone receptor antagonist or a corticosteroid.15 For this reason, in several subsequent trials, abiraterone was combined with lowdose prednisone, which also may enhance the efficacy of abiraterone.

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Table 1. Selected Ongoing Phase III Clinical Trials in Men With Metastatic CRPC Target/Pathway

Primary End Point

Identifier

Cabazitaxel 25 mg/m2 IV every 3 wk vs docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT01308567

III

Cabazitaxel 25 mg/m2 IV every 3 wk vs cabazitaxel 20 mg/m2 IV every 3 wk (post-docetaxel)

OS (noninferiority)

NCT01308580

Abiraterone

III

Abiraterone 1,000 mg orally daily vs placebo orally daily (pre-docetaxel)

OS and PFS (co-primary)

NCT00887198

Orteronel

III

Orteronel 400 mg orally twice daily vs placebo orally twice daily (pre-docetaxel)

OS and PFS (co-primary)

NCT01193244

III

Orteronel 400 mg orally twice daily vs placebo orally twice daily (post-docetaxel)

OS

NCT01193257

III

MDV3100 160 mg orally daily vs placebo orally daily (pre-docetaxel)

OS and PFS (co-primary)

NCT01212991

III

MDV3100 160 mg orally daily vs placebo orally daily (post-docetaxel)

OS

NCT00974311

III

Ipilimumab 10 mg/kg IV every 3 wk vs placebo IV every 3 wk (pre-docetaxel)

OS

NCT01057810

III

Bone irradiation, then ipilimumab 10 mg/kg IV every 3 wk vs placebo IV every 3 wk (post-docetaxel)

OS

NCT00861614

Agent

Phase

Treatment Arm(s)

Cabazitaxel

III

Cabazitaxel

Chemotherapeutic agents Microtubules (taxane)

AR-directed approaches CYP17 (androgen synthesis)

Androgen receptor

MDV3100

Immunotherapies CTLA-4 (immune checkpoint)

Ipilimumab

The initial efficacy of abiraterone in CRPC was investigated in several Phase II trials. In patients with chemotherapy-naive metastatic CRPC, PSA declines of at least 50% were seen in approximately 65% of men and radiographic tumor responses occurred in about 35% of men,16 with responses noted even among men who had prior ketoconazole exposure.17 Finally, in patients with docetaxel-refractory metastatic CRPC, PSA declines of at least 50% were observed in approximately 40% of men and objective tumor responses occurred in approximately 20% of cases.18,19 Notably, the use of a corticosteroid on PSA progression frequently led to subsequent secondary PSA declines, suggesting a reduction in androgen receptor (AR) activation by upstream steroidal precursors that are increased by feedback mechanisms.

To conclusively evaluate the efficacy and safety of abiraterone, a pivotal, multicenter, randomized, blinded, placebo-controlled Phase III trial (COU-AA-301) was conducted in men with docetaxel-pretreated, ketoconazole-naive metastatic CRPC.20 This trial randomized men (2:1) to receive either abiraterone 1,000 mg daily plus prednisone 10 mg daily (n=797) or placebo plus prednisone (n=398). The trial met its primary end point, demonstrating a median OS of 14.8 months in the abiraterone arm and 10.9 months in the placebo arm (HR, 0.65; P<0.0001). In addition, when compared with placebo,

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abiraterone prolonged radiographic PFS (5.6 vs 3.6 months; P<0.0001), improved time to PSA progression (10.2 vs 6.6 months; P<0.0001), and produced more PSA responses (38% vs 10%; P<0.0001). Notably, the OS duration seen here (14.8 months) is similar to that seen with cabazitaxel/prednisone (15.1 months) in this secondline population with similar baseline characteristics (Table 2); however, the survival of men treated with prednisone alone was slightly inferior to that associated with mitoxantrone/prednisone in the TROPIC trial (10.9 vs 12.7 months). Based on the results of the COU-AA-301 trial, on April 28, 2011 the FDA approved abiraterone with prednisone for patients with metastatic CRPC who have received prior docetaxel-based chemotherapy. Recently updated National Comprehensive Cancer Center guidelines specify that abiraterone acetate with prednisone should be considered for men who have failed docetaxelbased chemotherapy for metastatic CRPC or who are not candidates for chemotherapy.21 A second randomized Phase III trial (COU-AA-302) targeting men with docetaxeland ketoconazole-naive CRPC has completed accrual of more than 1,000 patients. Given the comfort level and safety of using this and other hormonal agents in patients with prostate cancer prior to chemotherapy, it is very likely that abiraterone will be used clinically in both the pre- and post-docetaxel settings.22

Table 1. Selected Ongoing Phase III Clinical Trials in Men With Metastatic CRPC Target/Pathway

Agent

Phase

Treatment Arm(s)

Primary End Point

Identifier

Other targeted therapies Src kinase (bone regulation)

Dasatinib

III

Dasatinib 100 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs placebo orally daily plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT00744497

Clusterin (apoptosis)

Custirsen

III

Custirsen 640 mg IV every 1 wk plus docetaxel 75 mg/m2 IV every 3 wk vs docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT01188187

III

Custirsen 640 mg IV every 1 wk plus docetaxel 75 mg/m2 IV every 3 wk vs placebo IV every wk plus docetaxel 75 mg/m2 IV every 3 wk (post-docetaxel)

Improvement in pain

NCT01083615

VEGF-Trap (angiogenesis)

Aflibercept

III

Aflibercept 6 mg/kg IV plus docetaxel 75 mg/ m2 IV every 3 wk vs placebo IV plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT00519285

Immunomodulatory drugs (angiogenesis)

Lenalidomide

III

Lenalidomide 25 mg orally (days 1-14) plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo (days 1-14) plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT00988208

S100A9 (angiogenesis)

Tasquinimod

III

Tasquinimod 1 mg orally daily vs oral placebo daily (pre-docetaxel)

PFS

NCT01234311

Endothelin (bone targeting)

Atrasentan

III

Atrasentan 10 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS and PFS (co-primary)

NCT00134056

Zibotentan

III

Zibotentan 10 mg orally daily plus docetaxel 75 mg/m2 IV every 3 wk vs oral placebo plus docetaxel 75 mg/m2 IV every 3 wk (pre-docetaxel)

OS

NCT00617669

AR, androgen receptor; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CYP17, cytochrome P450 17; OS, overall survival; PFS, progressionâ&#x20AC;&#x201C;free survival; Src, signal-regulated kinase; VEGF, vascular endothelial growth factor

DENOSUMAB: OSTEOCLAST-TARGETED THERAPY Interactions between tumor cells and the bone marrow microenvironment have been postulated as an important mechanism in the pathogenesis of bone metastasis.

Tumor-associated cytokines have been shown to induce the expression of RANKL (receptor activator of nuclear factor-ÎşB ligand), which binds and activates RANK found on osteoclasts.23 Inhibition of RANKL recently has been the focus of much clinical research and represents an effective osteoclast-targeting strategy for patients with bone metastases.

Denosumab (Xgeva, Amgen) is a fully human monoclonal immunoglobulin G2 antibody with a very high affinity for human RANKL.24 Denosumab, which has been examined in a variety of clinical settings, including postmenopausal osteoporosis and several cancers, has demonstrated efficacy in bone-metastatic solid tumors predominantly. An early Phase II study demonstrated that denosumab (120 mg subcutaneously every 4 weeks) was associated with a reduction of bone resorption compared with zoledronic acid (Zometa, Novartis) (4 mg IV

every 4 weeks), as indicated by a lowering of urinary N-telopeptide levels, and also resulted in fewer SREs, that is, pathologic fracture, radiation therapy, surgery to bone, spinal cord compression, or malignant hypercalcemia.25 Following these encouraging results, a pivotal, multicenter, randomized double-blind, Phase III study was conducted comparing denosumab with zoledronic acid for the prevention of SREs in patients with bisphosphonate-naive metastatic CRPC. In that trial of 1,904 patients, compared with men receiving zoledronic acid (n=951), men receiving denosumab (n=950) had an improved time to first SRE (20.7 vs 17.1 months; P=0.008) and longer time to first and subsequent SRE (HR, 0.82; P=0.004).26 Notably, there were no differences in OS or PFS between study arms. Based partially on the results of this study (and partially on 2 other large randomized studies in metastatic breast cancer and other solid metastatic tumors), the FDA approved denosumab in November 2010 for the prevention of SREs in patients with bone metastases from solid tumors. Common toxicities of denosumab include fatigue, nausea, hypophosphatemia,

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Immunologic escape/tolerance Proliferative signals (MAP kinases, Myc, tubulin signaling)

AR-independent mechanisms

Survival signals (PTEN loss, Akt activation, JNK, VEGF, MET) Bone microenvironment (Src kinase, endothelin, RANKL) Stem cell factors (hedgehog), antiapoptotic sig nals (Bcl-2, clusterin), EMT programs, DNA repair

Metastatic Androgen ablation prostate Antiandrogens cancer

CRPC AR amplification/overexpression AR gene mutation (activating) or mRNA splice variants

AR-dependent mechanisms

Ectopic androgen synthesis (adrenal, intratumoral) AR-dependent fusion proteins (TMPRSS2-ERG) Non-canonical AR signaling (Src, G proteins, Akt, PKA/PKC)

Figure 2. Mechanisms of castration resistance in prostate cancer.

AR, androgen receptor; CRPC, castration-resistant prostate cancer; EMT, epithelial to mesenchymal transition; JNK, Jun N-terminal kinase; MAP, mitogen-activated protein; MEK, MAP kinase kinase; PKA/PKC, protein kinase A/protein kinase C; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RANKL, receptor activator of nuclear factor-κB ligand; Src, signal-regulated kinase; VEGF, vascular endothelial growth factor

hypocalcemia (5% ≥ grade 3), and osteonecrosis of the jaw (2%). Prophylactic calcium and vitamin D supplementation is strongly encouraged when this agent is used.

Denosumab is a reasonable alternative to zoledronic acid for the prevention of SREs in patients with metastatic CRPC, with the advantage that it does not require dose adjustment or monitoring for renal impairment.

Emerging Agents in Phase III Testing: The Pipeline NOVEL HORMONAL APPROACHES: TARGETING

THE

AR

Orteronel. Orteronel (TAK-700) is a new oral, nonsteroidal, selective CYP17 inhibitor that is more potent than abiraterone at suppressing extragonadal androgen biosynthesis without impairing cortisol

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production,27 providing a theoretical advantage of preventing adrenocorticotropic hormone feedback upregulation and avoiding complications related to secondary mineralocorticoid excess. In a Phase I/II study using orteronel in patients with metastatic CRPC, 52% of men receiving daily doses 600 mg or greater demonstrated at least 50% PSA reductions (and 29% of men showed at least 90% PSA reductions).28 Importantly, the incidence of hypertension and hypokalemia in this trial was low, supporting the notion of preferential inhibition of C17,20-lyase over 17α-hydroxylase in humans. Based on the initial promising activity, 2 multicenter, randomized, Phase III trials have been launched comparing orteronel in combination with prednisone against prednisone alone both before and after docetaxel in patients with metastatic CRPC.

