Clinical Oncology News Hemotology Digital Edition - March 2012

Hematology/Oncology Edition

Independent News on Advances in Cancer Care clinicaloncology.com • March 2012 • Vol. 7, No. 3

HematOlogic DISEASE

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Gemtuzumab may still have a role to play in AML. FDA NEWS

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Methotrexate drug interactions examined.

CLINICAL TRIALS

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Money for Drugs: Part II of an ongoing series on physicians and the pharmaceutical industry.

PRN

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Clinical Conundrums: A quiz for the practicing hematologist/ oncologist.

SOLID TUMORS

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New Agent on the Horizon for Metastatic Colorectal Cancer

Cereblon Critical for IMiD Activity in Myeloma

Regorafenib touted as ‘potential new standard of care’

San Diego—The cytotoxic effects of immunomodulatory drugs (IMiDs) for the treatment of multiple myeloma are dependent on the presence of cereblon (CRBN), a protein that has a regula­tory role in several physiologic processes, according to a study presented at the 2011 annual meeting of the American Society of Hematology (ASH).

“A landmark paper recently identified cereblon as a primary target of thalidomide teratogenicity [Science 2010;327:1345 -1350, PMID: 20223979], which led us to our hypothesis that this protein would also be required for myeloma cytotoxicity,” of the IMiDs, noted investigator Yuan Xiao Zhu, PhD.

San Francisco—A first-in-class drug that jumped straight from a Phase I to a Phase III trial is expected to be approved in patients with refractory metastatic colorectal cancer (mCRC).

The Phase III data showed that treating this patient population with regorafenib (Bayer) increased median overall survival (OS) by 1.4 months.

“I would suggest the [benefits] are clinically meaningful for many, but not for all patients,” said Herbert Hurwitz, MD, associate professor of medicine at Duke Cancer

Using fluorescent antibodies to find pancreatic cancers.

Even with new data, the role of bisphosphonates remains murky.

Visit us Online At

see REGORAFENIB, page 30 

see CEREBLON, page 14 

A Provocative Intersection

Cereblon is a protein encoded by the CRBN gene that may be critical for the efficacy of immunomodulatory drugs in the treatment of multiple myeloma.

Rare cancers, “approved” antineoplastics and preclinical models

Credit: Image created using UCSF Chimera at the Sali Lab, University of California-San Francisco

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WWW. CLINICALONCOLOGY.COM

reclinical results describing a novel approach to the treatment of an uncommon malignant condition raise a provocative question: How, in the Maurie current increasingly rigid Markman, MD “guideline-based” era of cancer management, can such observations ever leave the realm of the laboratory to be examined in the clinic? And can a rational approach to this highly relevant dilemma be devised?

Primary mucinous tumors comprise a very small proportion (<5%) of see RARE CANCERS, page 14 

The Medical Arms Race T

he term “mad” has always had numerous uses, but during the 1960s Cold War, it became popular as an acronym— MAD—shorthand for “mutually assured destruction.” It referred to the bizarre logic of the nuclear arms race, whereby the United States and the Soviet Union kept building up their nuclear arsenals to equal and then exceed the opposition, presumably as a deterrent to aggression.

Eventually, the size of the arms buildups reached a point at which either country could destroy the other many times over.

This policy was truly deserving of its ominous yet descriptive acronym.

Today, there is a similar situation in medicine that has appropriately been named “the medical arms race,” whereby competing hospitals or medical systems try to purchase the most up-to-date equipment and technology, which then can be used as a marketing ploy to compete for patients. Insurers do not question the provision of these services but pass along the added expense to their customers. Many see ARMS RACE, page 8 

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

Hematology and Transfusion Medicine Board Review Made Simple Tony N. Talebi, MD; Joseph D. Rosenblatt, MD See page 29.

Approved in 3 indications

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • March 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

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

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

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

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

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Michigan Ann Arbor, MI

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

Richard Stone, MD

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

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

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

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

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

Policy and Management

University of Colorado Cancer Center Denver, CO

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

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

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

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

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

Steven Vogl, MD Medical Oncologist New York, NY

T

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

Editorial Philosophy

Steven D. Passik, PhD

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Vanderbilt University Medical Center Nashville, TN

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.

Joseph V. Pergolizzi Jr., MD

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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

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

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

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

Genitourinary Cancer Ronald M. Bukowski, MD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cindy O’Bryant, PharmD

Shaji Kumar, MD Mayo Clinic Rochester, MN

Leonard Saltz, MD

Betty Ferrell, RN, PhD

Pharmacy

Edward Chu, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Oncology Nursing

Hematologic Malignancies

Andrew Seidman, MD

Cathy Eng, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Johns Hopkins University School of Medicine Baltimore, MD

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

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

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FDA NEWS

Clinical Oncology News • March 2012

FDA Approves Updated Indication for Gleevec Extends treatment to 36 months for certain GIST patients after surgery On Jan. 31, the FDA approved a new indication for Gleevec (imatinib mesylate, Novartis) for use in certain adult patients following surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GISTs).

accelerated approval for adjuvant use for the treatment of patients with GIST who had had potentially curative resection of GIST, but who had an increased risk for recurrence.

Approval for the metastatic GIST indication also was granted in 2008.

“The development of Gleevec over the past decade highlights the need to further study drugs after approval to truly characterize their benefits,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a press release. “Although originally approved in the metastatic disease setting, this subsequent trial has demonstrated that longer use of Gleevec can prolong patients’ lives in earlier disease settings.”

GIST is a rare form of cancer that originates in cells found in the wall of the gastrointestinal tract. These cells, known as interstitial cells of Cajal, are

part of the autonomic nervous system, which regulates body processes such as food digestion. The major cause of GIST is an abnormal form of the protein KIT, which causes cells to grow uncontrollably and become cancerous. Gleevec is indicated for the treatment of patients with KIT-positive GISTs that are cancerous, cannot be surgically removed and/or have spread to other parts of the body.

The drug also is approved for use after surgery in patients who have had KITpositive GISTs completely removed.

Additionally, Gleevec is approved for the treatment of other cancers; it was first approved by the FDA in 2001 to treat patients with advanced Philadelphia chromosome–positive chronic myeloid leukemia.

For more information about Gleevec, visit www.gleevec.com.

The new labeling recommends 36 months of treatment with Gleevec after surgery in adult patients with KIT-positive GIST who meet the risk for recurrence inclusion criteria of the pivotal trial. The 36-month treatment regimen was shown to improve recurrence-free survival (RFS) and overall survival (OS) in patients with KIT-positive GIST compared with 12 months of treatment.

The new approval is based on data from an international, multicenter, open-label Phase III clinical trial (SSG XVIII) conducted by the Scandinavian Sarcoma Group and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie. The primary end point of the study was to compare, within the first five years, RFS in patients with a greater than 50% estimated risk for GIST recurrence following diagnosis

and treatment with adjuvant Gleevec for either 12 or 36 months. Results of the study revealed that RFS was longer for patients assigned to receive 36 months of Gleevec after surgery compared with those who received 12 months of treatment, including a 54% reduction in risk for GIST recurrence (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.32-0.65; P<0.0001). Additionally, OS was longer in the 36-month treatment group, which resulted in a 55% reduction in the risk for death (HR, 0.45; 95% CI, 0.22-0.89; P=0.0187). Gleevec manufacturer Novartis provided funding for the study.