MDV3100. A slightly different AR-directed approach has focused on the development of secondgeneration antiandrogens that have advantages over the established agents in this class (bicalutamide, nilutamide, flutamide). One such drug is MDV3100, a potent oral nonsteroidal AR antagonist.29 Importantly, MDV3100 remains a potent antagonist of the AR in the castration-resistant state, even in the setting of overexpressed or constitutively activated AR. 30 In addition, unlike other antiandrogens that also may

Bevacizumab, aflibercept

Abiraterone, orteronel

Adrenal gland

function as partial AR agonists, MDV3100 does not exhibit any measurable agonistic activity and is able to prevent AR nuclear translocation with resultant tumoricidal (not cytostatic) activity.31 Notably, recent studies have demonstrated the emergence of ligandindependent AR splice variants in CRPC, some of which may also be inhibited by MDV3100.

A Phase I/II study of oral MDV3100 in men with chemotherapy-naive (n=65) or taxane-pretreated (n=75) metastatic CRPC recently was published.32 In that trial,

Ipilimumab

Sipuleucel-T GM-CSF

PAP

APC

Cabozantinib

Dasatinib

A

IGF-1R

Src

VEGF-R

CTLA-4

T cell

PAP peptide

T cell

Ras P13K Raf

AR

Src

PTEN

Cell death Akt

MEK Stress TOK-001

A

HSP

HSP

ERK

mTOR

AR

Clusterin

MDV3100

Growth, differentiation, transformation

Survival, proliferation, angiogenesis Custirsen

Apoptosis HDAC PARP

DNMT

A CoAct

Transcription

AR

Figure 3. Promising pathways and targets in metastatic CRPC. A, androgen; APC, antigen-presenting cell; AR, androgen receptor; CoAct, transcriptional coactivators; DNMT, DNA methyltransferase; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte macrophage colony-stimulating factor; HDAC, histone deacetylase; HSP, heat shock protein; IGF-1R, insulin-like growth factor receptor-1; MEK, MAP kinase kinase; mTOR, mammalian target of rapamycin; PAP, prostatic acid phosphatase; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; Src, signal-regulated kinase; VEGF-R, vascular endothelial growth factor receptor

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Table 2. Pivotal Second-line Trials For Men With Metastatic CRPC: COU-AA-301 Versus TROPIC Cabazitaxel/ Prednisone (TROPIC)

Abiraterone/ Prednisone (COU-AA-301)

Median baseline PSA, ng/mL

144

129

Pain at baseline, %

46

44

Presence of visceral disease, %

25

29

2 (or more) prior chemotherapies, %

31

30

Median OS, mo

15.1

14.8

Median time to tumor progression, mo

8.8

5.6

Median time to PSA progression, mo

6.4

10.2

PSA response rate (â&#x2030;Ľ50% PSA decline), %

39

29

Objective response rate, %

14

14

Pain response, %

9

44

OS, overall survival; PSA, prostate-specific antigen

PSA declines of at least 50% were seen in 62% and 51% of chemotherapy-naive and taxane-pretreated patients, respectively, and objective tumor responses were observed in 36% and 12%, respectively. Radiographic PFS was 6.7 months in the docetaxel-pretreated patients, and more than 17 months in chemotherapy-naive patients.

Side effects of MDV3100 are generally mild, and include fatigue (27%) and nausea (9%). Rare seizures (3 of 140 patients), perhaps mediated by a direct effect of AR antagonism on central nervous system Îł-aminobutyric acid-A receptors, also were reported.33 A pivotal, double-blind, placebo-controlled Phase III study (AFFIRM), randomizing 1,170 patients with docetaxel-pretreated ketoconazole-naive CRPC to MDV3100 160 mg daily (n=780) or placebo (n=390), has completed accrual. A second randomized Phase III trial (PREVAIL) investigating the same treatment arms in men with chemotherapy-naive CRPC is under way. One advantage of MDV3100 over agents such as abiraterone or orteronel is the lack of requirement for concurrent corticosteroid administration. However, the optimal sequencing of this agent, if approved, with immunotherapies and other emerging hormonal therapies will need to be defined through future clinical trials.

NOVEL IMMUNE APPROACHES Ipilimumab. Because of ongoing host immunologic pressures on evolving tumors, cancers have developed

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mechanisms to escape immune surveillance, effectively inducing a state of immune tolerance.34 One way to inhibit immunologic evasion by tumor cells is through blockade of the immune checkpoint molecule cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), thus preventing the normal attenuation of antitumor T-cell responses.35 In murine prostate cancer models, CTLA-4 inhibition has been shown to potentiate T-cell effects and induce tumor rejection.

Several clinical trials using the monoclonal anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) have been conducted in men with metastatic CRPC. These include Phase I and II studies of ipilimumab as monotherapy or in combination with radiation,36 as well as a Phase I study combining ipilimumab with GM-CSF.37 PSA reductions of at least 50% were observed in approximately 20% of patients, and radiologic tumor responses were seen in approximately 5% of patients, which is particularly noteworthy, given that PSA and tumor responses were rarely reported in the immunotherapy trials with sipuleucel-T or other therapeutic vaccines. Common AEs of ipilimumab include fatigue (42%), nausea (35%), pruritus (24%), constipation (21%), and rash (19%). In addition, because CTLA-4 normally serves to attenuate autoimmunity, immunologic toxicities resulting from an unchecked immune response may occur. Such immune-related AEs include colitis (8%), adrenal insufficiency (2%), hepatitis (1%), and even hypophysitis (1%).38 Ipilimumab is in placebo-controlled Phase III testing in the post-docetaxel setting in men with CRPC following a palliative (and perhaps immunestimulatory) dose of radiation to a metastatic site, with the intent to demonstrate a survival advantage over radiation alone. A second pre-docetaxel placebocontrolled Phase III study also is under way.

NOVEL TARGETED THERAPIES Src kinase inhibitors. Src is a non-receptor tyrosine kinase signal transduction protein that is involved in tumor cell proliferation, migration, angiogenesis, survival, and transition to the castration-resistant state.39 Src also controls osteoclastic activity and has been implicated in the development and progression of bone metastases.40 Dasatinib is an oral inhibitor of multiple oncogenic kinases including Src. In experimental models, dasatinib reduced proliferation of prostate cancer cells, adhesion, migration, invasion, tumor growth, and lymph node involvement in a prostate cancer mouse xenograft model.41,42 Although single-agent dasatinib (Sprycel, BristolMyers Squibb) has demonstrated little clinical activity, more than half of CPRC subjects had at least 40% declines in urinary N-telopeptide levels (a marker of bone resorption), and 60% showed reductions in bone

alkaline phosphatase, suggesting benefits on bone turnover independent of bisphosphonate use.43 In a separate Phase I/II study combining dasatinib with docetaxel in a similar patient population, PSA responses were observed in 57% of participants, objective responses were seen in 60% of patients, and 30% of patients with bone metastases showed amelioration in bone scans.44 A large randomized, placebo-controlled Phase III study evaluating this combination in 1,500 men with metastatic chemotherapy-naive CRPC has completed accrual and is powered to detect an OS advantage.

Adverse effects of dasatinib include diarrhea (62%), nausea (47%), fatigue (45%), and fluid retention (21%).

Pro-apoptotic drugs. Clusterin, a stress-induced anti-apoptotic chaperone protein expressed in various cancers including prostate cancer,45 has received renewed attention due to the development of antisense inhibitors to this protein.

Expression of clusterin in prostate tumors increases after androgen ablation or chemotherapy treatment,46 conferring a more resistant phenotype. Custirsen (Oncogenex) is a novel intravenously administered antisense oligonucleotide that inhibits clusterin at the mRNA level, increasing sensitivity to androgen deprivation as well as chemotherapy in prostate cancer cell lines and xenograft models.47 In a randomized Phase II study of docetaxel with or without custirsen in 82 patients with metastatic CRPC, PSA responses (58% vs 54%) and PFS (7.3 vs 6.1 months) were similar in both arms.48 However, OS trended in favor of the combination arm (23.8 vs 16.9 months; P=0.06), even though survival was not the primary end point of this study and was potentially confounded by subsequent therapies. AEs associated with custirsen include fatigue (>80%), fever (30%-50%), rigors (40%-60%), diarrhea (40%-60%), and rash (20%-40%). A placebo-controlled Phase III study of docetaxel retreatment with or without custirsen for the second-line management of men with docetaxelrefractory disease was recently launched. However, the recent approvals of cabazitaxel and abiraterone and changing standards of care call into question the value of docetaxel retreatment in all but a select group of men in this setting.

A n t i a n g i o g e n i c s t ra t e g i e s .

Tumor angiogenesis may play an important role in prostate cancer maintenance and progression, and elevated plasma levels of vascular endothelial growth factor (VEGF) have been correlated with advanced clinical stage and decreased survival.49 Antibodies to VEGF slow tumor proliferation in prostate cancer xenograft models, especially when combined with chemotherapy.50 However, despite a strong preclinical rationale, a Phase III randomized study in men with chemotherapyu n t r e a t e d C R P C (C A LG B 90401) failed to show a survival advantage with the anti-VEGF antibody bevacizumab (Avastin, Genentech) when combined with docetaxel compared with docetaxel alone (22.6 vs 21.5 months), although significant improvements were seen in PSA responses (70% vs 58%), radiographic responses (53% vs 42%), and PFS (9.9 vs 7.5 months).51 Additionally, a Phase III trial of sunitinib malate (Sutent, Pfizer) versus prednisone in men with docetaxelpretreated metastatic CRPC failed to demonstrate an OS advantage, despite modest improvements in response rates and PFS.52 These results call into question the role for VEGF-based therapies in unselected men with CRPC. Future development of this and other antiangiogenic agents may rely on combinations with other classes of angiogenesis inhibitors or other chemotherapeutic drugs whose toxicities do not overlap and will require careful patient selection for those men who are most likely to benefit from this class of agents.

Another angiogenic/metastatic target that has received recent attention is MET, a transmembrane receptor whose only known ligand is hepatocyte growth factor. Aberrant activation or overexpression of MET is a common event in prostate cancer (especially in castration-resistant bone metastases) and is associated with proliferation, invasion, and angiogenesis.53 Moreover, androgen suppression can induce increased MET expression.54 Cabozantinib (XL184, Exelixis) is a potent oral inhibitor of MET and VEGF-receptor 2 that has demonstrated robust antiangiogenic, antiproliferative, and anti-invasive activity in preclinical systems.55 Preliminary results from a Phase II study in men with metastatic CRPC with up to one prior chemotherapy revealed objective responses in 10% of evaluable patients, and improvements in bone scans after 12

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weeks in 95% of men with osseous metastases (often accompanied by pain improvements).56 Toxicities with this agent include fatigue (67%), diarrhea (55%), anorexia (51%), emesis (44%), and hypertension (22%).

Although the 12-week success rates in bone lesions are striking (including complete resolution of skeletal abnormalities in some bone scans), the lack of robust PSA responses and the uncertainty over the durability of these results will require confirmatory controlled trials to assess the overall clinical benefit of this agent.

Further investigation of this agentâ&#x20AC;&#x2122;s activity in the bone using novel imaging techniques (eg, 18Fluoride-positron emission tomography) or pharmacodynamic studies should also be considered to further understand how cabozantinib influences metastatic disease.

A final angiogenesis-inhibiting agent that has received renewed attention is the oral quinoline derivative tasquinimod. Although the antiangiogenic properties of this agent have been amply demonstrated in several in vitro and in vivo prostate cancer models,57 the exact mechanism of action remains elusive and appears to be unrelated to VEGF receptor inhibition. It may include inhibition of S100A9, a calcium-binding protein involved in cell cycle progression and differentiation as well as recruitment of tumor-infiltrating myeloid-derived suppressor cells.58 A randomized, double-blind placebocontrolled Phase II study involving 200 patients with chemotherapy-naive metastatic CRPC demonstrated that patients receiving oral tasquinimod had a median PFS of 7.6 months versus 3.2 months in those receiving placebo (P=0.001).59 AEs with this agent included gastrointestinal disorders (40%), fatigue (23%), musculoskeletal pain (12%), and asymptomatic pancreatic enzyme elevations.

Rare but serious toxicities were venous thrombosis (4%), heart failure (1%), myocardial infarction (1%), and stroke (1%). A multicenter, randomized Phase III trial of tasquinimod versus placebo in patients with chemotherapy-untreated metastatic CRPC is under way.

Conclusion Despite more drugs for the treatment of metastatic CRPC at our fingertips than ever before and an increasing number of novel therapeutic targets being discovered every day, we are still left with several challenges and unanswered questions. First, we must determine how these approved and experimental therapies should ideally be sequenced in individual patients with CRPC. For example, should sipuleucel-T routinely be given prior to chemotherapy or abiraterone with prednisone?

Should abiraterone be reserved for docetaxel-resistant patients? How should we treat cabazitaxel-refractory patients? Second, we need to develop strategies to optimally combine these drugs in a rational manner, taking advantage of our understanding of negative

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feedback loops and alternative pathway activation to overcome resistance to monotherapies. Ultimately, only prospective trials incorporating biomarker-driven hypotheses will be able to address these key clinical questions. Thus, the collection of tumor specimens or correlative samples may be essential in identifying novel targets or developing enrichment strategies for future study of these agents. Third, we must design smarter trials with the goal of quickly yet reliably identifying agents that do not hold promise while enabling those that do to move swiftly to registrational studies. For example, in the clinical development of MDV3100 and cabazitaxel, pivotal Phase III trials were designed directly following the initial Phase I/II studies that demonstrated significant drug activity in men with CRPC. Finally, we must select our patients more carefully based on clinical or molecular characteristics to identify the subset most likely to benefit from a particular therapy. For example, in men with significant pain, perhaps sipuleucel-T is not appropriate systemic therapy given the prolonged onset of action and lack of palliative benefits; additionally, immune-based biomarkers may shed light on which men may obtain a greater degree of benefit from immunotherapies.

In summary, cabazitaxel was the first agent to be approved by the FDA for men with metastatic CRPC who have progressed after docetaxel chemotherapy, and abiraterone acetate also recently was approved in this same population. In addition, sipuleucel-T has been FDA approved for patients with asymptomatic or minimally symptomatic metastatic CRPC and may be best used in men without visceral metastases. In addition, denosumab gained FDA approval for the prophylaxis of skeletal-related events in men with castration-resistant bone metastases and may have some advantages over zoledronic acid. Palliative radiation or radiopharmaceuticals (eg, samarium, strontium, or investigational radium) also may play a significant role in the management of men with symptomatic disease, before or after systemic therapies. Several additional active agents are in Phase III development, and some of these therapies also are likely to further expand our therapeutic arsenal for men with metastatic CRPC in the near future.

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NEWS FROM THE JOURNALS

Clinical Oncology News • August 2011

Long-term Data Confirm Value of CMV Regimen for Bladder Cancer From Journal of Clinical Oncology

C

isplatin, vincristine, and vinblastine (CMV) chemotherapy together with local therapy improves survival outcomes as first-line adjunctive treatment in invasive bladder cancer, according to long-term results from a la rg e i n t e r n at io n a l Phase III trial.

Reflecting follow-up for patients alive at eight years, these updated results from the BA06 30894 trial (J Clin Oncol 2011;29:2171-2177, PMID: 21502557) confirm the four-year results published in 1999 (Lancet 1999;354:533-540, PMID: 10470696). The latest results show a statistically significant 16% reduction in the risk for death, which corresponds to an increase in 10-year survival from 30% to 36%, among patients treated with CMV. Patients in the study had histologically proven muscle-invasive urothelial cell carcinoma of the bladder (T2, in 34% of patients; T3, in 58%; and T4a, in 8%), with glomerular filtration rates greater than 50 mL per minute. This trial recruited 976 patients from 106 institutions in 20 countries between 1989

and 1995. Of these, 491 patients were randomized to receive CMV chemotherapy and 485 were not. Most (88%) were men; the median age was 64 years; and most (88%) had grade 3 disease.

The choice of local treatment was up

to the patient, with 43% choosing local radical radiotherapy, 50% choosing cystectomy and 8% choosing a combination of the two. The data used in this trial were locked in 2005, with further analyses being problematic for institutional reasons.

The CMV regimen—repeated every 21 days for three cycles—consisted of methotrexate 30 mg/m2 IV bolus and vinblastine 4 mg/m2 IV bolus, on day 1; cisplatin 100 mg/m2 IV infusion, on day 2 before hydration, and folinic acid

15 mg (oral or IV) every six hours for four doses commencing 24 hours after methotrexate, on day 2 after hydration; methotrexate 30 mg/m2 IV bolus and vinblastine 4 mg/m2 IV bolus, on day 8; and oral folinic acid 15 mg every six hours for four doses after methotrexate, commencing on day 9.

The updated analysis showed a 16% reduction in the risk for death after CMV chemotherapy (hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99; P=0.037), corresponding to statistically significant increases in three-year survival from 50% to 56% and in 10-year survival from 30% to 36%. Median survival increased seven months, from 37 to 44 months.

Serious adverse effects from the CMV regimen were uncommon, but five patients receiving the chemotherapy died from toxicity during treatment, for a mortality rate of 1%. Grade 3 or 4 leukopenia occurred in 16% of patients, thrombocytopenia in 6.5% and neutropenic fever in 10%.

The investigators concluded that the addition of CMV chemotherapy together with local therapy improves survival outcomes as first-line adjunctive

treatment in invasive bladder cancer and should be viewed as the state of the art, but they added that these survival benefits must be weighed against the inherent toxicity of chemotherapy.

EXPERT INSIGHT Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

“This article provides additional support for the paradigm of neoadjuvant chemotherapy in patients with muscleinvasive bladder cancer. This approach should be considered a standard of care, but adoption of this therapeutic strategy remains inconsistent. Collaboration between urologists and medical oncologists is now crucial for integration of this multimodality approach utilizing neoadjuvant chemotherapy prior to local treatment in patients with muscle-invasive localized bladder tumors.”

National Data Indicate Prostate Screening Is Overused From Journal of Clinical Oncology

P

rostate-specific antigen (PSA) screening is being performed unnecessarily, particularly among those with limited life expectancies, according to a recent review of nationwide data.

Although the widespread use of PSA screening for prostate cancer has resulted in a decline of more than 30%

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

relevance because it provides further support for the important role of MMR as a prognostic marker for stage II and III colon cancer. Specifically, this study showed that tumors with MMR-D have improved fiveyear DFS and OS. In sharp contrast to MMR status, 18qLOH assessment does not have prognostic significance in patients with stage II and III colon cancer.”

in mortality rates over the past two decades, it has been estimated that 1.3 million men, who would otherwise not have known they had the disease within their natural life span, have been diagnosed with and treated for prostate cancer. There is significant controversy over the role of PSA screening for prostate cancer, and advocates for screening do not always agree when the initial PSA level should be obtained or how frequently the screenings should be undertaken.

The present study (J Clin Oncol 2011;29:1736-1743, PMID: 21444863) sought to estimate the proportion of men in the United States aged 70 years or older who have had PSA-based prostate cancer screening and to determine whether estimated life expectancy was associated with PSA screening patterns. Investigators extracted data from the cancer screening survey supplement of the National Health Interview Survey, which is a face-to-face survey administered every five years by the U.S. Census Bureau; data from 2000 and 2005 were used.

The investigators included men aged 70 years or older (N=2,623), dividing

them into four five-year groups: 70 to 74, 75 to 79, 80 to 84, and 85 years or older. Data from men between the ages of 40 to 69 (N=11,984) were used as a comparator group. Researchers looked for a PSA test as part of a routine physical exam within the past year. In addition, demographic, socioeconomic and certain functional characteristics were collected, from which a validated fiveyear estimated life expectancy was calculated. The rate of PSA screening for each age grouping was determined, as were predictors for screening.

PSA screening rates were found to be 24.0% in men aged 50 to 54 years; 31.5% at 55 to 59 years; 38.2% at 60 to 64 years; 44.6% at 65 to 69 years; 45.5% at 70 to 74 years; 44.2% at 75 to 79 years; 35.7% at 80 to 84 years; and 24.6% in men aged 85 or older. In men aged 70 and older, screening varied by five-year life expectancy: 47.3% in men who had high life expectancy (15% or lower probability of five-year mortality), 39.2% in men who had intermediate life expectancy (16% probability of five-year mortality) and 30.7% in men who had low life expectancy (48% probability of five-year mortality).

This study demonstrated that PSA-

based prostate cancer screening is performed at “an unnecessarily high rate.”

The findings suggest that 750,000 men with a life expectancy of five years received PSA screening last year, from which they were unlikely to benefit. The investigators noted that excessive PSA screening leads to unnecessary anxiety and diagnoses, overtreatment, morbidity stemming from treatment and additional expenditures without meaningful clinical benefit. They suggest that a more thorough discussion with patients about the merits and limitations of PSA screening is warranted.