Gleevec was originally granted accelerated approval for the treatment of advanced or metastatic GIST in 2002. In 2008, the drug was granted

Letter to the Editor

Ms. Shaw’s manuscript did not address the overrepresentation of descriptive and observational as opposed to interventional research studies within cancer survivorship literature. According to a 2011 literature review in Cancer Epidemiology, Biomarkers & Prevention, research studies and their associated funding is disproportionally invested in observational research.1 Their study found 72 interventional studies compared to 111 observational studies. This represents a 54% greater incidence of observational studies. While these are important studies, greater understanding and exploration of effective interventions for improving care delivery and coordination as well

as quality of life and resiliency is needed. In “A National Plan for Cancer Survivorship,” equal attention is given to all these issues, yet this equality has not been realized in research projects and their funding. According to this public health plan, one-third of cancer survivors will experience detrimental consequences resulting from their history of a cancer diagnosis and treatment. As evidence of the multiple dimensions of these consequences mounts, development and testing of effective interventions are not keeping pace. We must work to resolve the issue of skewed focus on medical prevention, surveillance and follow-up care in favor of greater attention to exploration of

interventions aimed at augmenting quality-of-life issues and resiliency among cancer survivors.

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McMahon Publishing

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Van Velle, President, Partner

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Matthew McMahon, General Manager, Partner

To the Editor:

I

am writing in response to Gina Shaw’s article, “They Will Survive: Building a Cancer Survivorship Program” in the June 2011 issue of Clinical Oncology News. This manuscript does an excellent job informing health care professionals about the need for cancer survivorship programs, practical advice for development of such programs and potential benefits to cancer survivors. Such publications heighten awareness of these public health needs but do not address the equally important needs for cancer survivor quality of life and resiliency intervention research.

TM

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company.

McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

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

Office, 83 Peaceable Street, Redding CT 00896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

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

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James Prudden, Group Editorial Director David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics

—Based on press releases from the FDA and Novartis Pharmaceuticals

Sincerely, Elizabeth Grahn, MSN, NPC Clinical Nurse Specialist Memorial Sloan-Kettering Cancer Center, New York, NY

References 1. Harrop JP, Dean JA, Paskett ED. Cancer survivorship research: a review of the literature and summary of current NCI-designated cancer center projects. Cancer Epidemiol Biomarkers Prev. 2011;20:2042-2047, PMID: 21980012.

2. Centers for Disease Control and Prevention and the Lance Armstrong Livestrong Foundation. 2004. A national plan for cancer survivorship. http://www.cdc.gov/cancer/survivorship/pdf/plan.pdf.

Brandy Wilson, Circulation Coordinator

Raymond E. McMahon, Publisher & CEO, Managing Partner

Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

HEMATOLOGIC DISEASE

Clinical Oncology News • March 2012

AML

Study May Resuscitate Gemtuzumab for AML Therapy San Diego—Eighteen months after gemtuzumab ozogamicin was withdrawn from the market, a multicenter Phase III study suggested that the agent may still have a valuable role to play in acute myeloid leukemia (AML) induction therapy.

The study was conducted with a lower per-dose amount of gemtuzumab (Mylotarg, Pfizer) relative to previous protocols to see if that would lessen the side effects that had led to the drug’s withdrawal from the market, particularly induction-related deaths. Among the population of previously untreated patients with AML between the ages of 50 and 70 years, those who received gemtuzumab did better with respect to the primary end point of event-free survival (EFS) as well as overall survival (OS) than those who did not receive the drug, with a similar rate of inductionrelated deaths (abstract 6).

“On the basis of these results, we think that gemtuzumab can benefit AML patients, with acceptable toxicity,” said investigator Sylvie Castaigne, MD, of the Department of Hematology, Hôpital de Versailles, in France. Presenting the data on behalf of the Acute Leukemia French Association (ALFA) at the 2011 annual meeting of the American Society of Hematology (ASH), Dr. Castaigne said she hoped the data would lead regulatory agencies and Pfizer to reconsider the role of this agent in AML. The results of this 280-patient Phase III study corroborate the results of two previous Phase II trials in patients with relapsed disease. In the latest study, patients received a single induction of 60 mg/m2 daunorubicin (DNR) on days 1 to 3 along with 200 mg/m2 of cytarabine (AraC) on days 1 to 7 of a 28-day cycle and were randomized to receive either 3 mg/m2 of gemtuzumab on days 1, 4 and 7 or no third agent. If marrow blasts persisted at day 15, patients received 35 mg/ m2 of DNR on days 1 and 2 and 1,000 mg/m2 of AraC every 12 hours on days 1

‘We think that gemtuzumab can benefit AML patients, with acceptable toxicity.’