EXPERT INSIGHT Ronald M. Bukowski, MD

“The results of this study examine the value of PSA-based prostate cancer screening, an approach that remains controversial. The authors demonstrate the excessive use of PSA for prostate cancer screening in elderly men with a limited life expectancy, and suggest that this approach is unwarranted and is not associated with clinical benefit. Overall, the benefit of PSA-based screening remains poorly defined, but it is probably limited to men below the age of 70 years. Screening should not be routine in elderly patients, and it should be limited to patients with signs or symptoms of prostate cancer.”

17

KNOW YOUR PATIENTS’ HISTOLOGY AND BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ALIMTA is available in 100 mg and 500 mg vials.

Important Safety Information for Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia).

Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

PM70198

0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

ALIMTA® (pemetrexed for injection) Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence)— 1st-line NSCLC The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

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ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities 75% of previous dose (pemetrexed and Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin).

50% of previous dose (pemetrexed and Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials.

Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reactionb (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal — colitis General Disorders and Administration Site Conditions — edema

ALIMTA® (pemetrexed for injection)

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NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose b

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Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal.

7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3)].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-to-treat population.

8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay).

Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

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

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

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SOLID TUMORS

Clinical Oncology News • August 2011

Colorectal

All KRAS Mutations Are Not Created Equal Chicago—Tumor KRAS mutation status appears to have a far more complex effect on response to cetuximab in patients with metastatic colorectal cancer (mCRC) than previously thought.

Published studies have led researchers to conclude that wild type (WT) KRAS is a prerequisite for potential benefit from epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab (Erbitux, Merck) and panitumumab (Vectibix, Amgen), but a re-evaluation of tissue from two key trials indicates that the specific codon mutation is also important. Based on the data collected thus far, tumors with codon 13–mutant KRAS appear to retain some sensitivity to cetuximab. However, mutations in other codons, 12 and 61, not only appear to predict no benefit to anti-EGFR antibody therapy, but may predict a deleterious clinical outcome.

“These data suggest a heterogeneous treatment effect [from cetuximab] according to tumor KRAS mutation status,” reported Sabine Tejpar, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.

Speaking at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3511), Dr. Tejpar reported that one of the more intriguing findings from the retrospective analyses was that KRAS G13D mutation is an adverse prognostic sign—patients did less well on chemotherapy alone if they had this mutation.

“What is important to understand is that the absolute effect of cetuximab in tumors with KRAS G13D mutations is still lower than that obtained in the wild type [gene],” Dr. Tejpar reported, but those with KRAS G13D did less well even in the absence of cetuximab. She indicated that this was particularly true in the OPUS study, in which the presence of G13D predicted poor response, suggesting there may be a difference in how these types of tumors respond to

irinotecan compared with oxaliplatin, independent of the effect of cetuximab.

Although these data are considered preliminary because they are based on retrospective analyses, the researchers made a strong case for further subtyping KRAS mutations by codon. For their analysis, the investigators evaluated KRAS status in tumors from 1,378 patients participating in the CRYSTAL or OPUS studies. In CRYSTAL, 1,198 patients with EGFR-positive unresectable mCRC received FOLFIRI (irinotecan, fluorouracil and leucovorin) with or without cetuximab (N Engl J Med 2009;360:1408-1417, PMID: 19339720).

In OPUS, 337 patients received FOLFOX-4 (oxaliplatin, fluorouracil and leucovorin) with or without cetuximab (J Clin Oncol 2009;27:663-671, PMID: 19114683). In both studies, the advantage of cetuximab was restricted to patients with KRAS WT tumors.

When response was stratified by KRAS mutation type, Dr. Tejpar and her colleagues identified significant interactions for progression-free survival (PFS) (P<0.0001) and overall survival (OS) (P=0.0219). Dr. Tejpar noted that this was not the first study to suggest that the specific type of KRAS mutation was important for predicting response to cetuximab. She cited a pooled analysis that observed longer OS and PFS among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors (JAMA 2010;304:1812-1820, PMID: 20978259).

Dr. Tejpar said there is now growing

‘Future studies, of course, with anti-EGFR antibodies should include and stratify for G13D KRAS mutations.’

—Tanios S. Bekaii-Saab, MD

data that indicate that not all KRAS mutations are created equal.

Some experimental work also supports this premise. In a study of an mCRC cell line, the addition of KRAS codon 12 cells, but not G13D KRAS cells, reduced sensitivity to cetuximab, according to Dr. Tejpar. She noted that these data strengthen the potential importance of routinely assessing KRAS status in tumor samples for mCRC, but she also characterized the data as “exploratory” and as a basis for conducting prospective studies.

Among KRAS mutations, the G13D is the third most common, but it accounts for only about 8% of mCRC tumors, according to Dr. Tejpar. So far, the presence of G13D KRAS has not been predicted by any patient demographic characteristics.

Tanios S. Bekaii-Saab, MD, medical director of the gastrointestinal cancer program at The Ohio State University Comprehensive Cancer Center, in Columbus, was invited by ASCO to comment on this and several related papers, and he agreed that the study presented

by Dr. Tejpar supports other evidence that KRAS G13D mutations are prognostic of potential response to therapy.

He suggested the possibility that other KRAS mutations may also define different tumor behaviors, but that these will be more difficult to show in prospective studies because of the limited number of tumors expressing other codons.

The clinical significance of the initial evidence that the type of KRAS mutation might affect response to specific types of chemotherapy is less clear. Both Dr. Tejpar and Dr. Bekaii-Saab speculated that differences might be determined less by the mutation than by the gene expression associated with the mutation.

Although Dr. Bekaii-Saab agreed with Dr. Tejpar that KRAS mutation stratification might be potentially important in selecting therapy for mCRC, he said there was a risk for oversimplification.

“The EGFR signaling network is really quite large and complex, so we really need to leave behind the binary image of black and white—[the idea that everything can be explained by] the presence or absence of a mutation—and move to looking for a gene expression profiling,” Dr. Bekaii-Saab said. In the meantime, “future studies, of course, with antiEGFR antibodies should include and stratify for G13D KRAS mutations.”

The concept that gene expression profiles will be an even better indicator of heterogeneous mCRC biology than the KRAS DNA-based mutation status alone was also strongly endorsed by Dr. Tejpar.

“This is something I strongly believe in,” Dr. Tejpar said. “It could be useful to realize that DNA status may not be the best representation of the heterogeneous cellular states of KRAS mutations and that the near future will give us more tools to refine the molecular subclassification of this malignancy.”

—Ted Bosworth Dr. Tejpar disclosed she has received honoraria and research funding from Merck Serono. Dr. Bekaii-Saab reported no relevant disclosures.

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24

NEWS FROM THE JOURNALS

Clinical Oncology News • August 2011

Earlier Dx of Ovarian Ca Not Associated With Improved Survival From Journal of Clinical Oncology

E

arly diagnosis of ovarian cancer does not always lead to better survival rates, according to a recent report from Australian investigators.

About 75% of ovarian cancer diagnoses occur at International Federation of Gynecology and Obstetrics (FIGO) stages III or IV, and thus the prognosis for these women is poor, with less than 30% survival at five years. By contrast, those diagnosed at stage I have a five-year survival rate greater than 90%. Thus, if women could be diagnosed earlier in the progression of this disease, it seems logical that survival rates would improve.

However, despite attempts, evidence in support of the notion that earlier diagnosis leads to improvements in survival rates has been lacking because the interrelationship among symptom duration, diagnostic delay and stage of disease is muddled. Several studies both support and refute this hypothesis.

The investigators in the present study (published online ahead of print on May 2, 2011, J Clin Oncol 10.1200/ JCO.2010.32.2164) tested the

hypothesis that a shorter time to diagnosis results in a more favorable prognosis and greater survival in a sample of 1,463 women from the Australian Ovarian Cancer Study. Patients in this population-based, case–control study were interviewed and followed for five years.

The study found that 1,318 (90%) of the women initially presented to a physician after experiencing symptoms and 145 (10%) of women were diagnosed incidentally when the women visited a health care provider first for another reason. Among the first group, the time to diagnosis following symptom onset was less than two months in 39% of the women, less than three months in 61%, and less than six months in 78%. No significant differences were observed between the time to onset of symptoms to either initial medical consultation or diagnosis among women with borderline, early (FIGO stages I

and II) or late (stages III or IV) ovarian cancer. The asymptomatic cancers that were found incidentally (n=145) predominated in younger women (P=0.01) who were more likely to have borderline or stage I disease than symptomatic women (54% vs. 33%) and less likely to have stage III or IV disease (59% vs 34%; P<0.001). There also was no association noted between the time from clinical diagnosis and survival, with the adjusted hazard ratio for long delay (>12 months from symptom onset to diagnosis) compared with short delay (≤1 month) being 0.94 (95% confidence interval, 0.68-1.30).

The investigators concluded that the common assumption that decreasing the time to diagnosis in symptomatic advanced-stage ovarian cancer would necessarily lead to better survival rates was not borne out in this study. These results repeat similar findings from the majority of studies asking the same question. The investigators concluded that “once a cancer is sufficiently advanced to cause symptoms, its clinical course is largely determined and that efforts to improve diagnosis of these tumors will not lead to improvements in survival.”

More Screening Does Not Lower Ovarian Ca Mortality From JAMA

S

creening with cancer antigen 125 (CA-125) and transvaginal ultrasound in women from the general U.S. population conferred no reduction in ovarian cancer mortality, according to the results of a large study.

Hypothesizing that early detection of ovarian cancer may greatly improve prognosis, investigators evaluated the efficacy of transvaginal ultrasound and serum CA-125 for ovarian cancer screening as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (JAMA 2011;305:22952303, PMID: 21642681).

This randomized controlled, multicenter trial included 78,216 women aged 55 to 74 years who were assigned into either an annual screening group (n=39,105) or a usual-care group (n=39,111). Those in the screening group were offered annual CA-125 screening for six years and then transvaginal ultrasound for four years; the usual-care group did not receive formalized, annual screening. Patients were followed for any cancer diagnoses or death for as long as 13 years, with a median of 12.4 years (range, 10.9-13 years). The primary outcome measure was ovarian cancer, which

included primary peritoneal and fallopian tube cancers; secondary outcomes were incidence of ovarian cancer and complications from both screening methods and diagnostic procedures.

In the screening group, ovarian cancer was diagnosed in 212 women (amounting to 5.7 per 10,000 personyears); in the usual-care group, cancer was diagnosed in 176 women (4.7 per 10,000 person-years). The screening group experienced 118 deaths from ovarian cancer (3.1 per 10,000 person-years) and the usual-care group had 100 deaths (2.6 per 10,000 personyears), for a mortality rate ratio of 1.18 (95% confidence interval, 0.82-1.71).