— Sylvie Castaigne, MD to 3. Patients who achieved a complete response or a complete response with incomplete platelet recovery were given two consolidation courses of 60 mg/ m2 of DNR on day 1 and 1,000 mg/m2 of AraC every 12 hours on days 1 to 4, with or without 3 mg/m2 of gemtuzumab on day 1 depending on the randomization arm.

The EFS at two years was 41.4% among patients who received gemtuzumab versus 15.6% among those who did not, a 43% improvement (hazard ratio, 0.57; 95% confidence interval, 0.45-0.77; P=0.0018). Diseasefree survival was 18.1% versus 48.5% (P=0.0009). This correlated with an increase in survival, with a median OS of 15.3 months in the arm without gemtuzumab versus 25.4 months in the arm that received gemtuzumab (P=0.037).

The advantage for EFS was similar in patients over the age of 65 and those younger. Moreover, the EFS advantage for gemtuzumab remained significant even after censoring the 39 patients

in this study who underwent stem cell transplantation (P=0.015).

The greatest advantage of gemtuzumab, an anti-CD33 antibody linked to a cytotoxic calicheamicin, was observed in patients with favorable cytogenetics.

Although the EFS advantage for gemtuzumab remained significant even among those with unfavorable cytogenetics, the OS advantage was lost in this group. The only factors predictive of an advantage for the primary outcome were treatment with gemtuzumab and favorable cytogenetics.

The most commonly used schedule at the time that the FDA recommended withdrawing gemtuzumab’s indication for AML was 9 mg/m2 on days 1 and 14 of a 28-day schedule. The rate of adverse events, particularly the higher fatal toxicity rate associated with this dose in the SWOG (Southwest Oncology Group) S0106 induction trial (5.7% vs. 1.4%; P=0.01), was the primary reason that Pfizer agreed to a

voluntary withdrawal on the basis of the FDA recommendation (http://www. cancer.gov/cancertopics/druginfo/ fda-gemtuzumab-ozogamicin).

In the new trial evaluating 3 mg/m2 on days 1, 4 and 7, there was no significant difference between the two groups in the rate of induction deaths possibly related to treatment (8.7% for gemtuzumab vs. 6.7%; P=0.65]. The rates of grade 3 or higher neutropenia (P=0.0049) and thrombocytopenia (P=0.0001) were significantly higher in the gemtuzumab arms, but the rates of severe sepsis and intensive care unit admissions did not differ significantly.

“The study suggests that the lower dose of gemtuzumab used in this study [relative to that used in such studies as SWOG S0106 is] active but … less toxic,” Dr. Castaigne explained. She said that she believes that gemtuzumab has a role over the current standard for newly diagnosed AML patients between the ages of 50 and 70 years.

Reviewing the data during the Plenary Program at the ASH meeting, Martin S. Tallman, MD, chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center in New York City, indicated that there have been few improvements in the standard of care for older patients and those with unfavorable karyotypes over the past several decades. Dr. Tallman said that the degree of activity reported in the trial indicates that gemtuzumab has the potential to become a new standard of care in AML, but he noted that additional trials are needed to determine the optimal dose and schedule and to better determine which patients are the best candidates for this treatment.

—Ted Bosworth Dr. Castaigne reported that she has been a consultant for and has received honoraria from Pfizer. Dr. Tallman reported no relevant conflicts of interest.