Of the patients diagnosed with ovarian cancer, 95 women in the screening group and 91 in the usual-care group experienced one or more major complications associated with diagnostic procedures, including infection, blood loss, bowel injury and cardiovascular events. There were 3,285 patients who received false-positive screening results, of whom 1,080 underwent surgical follow-up; of these, 163 women (15%) experienced one or more serious complications (at a rate of 20.6 complications per 100 surgical procedures).

The investigators concluded that

screening with CA-125 and transvaginal ultrasound in women from the general U.S. population conferred no reduction in ovarian cancer mortality. Additionally, complications were noted from diagnostic procedures following false-positive screening tests.

EXPERT INSIGHT Maurie Markman, MD

“This is an important study because it rather definitively documents the fundamental lack of utility of available screening strategies for ovarian cancer. For several reasons, including the specific well-protected location of the ovaries and the ease with which viable cancer cells escape from the confines of the organ and are quickly disseminated throughout the peritoneal cavity (via peristaltic motion of the bowel), it not surprising that the development of a test that can document the presence of truly localized cancer has been so difficult. It is important to note that research continues in this area. However, for the present it is most reasonable to conclude that we have no evidence that routine screening is a useful approach to improving outcome in epithelial ovarian cancer.”

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

“While not from a randomized trial, these important data strongly suggest that the somewhat earlier detection of advanced ovarian cancer does not significantly influence a patient’s ultimate outcome. From the perspective of the biology of ovarian cancer, the results of this analysis are certainly quite rational, since it is highly likely an individual ovarian cancer patient’s survival will be influenced far more by the inherent chemosensitivity (or resistance) of the cancer and its rate of progression and spread, rather than on the time from development of symptoms to initiation of therapy (surgery/chemotherapy). Of course, the sooner a diagnosis is made the earlier appropriate treatment can be initiated, which in the majority of patients will result in a substantial improvement in existing symptoms and overall quality of life.”

Bevacizumab Shows Promise in Phase II Endometrial Ca Trial From Journal of Clinical Oncology

L

ong-term outcomes for women with advanced-stage endometrial cancer are poor, as are outcomes for women with recurrent disease. A multicenter Gynecologic Oncology Group (GOG) Phase II study of bevacizumab in these patients yielded promising results and may encourage further investigation.

Earlier studies have shown that bevacizumab (Avastin, Genentech) monotherapy elicited positive results in patients with persistent or recurrent ovarian and cervical cancers (J Clin Oncol 2007;25:5165-5171, PMID: 18024863; J Clin Oncol 2007;25:51805186, PMID: 18024865; J Clin Oncol 2009;27:1069-1074, PMID: 19139430).

Because of this clinical activity against other tumor types, the investigators of the current Phase II study sought to test the efficacy of single-agent bevacizumab therapy in patients with persistent or recurrent endometrial cancer who had received one or two prior chemotherapy regimens, had measurable disease and had a

FDA NEWS

Clinical Oncology News • August 2011

Fentanyl Nasal Spray Approved For Breakthrough Cancer Pain

Strategy (REMS) program in order to dispense, distribute and prescribe Lazanda. The REMS program is designed to help reduce the risk for misuse, abuse, addiction, overdose and other medication errors.

Lazanda is created by England-based Archimedes Pharma Ltd., and its subsidiary Archimedes Pharma U.S. Inc. According to Archimedes Pharma CEO Jeffery H. Buchalter, Lazanda uses the patented PecSys drug-delivery system, which is designed to deliver the medicine in a quick but controlled manner.

The drug is an alternative option for

T

he FDA has approved the use of Lazanda (Archimedes) nasal spray in the United States. Lazanda is a nasal spray formulation of the opioid fentanyl that helps manage breakthrough pain in cancer (BTPc). Patients who are aged 18 years and older and already receiving and tolerant to opioid therapy are eligible to use the drug.

Lazanda is the first fentanyl nasal spray in the United States and will be available for patients at the end of this year. Pharmacies, distributors and

GOG performance status of at least 2 (J Clin Oncol 2011;29:2259-2265, PMID: 21537039).

The investigators administered bevacizumab at a dosage of 15 mg/kg intravenously every three weeks until either disease progression or toxicity forced suspension. Primary end points were progression-free survival (PFS) at six months and overall clinical response rate.

There were 52 evaluable patients of median age 62 years; 33 (63.5%) patients had prior treatment with one chemotherapy regimen, 19 (36.5%) had two such treatments and 29 (55.8%) had undergone prior radiation. There were seven patients (13.5%) with verified clinical responses (one complete, six partial; median duration of response was six months) and no adverse events inconsistent with bevacizumab therapy.

Twenty-one patients (40.4%) attained PFS for at least six months; the median PFS was 4.2 months, and median overall survival was 10.5 months.

The percentages of patients who were alive and progression-free at six months were similar for serous and endometrioid histologies, which the investigators felt was interesting and worth further study. Because bevacizumab proved active based on PFS data at six months and because it was relatively well tolerated, the researchers concluded that it deserves further study in patients with recurrent or persistent endometrial cancer.

EXPERT INSIGHT Maurie Markman, MD

“These data add endometrial cancer to the list of malignances for which anti-angiogenic agents have demonstrated both biological and (most relevant) meaningful clinical activity. The experience, including the fact the drug resulted in acceptable toxicity, suggests singleagent bevacizumab should be considered a reasonable therapeutic option for advanced/metastatic endometrial cancer patients who have failed front-line cytotoxic chemotherapy.”

health care professionals must enroll in a Risk Evaluation and Mitigation

25

patients who suffer from BTPc. BTPc is described as a sudden and intense pain that is unpredictable for patients. It can occur even while patients are properly using opioid therapy for background pain. The pain increases rapidly but is only extreme for a short duration, while the lasting effects can be felt for about 30 to 60 minutes after initial pain. More than 50% of patients with cancer are reported to experience BTPc. The drug is currently in use in five European countries under the name PecFent.

The Greenspan Meeting XXIX

November 8-12, 2011, New York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ® Practical Applications for the Practicing Oncologist New Agents, Clinical Trials, Emerging Developments Tuesday, November 8 Pediatric Oncology Therapeutic Advances in Cancers of Childhood

Saturday, November 12 Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Therapeutic Advances, Treatment Related Complications, Supportive Care, Symptom Management, Targeted Therapies Schedule Nov. 8 Pediatric Oncology Nov. 9 Hematology, GI Cancers Nov. 10 GYN, Thyroid, Head & Neck, Breast Cancers Nov. 11 GU, Lung, Melanoma, Novel Agents, Neuroendocrine, Melanoma, Practice Issues Nov. 12 New Perspectives in Oncology Practice

Conference Highlights

Wednesday, November 9 Keynote Lecture: The Oncologic Time Warp James F. Holland, MD Thursday, November 10 Ezra M. Greenspan Memorial Lecture: Cure of Her2 Positive Breast Cancer With No Or Minimal Chemotherapy at The Door Step?

Martine Piccart, MD Friday, November 11 Judah Folkman Memorial Lecture: Anti-Angiogenesis: Paradise Lost?

Norman Wolkmark, MD

Complimentary Breakfasts, Lunches, Dinners

A CME Oncology Conference presented by the Mount Sinai School of Medicine and The Chemotherapy Foundation

Register on line at www.chemotherapyfoundationsymposium.org Contact: jaclyn.silverman@mssm.edu, (212) 866-2813

26

HEMATOLOGIC DISEASE

Clinical Oncology News • August 2011

Lymphoma

Vogl, New York …

40 Years of DLBCL: Give CHOP, Add Rituxan—Is That All? The American Society of Clinical Oncology (ASCO) 2011 meeting proved very disappointing for oncologists caring for patients with diffuse large B-cell lymphoma (DLBCL).

This is a very important disease for most general oncologists. There are not enough cases of choriocarcinoma, Hodgkin’s lymphoma and testis cancer to go around—most of the patients whom oncologists like me get to cure with chemotherapy alone have DLBCL. Curing cancer is very rewarding, so DLBCL is very important. DLBCL is also important to the 20,000 Americans who get it every year. Information presented at the ASCO meeting was not good for those of us who thought we were curing more patients than we actually were using tricks with drugs that have been around for the last 15 years—or was it?

Cure Is the Goal Any discussion of DLBCL should focus on cure rates (which is essentially equivalent to long-term survival free of disease).

At the meeting, Christian Gisselbrecht, MD, Hôpital Saint-Louis, Paris, presented a study of maintenance rituximab (Rituxan, Genentech) after high-dose chemotherapy given for relapsed DLBCL.1 As I would have predicted, it did not cure anyone and showed no benefit. In terms of improving cure rate, maintenance therapy makes no sense—if patients are cured, they do not need it. If patients are not cured, no therapy called “maintenance” will cure them.

If the reader wants a superb summary of where we are and how we got to the current state of therapy for this disease, I suggest listening online to the ASCO 2011 educational session on DLBCL. The first speaker, Jeremy Abramson, MD, clinical director of the Lymphoma Program at the Massachusetts General Hospital Cancer Center, Boston, manages in 10 minutes to clearly summarize 40 years of complicated research on disseminated DLBCL, and put it in perspective. The other two speakers, Ari Melnick, MD, an associate professor of medicine at Weill Cornell Medical College, New York City, and Dr. Gisselbrecht, go through complicated and interesting early and more advanced new treatment ideas.

What we learned at the oral presentations this year was that every-2-week (dose-dense) R-CHOP was not better than every-3-week R-CHOP, and that even massive intensification of doses of the CHOP drugs plus etoposide with multiple stem cell rescues (a regimen the Germans call R-MegaCHOEP) did not increase cure rate (Table). We also learned that early application of the usual

high-dose chemotherapy or cytoxan-TBI in first remission prevented some relapses but failed to improve survival because an equivalent number of relapsers after conventional R-CHOP were salvaged by giving the same therapy only after relapse. This spared the majority of the responding patients the high-dose chemotherapy and its toxicity.

I was most disappointed by the Cunningham et al. report of no detectable advantage of 6 cycles of R-CHOP (followed by 2 more doses of rituximab) given every 2 weeks compared with 8 cycles of R-CHOP given every 3 weeks.2 The background for this trial is a milestone German study, or 2 studies (NHL-B1 and NHL-B2), because the patients younger than and older than 60 years were reported separately, that showed a survival advantage for dose-dense CHOP in both populations.3,4 Five-year survival in patients older than 60 was 53% for CHOP-14 and 41% for CHOP-21. For those younger than 60, 5-year survival increased from 75% to 85% with use of every-14-day dosing (this study excluded patients with high LDH, so the outcomes are better). These studies are somewhat confusing because the primary end point, event-free survival, was muddied by including as events major protocol

violations (such as the administration of irradiation when it was not called for or the failure to give radiation when it was mandated by protocol), even if the lymphoma did not relapse.