SOLID TUMORS

Fluorescence Could Improve Pancreatic Cancer Diagnosis A

new laparoscopic technique that uses fluorescent antibody markers and an LED light source has the potential to improve pancreatic staging and treatment, according to a report presented at the 2011 Clinical Congress of the American College of Surgeons.

Researchers took two antibodies commonly expressed by pancreatic cancer and tagged them with a fluorescent marker, making the cancer cells light up in bright green or red. The researchers then administered the fluorescent antibodies into mice and studied the mice

under LED light and during traditional laparoscopy.

Analysis showed that the LED light vividly identified the primary and metastatic tumors, with a sensitivity rate of 96% compared with 40% for traditional laparoscopy. Fluorescence laparoscopy rendered fewer false-positives than traditional laparoscopy and was sensitive enough to illuminate metastatic lesions smaller than 1 mm, which are not visible with a standard laparoscope.

The combination of fluorescent markers and LED light potentially could

sharpen how surgeons detect and treat pancreatic cancer in human patients, said investigators Michael Bouvet, MD, and Robert M. Hoffman, PhD, both professors of surgery at the University of California, San Diego (UCSD).

The LED light improves visualization of both the tumor and the surrounding anatomy in the abdominal cavity of the mice. “You can see both the normal background of the anatomy plus the fluorescent tumor signal at the same time,” said Dr. Bouvet, in a press release.

The technology also could be used to

target tumor cells for treatment with drugs, but the work is still in early stages. The surgeons plan to join forces with industry to secure FDA approval for clinical trials of the fluorescent antibodies in humans.

The research was funded by a fiveyear grant to UCSD and AntiCancer, Inc., from the National Cancer Institute. The UCSD team worked with AntiCancer Inc., on the mouse model and with laparoscopic technicians at Stryker Corporation.

—Christina Frangou

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FDA NEWS

Clinical Oncology News • March 2012

Patient Care

Methotrexate Drug Interactions:

Are They Slipping Under The Radar?

On Dec. 21, the FDA issued a warning to physicians and pharmacists that administering a proton pump inhibitor (PPI) in conjunction with IV methotrexate could lead to elevated serum levels of the IV agent, potentially resulting in methotrexate toxicity. The warning cited case reports and pharmacokinetic studies.

But experts say that PPIs represent just the tip of the iceberg in terms of commonly used medications that may pose serious hazards when given concomitantly with methotrexate, a chemotherapy drug that also is used in the treatment of rheumatoid arthritis (RA).

“It’s pretty scary how many of these interactions there are,” said Ali McBride, PharmD, clinical pharmacy specialist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital in St. Louis.

In addition to PPIs, other drugs that can delay the elimination of methotrexate from the body, potentially with toxic consequences, include: • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Salicylic acid (aspirin) • Many antibiotics, including penicillin, vancomycin and amoxicillin “We’ve had several cases of methotrexate toxicities in our setting,” Dr. McBride said. “We treat a lot of acute leukemic patients, and also lymphoma patients who require high-dose methotrexate. With this drug, in oncology, we use a high dose, it gets into the cell, and then we use leucovorin to rescue the cells that aren’t replicating as quickly as the cancer cells. In that protocol, you have to maintain the patient’s urine pH at greater than 7.0 in order to maximize the elimination of the drug and prevent any toxic side effects.” But patients taking PPIs, NSAIDs, antibiotics and/or aspirin may have a difficult time maintaining that pH, he noted.

The signs of acute methotrexate toxicity can include the following: • Severe vomiting, diarrhea or mucositis • Low white cell count • Low blood platelets • Renal failure Although the potential for a toxic interaction may be more significant with the high doses of methotrexate used in chemotherapy, these risks are still present with the low doses of the drug used to treat RA—but they are likely to be less well understood, experts note.