Dr. Cunningham’s study may be a false negative if the extra 2 cycles of R-CHOP given to the R-CHOP-21 patients actually cured some patients who would not have been cured by 6 cycles. Duration of therapy is very difficult to study in oncology. The RICOVER-60 study did study it and found increased progression (3-year PFS, 69% from 73%) and decreased survival (3-year survival, 73% from 78%) for an extra 2 cycles of dose-dense R-CHOP in the olderthan-60 population.5 Patients were randomized at entry, though, and the paper gives no details of what happened in the first 6 cycles to the patients assigned to 8 cycles compared with what happened to those assigned to only 6 cycles.

I believe that the best way to study treatment duration is to randomize patients at the decision point (i.e., after 6 cycles of R-CHOP), collecting detailed information about the chemotherapy patients already have received, their toxicity, dose intensity, dose delays, response (preferably measured on serial PET scans) and general condition. Researchers can then use the most important of these to stratify patients, randomizing patients who could reasonably be considered for another 2 cycles of chemotherapy (one would not randomize those who

Table. Chemotherapy Regimens ACVBP: doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone 4 induction courses given every 2 weeks: doxorubicin (75 mg/ m2) on day 1, cyclophosphamide (1,200 mg/m2) on day 1, vindesine (2 mg/ m2) on days 1 and 5, bleomycin (10 mg) on days 1 and 5 and prednisone (60 mg/m2) from day 1 to day 5; and intrathecal methotrexate (IT) (15 mg) on day 2 and G-CSF from day 6 to day 13. Patients then receive a sequential consolidation therapy: 2 courses of methotrexate (3 g/m2) plus leucovorin rescue, etoposide (300 mg/m2) and ifosfamide (1,500 mg/m2) on day 1, and 2 courses of cytosine-arabinoside (100 mg/m2, SC) for 4 days, each consolidation course being administered at a 14-day interval.

CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone CHOP-14: CHOP given every 2 weeks CHOP-21: CHOP given every 3 weeks MegaCHOEP: cyclophosphamide (1,500 mg/m2 in cycle 1; 4,500 mg/m2 in cycles 2 and 3; 6,000 mg/m2 in cycle 4), doxorubicin (70 mg/m2 in all cycles), vincristine (2 mg in all cycles), etoposide (600 mg/m2 in cycle 1; 960 mg/m2 in cycles 2 and 3; 1,480 mg/m2 in cycle 4) and prednisone (500 mg in all cycles) to be administered every 21 days.

R-ACVBP: rituximab plus ACVBP R-CHOP: rituximab plus CHOP

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

are too ill or frail to continue, especially if they are in complete remission; one also might consider not randomizing those who enter a PET-negative CR after just 2 doses of chemotherapy and rituximab). It is clear that the majority of patients with DLBCL are cured by 6 cycles of R-CHOP. The only patients who can be helped by an additional 2 cycles are those who have not already had disease relapse or progression and also still have not been cured. It is foolish not to use information gathered during the first 6 cycles to analyze the benefit of the additional 2 cycles.

To my knowledge, no study of 6 versus 8 cycles of CHOP or R-CHOP has been done this way.

If dose-dense CHOP is superior to CHOP-21 (as shown in the German NHLB1 and NHL-B2 studies), then how can dose-dense R-CHOP not be superior to R-CHOP-21? One possibility is that the extra patients who are cured when they receive chemotherapy every 2 weeks are the same extra patients who are cured when rituximab is added. We actually have good data relevant to this point from the RICOVER-60 trial.5 In this trial, adding rituximab to CHOP-14 improved the cure rate. This means that the two maneuvers (every-2-week therapy and addition of rituximab) do not totally overlap in whom they benefit.

Perhaps the benefit noted in NHL-B1 and NHL-B2 for CHOP-14 was not from the 14-day intertherapy interval, but from the neupogen given with it that made the shorter interval possible. Patients, especially the elderly and frail, probably benefit a lot in terms of their general health from avoiding neutropenia and its complications. Maybe some or all the benefit attributed to dose-dense CHOP therapy was from the neupogen, not from the chemotherapy dosing frequency.

A French study presented at the annual American Society of Hematology meeting in 2009 tried to give R-CHOP-14 to patients older than 60 years with an age-adjusted IPI score of 1 or greater without mandated neupogen.6 Early on, R-CHOP-14 had a 9% toxic death rate; however, recent follow-up shows an equal treatment-related mortality of 4.6%

HEMATOLOGIC DISEASE

Clinical Oncology News • August 2011

Is there more work to be done tweaking the old drugs to make them more effective? Three “tweaks” come to mind: adding cyclic intensive consolidation with other drugs, adding etoposide to CHOP, and infusing the drugs over 4 days. for R-CHOP-14 and R-CHOP-21, with no advantage to 14-day dosing. In addition to failing to require neupogen in the first cycle for CHOP-14 patients, this protocol lacked what Pfreundschuh calls a “prophase” of low-dose chemotherapy that reduces toxicity in the elderly. In spite of these failings, the French study is still a 600-patient randomized trial showing no benefit to 14-day dosing. Based on a large pilot experience, Pfreundschuh wonders whether R-CHOP-14 loses some of its benefit because rituximab is administered over too short a period. The German Lymphoma Study Group is about to begin a randomized Phase III trial in which rituxumab is “front loaded” and extended “out back” to optimize rituximab pharmacokinetics. This is based on favorable early results from a 200-patient pilot study that compared this strategy to prior RICOVER-60 results in a similar population of DLBCL patients.

Where Do We Go From Here?

I have to admit, though, that I suspect the Cunningham and Delarue studies are correct in their conclusions and that there is no substantive benefit from giving R-CHOP every 14 days for 6 cycles.

Many British oncologists are rumored to be choosing R-CHOP-14 off protocol because it gives less cumulative doxorubicin (and thus less cardiac risk) and because it is completed in only 71 days (vs. 148 days for 8 cycles of R-CHOP-21).

So do we just wait for new drugs to come along (work is ongoing adding lenalidomide [Revlimid, Celgene], bortezomib [Velcade, Millennium], everolimus [Afinitor, Novartis], and enzastaurin [Eli Lilly] to R-CHOP; and new small molecules aimed at molecular targets are in early development), or is there more work to be done tweaking the old drugs to make them more effective? Three “tweaks” come to mind: adding cyclic intensive consolidation with other drugs, adding etoposide to CHOP, and infusing the drugs over 4 days.

A French regimen misleadingly called ACVBP was superior to CHOP in overall survival as well as in surrogate end points.7 When studied with rituximab in patients between the ages of 18 and 59 with an age-adjusted IPI score of 1 in the GELA study LNH03-2B, R-ACVBP was 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

korourke@mcmahonmed.com.

superior to R-CHOP, with 3-year survival improving from 84% to 92%.8 The usual excuse given by North American lymphoma oncologists for not using the regimen is that the V stands for vindesine, which is not available in North America. However, we could easily substitute any of the 3 vincas that we do have (vinblastine, vincristine, vinorelbine). The ACVBP regimen, though, includes much more than the 5 drugs in the acronym given in a dosedense fashion. It includes a complicated, intensive, prolonged consolidation phase with progressive introduction of four new drugs (Table). There is probably some added benefit to something in this complex program, which was much more toxic than R-CHOP with a 39% rate of febrile neutropenia, but it will take decades of large randomized trials to sort this out.

Pfreundschuh points out that in a similar good-risk population, R-CHOP-21 with radiation to bulk disease in the MINT trial gave equivalent results when compared with R-ACVBP plus consolidation, but with much less toxicity. We should treat this cross-trial comparison with caution, but with interest.

The role of adding etoposide to R-CHOP is still unclear. The German studies NHL-B1 and NHL-B2 (only 71% of patients had DLBCL) suggested excess toxicity in patients older than 60 when etoposide was added to either CHOP-14 or CHOP-21 regimens. Five-year survival decreased from 53% to 50% for CHOP14 and increased nonsignificantly from 41% to 46% for CHOP-21. In patients younger than 60, etoposide added nothing to the 5-year survival with CHOP-14 but improved 5-year survival from 75% to 83% with CHOP-21. The German group still considers etoposide an essential part of chemotherapy in those younger than 60, even though a retrospective analysis of the MINT trial, which showed the benefits of adding rituximab to better-risk young patients with DLBCL, found that those treated in areas where etoposide was not given (like Poland) did as well as those treated in areas where it was given (like Germany).

Slow infusion over several days of the same drugs we have been giving for decades may improve disease control.

This was first suggested in relapsed lymphoma studies at the National Cancer Institute (NCI), decades ago, when regimens using infusional doxorubicin, vincristine and etoposide produced response rates so high that Susan Bates, MD, now head of the Molecular Therapeutics Section at the NCI, Bethesda, MD. and Bruce Chabner, MD, now at Massachusetts General Hospital, Boston, had trouble finding refractory patients to study whether R-verapamil could reverse multidrug

Lymphoma

resistance. (Their original plan was to demonstrate that the lymphomas were refractory to infusional chemotherapy and then show responses when R-verapamil was added to the infusional therapy.)

Currently, Wyndham Wilson, MD, head of the NCI’s Lymphoma Therapeutic Section, is chairing a Cancer and Leukemia Group B study that already has randomized about 400 patients to either R-CHOP or R-EPOCH. The R-EPOCH infusional scheme includes a scheme of individual patient dose escalation to toxicity that is different from the uniform high dosing explored in the MegaCHOEP trial, so a positive result in this trial will require more work to separate the effects of dose escalation from those of slow drug infusion.9 Given the MegaCHOEP results, however, it seems unlikely that many patients will benefit from dose escalation, so if any benefit for R-EPOCH is demonstrated, it probably comes from the prolonged infusions (or even maybe from the etoposide infusion).

Personally, I have always found prolonged infusions attractive because they halve the incidence of cardiomyopathy from adriamycin. In a disease for which cure is common, avoiding long-term toxicity is very important. Even in younger patients without heart disease, halving cardiac damage is desirable because the goal is to allow them to age like the rest of us. Then they will presumably acquire coronary artery disease, like the rest of us, and be grateful for their nonimpaired myocardial function.

In the 45 years of my professional career, the name we use to describe what we now call DLBCL has changed from reticulum cell sarcoma to diffuse histiocytic lymphoma to high-grade lymphoma to DLBCL. With each name change, patients moved into and out of the diagnosis, so one cannot compare study results from the 1970s or 1980s with those from 2011—the patients are not the same ones.

Similarly, the availability of special probes and stains to identify Burkitt’s lymphoma, mantle cell lymphoma and B, T, NK or null cell characteristics have moved patients in or out of the category of DLBCL. It is naive to think that the currently fashionable division of DLBCL by gene expression into 2 or 3 subtypes (which still have no clear-cut clinical significance) is the last word on classification of this complicated group of diseases.

I hope to learn, before my career ends, the exact mode of development of each of the types of curable lymphoma now included in the DLBCL category. We could then design drugs to target the driving mutation, translocation, virus,

PET images for a 76-year-old woman with DLBCL and massive left groin adenopathy extending up iliac and paraaortic chains with invasion of paraspinal and psoas muscles. One month after beginning R-CHOP14 with infusion of doxorubicin and vincristine, the PET positive masses are largely gone, with some physiologic uptake in bowel.

or immune stimulus and then design trials for each disease to maximize cure and minimize toxicity. In the meantime, I guess we have to slog along, optimizing the choice and delivery of the drugs we have, while minimizing toxicity. The ASCO 2011 meeting showed how difficult this process actually is. I will be surprised if the drugs in R-CHOP, which now cure 50% to 90% of patients, are completely replaced by new agents in the next 10 or 20 years, so whatever we learn about how to give them optimally may prove valuable for patients for decades to come.

References 1. Gisselbrecht C, Glass B, Laurent G. Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis. J Clin Oncol.

2011;29(suppl): Abstract 8004.

2. Cunningham D, Smith P, Mouncey P et al.

R-CHOP14 versus R-CHOP21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. J Clin Oncol. 2011;29 (suppl): Abstract 8000.

3. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004;104:634-641, PMID: 15016643.

4. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with goodprognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004;104 (3):626-633, PMID: 14982884.

5. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol.

2008;9(2):105-116, PMID: 18226581. see DLBCL, page 28 

27

28

HEMATOLOGIC DISEASE

Clinical Oncology News • August 2011

Multiple Cancers

p53 Mutation Associated With Poor Prognosis in Patients With CLL From Journal of Clinical Oncology

I

nvestigators in the Czech Republic have identified missense mutations in patients with chronic lymphocytic leukemia (CLL) that portend an extremely low rate of survival. The finding is important for prognosis and choice of therapy, and suggests a direction for further investigative efforts.

Prognosis in patients with CLL varies significantly and is heavily influenced by the presence of cytogenetic aberrations and the mutational status of the immunoglobulin heavy-chain variable region gene (IgVH). Patients with leukemia with the p53 mutation, with or without del(17p), have a particularly poor prognosis. They respond poorly to therapy with DNAdamaging agents such as fludarabine and chlorambucil, and chemoimmunotherapy and alemtuzumab therapy offer only short-term relief. The National Cancer Institute’s Working Group/International Workshop on CLL guidelines suggest that such patients should be enrolled in investigative clinical studies or offered

allogeneic stem cell transplantation.

The investigators in the Czech study wanted to explore whether all p53 mutations in CLL lead to a similar phenotype with a comparable prognosis (J Clin Oncol 2011;29:2703-2708, PMID: 21606432). Most p53 mutations in CLL represent missense substitutions occurring in the p53 protein’s DNA-binding domain.

These p53 missense mutations may result in a gain-of-function phenotype with highly oncogenic activity.

The investigators demonstrated that patients with CLL and TP53 mutations form two distinct prognostic groups, with those with missense substitutions within structural p53 DNA-binding motifs (DBMs) constituting the group with extremely poor survival rates.

The study consisted of 550 patients with CLL, 65% of whom harbored the unmutated IgVH locus, which meant that the cohort was biased toward highrisk disease. The p53 defects, which were found in 100 of the patients, were identified via a yeast functional assay; del(17p) was detected by complementary interphase fluorescence in situ hybridization analysis.

The p53 mutations were strongly associated with del(17p) as well as with the unmutated IgVH locus (P<0.001 for both). Survival was significantly reduced in patients with both missense (P<0.001) and non-missense p53 defects (P=0.004).

It was discovered that the patients with CLL with missense mutations in p53 DBMs had a significantly reduced median survival (12 months), compared with those patients with missense mutations outside DBMs (41 months; P=0.002), and those with non-missense alterations (36 months; P=0.005). A further analysis of patients with the mutation as well as del(17p) also found reduced survival among patients with DBM mutations in addition to del 17p.

The investigators concluded that both missense and non-missense p53 mutations lower survival rates in patients with CLL, and that the subgroup of patients with missense mutations in structural p53 DBMs have a markedly reduced survival rate and short time-to-first treatment (TTFT). The reduced survival rate and the short TTFT was suggestive of a strong mutated p53 gain-of-function phenotype in those patients with DBM mutations, the impact of which should be explored further in investigative clinical trials.

Additionally, patients with p53 DBMs mutation should be considered prime candidates for allogeneic stem cell transplantation.

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

“p53 mutations in CLL are known to be associated with poor prognosis, but it is unclear whether this prognostic group is homogeneous. This study is important because it subdivides p53 mutations by type, and finds that missense mutations affecting the DNA-binding domain are associated with a particularly poor prognosis, compared with missense mutations elsewhere or other types of mutations.

These findings suggest that the mutations affecting the DNA-binding domain may show gain-of-function activity which confers a uniquely poor prognosis, and suggest that future studies may need to subdivide p53 mutations when evaluating prognosis.”

R-CHOP With Relapse-Prevention Therapy May Boost PTL Survival From Journal of Clinical Oncology

A

modified chemotherapy regimen with rituximab added and relapseprevention measures including intrathecal methotrexate and radiation therapy (RT) achieved good results in patients with primary testicular non-Hodgkin’s lymphoma (PTL), according to a Phase II trial.

Relapse at distant extranodal sites, in particular the central nervous system (CNS) and contralateral testis, is one of the most vexing therapeutic challenges in patients with PTL, even in patients receiving doxorubicin regimens. Although the addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone every 21 days (R-CHOP21) has been found to improve overall survival (OS) and progression-free survival (PFS) compared with CHOP alone in patients with diffuse large B-cell lymphoma, data on the

efficacy of chemotherapy in PTL specifically have been lacking.

The study (IELSG-10) explored the safety and efficacy of the R-CHOP21 regimen together with both CNS and testicular prophylaxis in 53 patients with untreated stage I or II PTL (aged 22-79 years) (J Clin Oncol 2011;29:2766-2772, PMID: 21646602). The patients received six to eight courses of R-CHOP21; 50 patients also received intrathecal methotrexate (12 mg total dose, administered weekly for four weeks) as CNS prophylaxis, and 47 patients received RT to the contralateral testis (median, 30 Gy). Additionally, patients with stage II disease received a median 30 Gy RT to regional lymph nodes.

The standard R-CHOP21 regimen consisted of rituximab 375 mg/m2 on day 0 or day 1, cyclophosphamide 750 mg/ m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 (maximum 2

with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03-6B GELA study. Blood. 2009;114: Abstract 406.

DLBCL continued from page 27 

6. Delarue R, Tilly H, Salles G, et al. R-CHOP14 compared to R-CHOP21 in elderly patients

7. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005;352(12):1197-1205.

mg) on day 1 and prednisone 100 mg on days 1 to 5. The patients were restaged following the third course, with stage I patients receiving six courses. Stage II patients received six to eight courses of R-CHOP21, depending on whether they had a complete or partial response by the third course.

At a median follow-up of 65 months, five-year PFS was 74% (95% confidence interval [CI], 59%-84%) and OS was 85% (95% CI, 71%-92%). Ten patients experienced either relapse or progression: three in the CNS, two in lymph nodes and five in extranodal organs. The five-year cumulative incidence of CNS relapse was 6% (95% CI, 0%-12%); there were no contralateral testis relapses. Grades 3 and 4 toxicities were neutropenia (26%), neurologic (13%) and infection (4%). There were no deaths attributed to toxicity.

This trial demonstrated that the R-CHOP21 regimen, coupled with CNS

8. Recher C, Coiffier B, Haioun C. A prospective randomized study comparing dose intensive immunochemotherapy with R-ACVBP vs standard R-CHOP in younger patients with diffuse large B-cell lymphoma. Groupe d’Etude Des Lymphomes De l’Adulte (GELA) study LNH03-2B. Blood.

2010: Abstract 109.

and testicular RT, provides a good outcome in this rare non-Hodgkin’s lymphoma. Whereas RT proved effective in avoiding relapse to the contralateral testis, the CNS prophylaxis regimen requires further study.

EXPERT INSIGHT Jennifer Brown, MD, PhD

“Primary testicular lymphoma has been associated with poor prognosis, and in addition to RCHOP it is accepted practice to add CNS prophylaxis and radiation to the contralateral testis in an effort to reduce sanctuary site relapse. Until now data demonstrating improved survival with this regimen have been limited. This study presents a multicenter Phase II prospective trial that demonstrates promising PFS and OS with this therapeutic regimen, providing support for this treatment approach.”

9. Wilson WH, Dunleavy K, Pittaluga S. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers J Clin Oncol. 2008;26(16):2717-2724, PMID: 18378569.

POLICY & MANAGEMENT

Clinical Oncology News • August 2011

Practice

CONSOLIDATION continued from page 1 

which have shifted from increased payment to increased and improved coverage. These physicians are driving the future, and consolidation of providers is a major piece of their agenda. Private insurers also have much to gain from consolidation of the provider community.

As they look to changes in their marketplace under health reform and as they hear from major purchasers, costs must come down and competition must come up. This article looks at the intersection of all the issues driving the phenomenon called consolidation.

Who Is to Blame?

Medicare is being blamed for its declining payments. But, is the Centers for Medicare & Medicaid Services (CMS) the problem? Are we missing the much bigger declines taking place in private insurance payments? Private employers are driving commercial insurers to find the same cost savings that CMS is achieving. A recent study showed that employers believe that the Patient-Centered Outcomes Research Institute and comparative effectiveness are the most important pieces of the Accountable Care Act (ACA). Employers are anxious to learn more about comparison of treatments and costs and believe that it is the key to cutting the skyrocketing cost of health care. For example, Aetna claimed it saved 35% by working with US Oncology to standardize treatment for lung cancer patients.

Why Would Insurers Promote Consolidation?

During the late 1980s, insurers failed to control health care services through health maintenance organizations (HMOs). Consolidation feels like HMO insurer behavior reinvented. Thousands of doctors are difficult to manage and control, whereas hundreds of hospitals and large practices are easier. If you take a minute to look at your payments, you’ll notice that commercial insurers have reduced their fee schedules. Also, their model shows that to control their costs, they must eliminate fee-for-service payments or lower costs of care by keeping fee schedules down. If accountable care organizations (ACOs) and direct primary care are going to be successful in maintaining their business as insurance exchanges, they must reduce the cost of insurance, so reducing cost of care is important to them as well.