“Patients with rheumatoid arthritis are also commonly taking NSAIDs as well,” said Robert Ignoffo, PharmD, a clinical professor emeritus at the University of California, San Francisco and professor of pharmacy at Touro University College of Pharmacy in Vallejo, Calif.

“And if you’re taking an NSAID, you may

rescue drug in time, Dr. Ignoffo added. “The ability to get carboxy within 24 hours is an issue,” he noted, adding that because it’s experimental, permission to use it must be obtained from the FDA. “If your institution is in California, it’s going to take 12 hours to get to you,” Dr. Ignoffo said. “That may be too late. But even without that, there are a number of costly complications. If the interaction results in extreme myelosuppression, then the patient has to be hospitalized, given broad-spectrum antibiotics and monitored for at least a week. That’s costly to the system and unnecessary for the patient.”

Help at Hand

‘There are case reports where someone taking a low dose of methotrexate for rheumatoid arthritis has signs of toxicity even with only two to four weeks of NSAIDs.’ —Ali McBride, PharmD

also be taking a PPI because you have GI [gastrointestinal] side effects from the NSAIDs. So you have a double whammy—the NSAID and the PPI both interact with the methotrexate to delay its elimination.”

Although these drugs also may be prescribed concomitantly for cancer patients, the interaction is less likely to be missed, Dr. Ignoffo noted. “It’s highly unusual to see someone getting high-dose methotrexate and an NSAID, because it’s an oncology unit overseeing the administration. Up until the FDA alert, however, they would have been less familiar with the PPI interaction, so I think the FDA is on the mark here in issuing it.”

The dose and duration of methotrexate therapy that triggers toxic drug interactions has yet to be determined, according to Dr. McBride. “That’s the question everyone is still trying to figure

out,” he said. “There are case reports where someone taking a low dose of methotrexate for rheumatoid arthritis has signs of toxicity even with only two to four weeks of NSAIDs.” Until such questions are resolved, experts recommend a high degree of caution when prescribing the drug combinations—not just for the patient’s safety, but in order to avoid the high cost of complications.

“We had a patient taking methotrexate who was on a PPI and had delayed elimination. He had low platelets and acute renal failure and had a seizure, and ended up in the hospital for 33 days,” Dr. McBride said. “We had to use an investigational drug, carboxypeptidase G2, which costs tens of thousands of dollars. If someone had caught this early on and changed the drug, we could have prevented this interaction.”

Barnes-Jewish was lucky to get the

Fortunately, getting access to the rescue drug, also known as glucarpidase, may soon get easier. On Jan. 17, the FDA approved the medication (Voraxaze, BTG plc) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Although it will likely be a few months before the drug is available commercially, the approval “represents a significant gain in the limited arsenal for treating methotrexate toxicity,” said Leigh Boehmer, PharmD, BCOP, also a clinical pharmacist in medical oncology at Barnes-Jewish.

Dr. Ignoffo said he wouldn’t be surprised if pharmacists and prescribing physicians were missing methotrexate interactions at least 10% of the time. “It may go unnoticed if the patient doesn’t have an extreme reaction,” he said.

Moreover, drug–drug interactions may not be the only problem with methotrexate therapy. Anything that increases the acidity of urine may impair elimination of the drug—such as carbonated beverages. A 2010 case report in the British Journal of Clinical Pharmacology (2010;70:762-764, PMID: 21545633) found that unexplained low urinary pH in a lymphoma patient being treated with high-dose methotrexate was resolved in part by the elimination of cola drinks from the patient’s diet.

In St. Louis, Dr. McBride had a similar experience. “We had a patient who was set to begin a regimen for acute lymphocytic leukemia that included methotrexate, but we couldn’t get this patient’s pH within range to start the treatment. It turned out that he was constantly drinking those huge containers of Pepsi that you get at the 7-Eleven.

We told him to switch to water; he did, and his pH levels resolved.”

Dr. Ignoffo added, “The warning should go out to all oncologists, oncology pharmacists and nurses, as well as rheumatology [specialists]: These drugs should be put on the checklist of redflag items prior to the administration of methotrexate in any form.”

—Gina Shaw

FOCUSED ON YOUR

PATIENTS

© 2012 Novartis

February 2012

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Clinical Oncology News • March 2012

Opinion

ARMS RACE continued from page 1 

of these technologies need only be available in a single center in a local catchment area, but the rules of competition dictate that everyone who wants to be competitive must offer all of them. The result Jon C. White, MD is to duplicate unnecessary equipment, which is purchased and now requires use. As the expression goes, “when you have a hammer, everything starts to look like a nail.”

Potential health care consumers are constantly barraged with advertising hype about the best hospitals in the area, which usually highlight their advanced technologies that start with catchy words such as robotic, laser or cyber. When is the last time you heard an advertisement on television or the radio claiming that a medical center provides the least expensive or most appropriate care in the area? This sales approach is in sharp contrast to other industries that always advertise the lowest price for automobiles, computers, airfares, or any product or service they are selling. Consequently, the cost of medical care is higher in communities where there is a lot of competition between providers than in communities that have little to no

competition. This surprising finding runs contrary to long-held theories of capitalism, which postulate that competition should drive down the prices of services.

This aberration in health care economics can be explained by the medical arms race, which is more intensely practiced in medically competitive communities. Hospitals or medical centers that are not competing for their share of the market have a lower need to provide boutique services or unneeded cutting-edge technology to attract patients. They can apply themselves to providing the most cost-effective and appropriate care.

The medical arms race, which is as wrong-headed and financially destructive as its nuclear forerunner, is one reason that we find ourselves in the difficult financial situation we face today. There are other reasons, however, including a dysfunctional tort system, a failure to audit and control Medicare and Medicaid expenditures and an inability to control expenditures for futile care, especially in the terminal stages of life. All of these are difficult problems, but they can be fixed.

Another popular concept from the Cold War era, the “Nash Equilibrium,” is useful to consider in this context. This game theory concept, first suggested by John

The cost of medical care is higher in communities where there is a lot of competition between providers than in communities that have little to no competition.

Forbes Nash, holds that in most standoffs neither side gains by changing its behavior unilaterally, and therefore nobody changes. During the Cold War, neither the United States nor the Soviet Union would disarm unilaterally because each country feared that the loss of equilibrium would be at its own expense.

You might compare this standoff to situations occurring in medicine today. A huge increase in diagnostic studies is one problem that contributes to our rapidly increasing medical expenses. Doctors cannot be cost-conscious in their use of diagnostics because of the medical-legal consequences of not ordering the most sophisticated, and usually most expensive, diagnostic procedures. This situation should be addressed by appropriate tort reform. Lawyers, however, will not allow changes in the medical-legal system, which has been very profitable for them. Neither side will act unilaterally.

Another example is the sustainable growth rate (SGR) formula, which was developed to curb unsustainable inflation. Physicians, noting that their income will decrease with the

When is the last time you heard an advertisement on television or the radio claiming that a medical center provides the least expensive or most appropriate care in the area?

application of the SGR formula, have been successful in temporarily blocking it for years and are trying to get it repealed. Lawmakers who see the tremendous inflation in medical expenses do not want to abandon the SGR formula, which they see as the best way to rein in expenses. Every two to six months, the issue is painfully revisited to the detriment of both parties involved.

The eventual thawing of the Cold War was achieved by a progressive deescalation of the irrational arms buildups through a series of acts such as the Nuclear Test Ban Treaty (1963), the Nuclear Non-Proliferation Treaty (1970), the Helsinki Accords (1975), the Strategic Arms Limitation Treaties I and II (1972 and 1979) and the Strategic Arms Reduction Treaties I and II (1991 and 1993). This negotiated drawdown led to restructuring (perestroika) and openness (glasnost) in the Soviet Union, which culminated in opening that country’s borders to the West.