Insurers also are under pressure to meet requirements of spending regarding medical loss. Starting this year, health insurers must spend at least 80% to 85% of the premiums they collect on medical services or activities that improve quality of care, or they have to rebate money to consumers. Tied to this is another

ACA requirement that limits rate increases. If insurers are operating at 65% medical loss ratio (MLR; a common occurrence in individual and small business markets), then they will either drop out of the market or change coverage, which will increase rates. Insurers cannot use fee increases to maintain their profit numbers because of the limit. For example, if my product charge was $100 and I only spent $65 on MLR, then I could maintain my current administration and overhead at $35 by increasing my charges to account for the additional 15% needed for MLR. But, if I’m limited to 10% increase, I have to nearly double my price to keep $35 of profit at 80% MLR. Many insurers are looking to become insurance exchange providers or to create ACOs to expand their markets and sources of profit to replace losses from individual and small market business.

Having fewer competitors in the provider market offers them an increased chance of entering markets with new products.

What Will Insurance Exchanges Look Like?

According to a recent article by the Commonwealth Fund, “Health and Human Services officials aren’t going to make anybody happy when sometime around the July Fourth weekend they release a proposed regulation that will spell out what states must do to create health insurance exchanges. That’s because the data-crunching tasks involved are so complex, the design issues so controversial, and the timelines so tight that at some point advocates for states, consumers and insurers seem certain to toss their Federal Registers in disgust. … Many states are at a loss to figure out how to handle the complex data functions involved and are hoping that the proposed regulation will help them plot the path forward.

Consider the tasks exchange operators will have to perform. They will have to determine if a customer is an American citizen. They will have to decide how much money customers make and if it’s appropriate to enroll them in Medicaid or a private plan. They’ll have to determine if an individual is eligible for a subsidy and, if so, how much. They’ll have to pay plans. And they have to do it fast, because if the enrollment process is slow and cumbersome, if subsidy amounts are wrong, and if they’re slow to pay plans, there will many complaints” (Washington Health Policy Week in Review, June 21, 2011).

The job will require the swift exchange of data between states, the Treasury Department, the Department of Homeland Security, health plans,

Many insurers are looking to become insurance exchange providers or to create ACOs to expand their markets and sources of profit to replace losses from individual and small market business.

and, to the extent they participate, small employers. With states already under budget pressures, such challenges will strain their resources.

Washington and Lee University law professor Timothy Jost says flexibility is the watchword. “I think probably what most states want to see is maximum flexibility—it seems to be the key word—and as much funding as possible.” According to Mr. Jost, “states would like to be able to fit the exchange to their particular market and their particular politics.”

But that may work at cross-purposes with the needs of consumers. “From a consumer point of view, … there are a number of issues that we’re concerned about,” Mr. Jost said. “One issue right up front is governance, and … there the key concern is that the exchange be independent and basically not be run by the insurers and the people who market health insurance, that it be run in the interest of consumers. So, I would be hoping that there would be strong … provisions in the regulations to discourage exchanges where you have the insurers running their own market.”

The exchanges clearly have many opportunities to fail and many challenges to face. No wonder insurers are covering themselves—in case.

The Role of Direct Primary Care Direct primary care is an element of ACA that removes insurance overhead and profits and may be driving insurance to consolidate the market. A relatively little-known provision of ACA creates this affordable new choice for individuals and small businesses by allowing flat-fee primary care practices to compete within the state-based insurance exchanges.

This provision enables Americans to elect a more affordable health care option compared with traditional insurance plans—an alternative in which patients and/or employers pay a flat

monthly fee directly to a primary care provider for all primary and preventive care, chronic disease management and care coordination throughout the entire health care system. Under the new law, a flat-fee direct primary care medical home membership can be bundled with a new, lower-cost “wraparound” insurance plan that covers unpredictable and expensive services outside its scope, such as specialist care, hospital stays or emergency room visits.

Not unlike a health club membership, most of the direct primary care practices allow unlimited use. Further, since general practitioners don’t have to spend so much time billing, they are able to spend far more time with their patients.

How Consolidation Factors In On the surface, consolidation seems only to be about payments and expenses of maintaining a private physician practice or a hospital in today’s changing health care climate. Underneath, it is about the intersection of the roots of reform. There is a paradigm shifting—consolidation is not only about what is obvious. CMS gets lots of blame and although it is on the front line, it is not driving the revolution. Behind the scenes, practices and hospitals play a role, as they struggle to maintain in an era where big looks better. Young doctors want changes in medicine. They want to take care of patients, not hassle with insurance coverage. They will trade income for a well-rounded life, including personal time. Insurers want to maintain and increase market share and profits. Insurers gain many advantages by driving providers into larger groups by tightening reimbursement and creating preferred partnerships, such as ACOs. Insurers also are partnering to play in the insurance exchange environment, as a springboard for control over the ever-changing American health care system’s insurance market. This is a survival game that all the players are hoping to manage state by state.

—Mary Lou Bowers, MBA

President & CEO of The Pritchard Group, LLC Rockville, Md. www.thepritchardgroup.net

29

CLINICAL TRIALS

Clinical Oncology News • August 2011

New Phase II and III Clinical Trials

Hematologic Malignancies

Solid Tumors

The studies listed below are actively recruiting trials that were added to the National Cancer Institute’s list of U.S. clinical trials in the 30 days before July 12, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials/search, and enter the protocol ID.

Supportive Care

30

Protocol Type

Age

Protocol ID

Trial Sites

Randomized Study of Single Agent OSI-906 Versus Topotecan for Relapsed Small Cell Lung Cancer (SCLC), Phase II

18 and over

NCI#8873

FL

Pazopanib, Docetaxel, Prednisone Prostate, Phase I/II

18 and over

00026577

NC

Modified Tumor Infiltrating Lymphocytes for Metastatic Melanoma, Phase II

18 and over

110163

MD

Use of IL-15 After Chemotherapy and Lymphocyte Transfer in Metastatic Melanoma, Phase I/II

18 and over

110170

MD

Chemoradiotherapy With Elective Low Dose Nodal Radiation for Locally Advanced Head and Neck Cancer, Phase II

18 and over

CCRO11

NC

CHFR Methylation Status Esophageal Cancer Study, Phase II

18 and over J10130

MD

TRC105 for Liver Cancer That Has Not Responded to Sorafenib, Phase II

18 to 80

110181

MD

GSK1120212 Rollover Study (multiple cancers), Phase II

18 and over

114375

AZ, TN, WA

Ipilimumab + Androgen Deprivation Therapy in Prostate Cancer, Phase II

18 and over

2009-0378

TX

MR Image Guided Therapy in Prostate Cancer, Phase II

18 and over

110158

MD

Docetaxel and Lapatinib in Metastatic Transitional Cell Carcinoma in Bladder, Phase II

18 and over 4B-10-4

CA

Study of DCA (Dichloroacetate) in Combination With Cisplatin and Definitive Radiation in Head and Neck Carcinoma, Phase II

18 and over

DCA 2010

SD

Pilot Study of Cytokine-Induced Gene Expression in Patients With Cancer or in Healthy Participants (kidney, melanoma, colon, breast, prostate, other malignancy) Phase I, II

18 and over

CASECCF-3164

OH

Tolerability Study of Xerecept in Pediatric Patients, Phase I/II

1 to 18

CPDS 1001

IL, MA

Pilot Study of Cytokine-Induced Gene Expression in Patients With Cancer or in Healthy Participants (leukemia, lymphoma, myeloma), Phase I, II

18 and over

CASECCF-3164

OH

A Trial of Lenalidomide & Azacitidine in Low Risk Myelodysplastic Syndromes, Phase II

18 to 90

MDS 2008-01

IL

Entinostat and Imatinib Mesylate in Treating Patients With Relapsed or Refractory Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia, Phase I/II

18 and over J1023

MD

Study of Oral MLN9708 in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma, Phase I/II

18 and over

C16008

TX

Study to Evaluate Two Lenalidomide Dose Regimens With Low Dose Dexamethasone for the Treatment of Relapsed Multiple Myeloma, Phase II

18 and over

RV-MMPI-0345

CA, IL, MA, MO, PA, TX

GSK1120212 Rollover Study (multiple cancers), Phase II

18 and over

114375

AZ, TN, WA

Study of Imtox-25 in Adults With Refractory/Relapsed Cd25-Positive Adult T-Cell Leukemia/Lymphoma, Phase II

18 and over

Imtox 25

NY

Assessment of Efficacy and Safety in Relieving Opioid-induced Constipation in Patients With Cancer-related Pain, Phase III

18 and over

D3820C00006 AZ

Safety and Efficacy of Anamorelin in Patients With Non-Small Cell Lung Cancer-Cachexia, Phase III

18 and over

HT-ANAM-301 and HT-ANAM-302

CA, IN

Trial of Low-Dose MTX and I 131 Tositumomab for Previously Untreated, Advanced-Stage, Follicular Lymphoma, Phase II

18 and over

UMCC 2010.098

MI

New EHR Systems Have Benefits, But Transition Poses Safety Issues

A

recent study conducted by a team of physician-scientists from Weill Cornell Medical College in New York City, found that the newer electronic health record (EHR) systems reduce mistakes in filling prescriptions. However, the physicians who participated struggled with the transition from the older system to the new electronic system.

The researchers followed 17 doctors at an adult ambulatory clinic prior to the switch. Researchers tracked the physicians’ use 12 weeks after installation of the new EHR system and then again one year later. The new system is

designed to provide doctors with more guidance when prescribing drugs. For instance, the EHR system can alert doctors to incorrect abbreviations on prescriptions that could result in patient harm.

Analysis of almost 4,000 prescriptions for more than 2,000 patients revealed common errors. The errors recorded were in abbreviations, usage directions, dosage and amount of medications. The study found the amount of prescription mistakes

dropped by two-thirds, from around 36% to 12% one year after the EHR system was installed.

Although the new system reduced common prescribing errors, the transition was not easy. According to the study, 40% of the doctors were not satisfied with the implementation of the new system.

Approximately 66% suggested that the new EHR system slowed drug orders and refills.

Researchers suggested that systems should be designed

to identify the most common errors, especially the most clinically important mistakes, so that users of the system do not begin ignoring warnings.

The researchers concluded that a transition between systems could pose a safety concern. To best maximize safety, health care providers should identify the challenges to transition and refine clinical decision support in the system beforehand. The researchers plan to continue research that will evaluate prescription errors after two years using the new EHR system.

—Kevin Enright

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