On the other side of the world, things have changed as well. The North American Aerospace Defense Command (NORAD), the American–Canadian entity, which was built to detect and respond to intercontinental ballistic missiles, has been retooled in a swordsto-plowshares strategy. According to its Web site, the organization is now tracking mainly domestic flights. Recently, one of the highest-level alerts was for a small Cessna that had flown too close to the U.S. Capitol building.

The field of medicine needs the same kind of negotiated disarmament. First, physicians and lawyers have to discuss tort reform. Doctors should accept that malpractice does exist and sometimes the victims should be compensated. On the other hand, judgments should be reviewed and adjudicated by experts.

In the case that payment is appropriate, it should go to the victim. The lawyers should not be the main beneficiaries of the system but should work on an hourly basis and not for a percentage of the award. They should not work on contingency, and frivolous suits should be discouraged by appropriate penalties.

Additionally, there should be regulations to limit unnecessary diagnostics.

For example, the U.S. Preventive Services Task Force (part of the Department of Health and Human Services) has studied and advises against screening colonoscopies after 75 years of age, for prostate cancer after 75 and for cervical cancer after 65. In all these cases the risks outweigh the benefits, yet Medicare and

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Opinion

Medicaid pay for all procedures even when the recipients are outside of these recommended age limits.

Medicare and Medicaid also pay for implantable cardiac defibrillators, cardiac stents and certain vertebral procedures (such as vertebroplasty and kyphoplasty) for patients to whom these procedures provide no benefit and are sometimes harmful. In fact, it has been estimated that Medicare spends from 15% to 30% of its budget on contraindicated procedures, which translates roughly into $75 billion to $150 billion annually (nytimes. com/2011/05/26/opinion). Patients and their doctors insist on these procedures and the purchasers of health insurance and the taxpayers are saddled with the bill. End-of-life decisions also are a political hot potato that nobody wants to handle. A significant portion of our health care resources is poured into the last days or weeks of life, often when it is known that the efforts are futile. All these issues call for a negotiated de-escalation and should be on the table.

In each situation described, there are some people who want to continue business as usual and to receive every kind of medical device, advanced technology, diagnostic procedure or end-of-life measure that is available, despite evidence that it will not be helpful. I think this is fine: People should be allowed to

make choices about what treatment they negotiation became clear. I think we are wish to receive, but if the efficacy of the on the brink again, this time with health treatment they demand is not support- care financing, and it is time again for ed by clinical evidence, then they should us to roll up our sleeves and start on the purchase it at their own expense. The road to détente. medical insurance industry (and their When I was in school in the 1950s and SLUG customers) or the taxpayers should not FILE 1960s, we practiced what to do in case of Current file: AC124_CancerAgentsAd.indd 1ST PROOF LAYOUT APPROVED FINAL OK PROOF 1: 1/5 be obligated to pay for ineffective, futile were taught to crouch INITIALS AND DATE a nuclear war. We INITIALS AND DATE REV 1: 1/6 REV 2: 1/10 Full name of project Senior editor or harmful care. under our desks, put our heads between REV 3: Editor Taking on these very emotional issues our legs and so forth. SomeREVenterpris4: REV 5: Project no.

Copy editor will require the political will and couring families in our neighborhood were REV 6: Revision # R2 Sales REV 7: age of our profession, the legal indus- digging bomb shelters and stocking REV 8: Layout date/time March 1, 2012 3:49 PM Production try and lawmakers. In the 1960s, when them with nonperishable food. In conEditorial date/time Circulation our country was brought to the brink by trast, today’s students are being told Trim size COMMENTS: KEYWORDS: the Cuban Missile crisis, the need for what clothes to pack when they travel Color specs File path

to Moscow and Beijing on school trips.

Basements, these days, are for game rooms stocked with flat-screen TVs, Xbox consoles and snacks. It seems the negotiated de-escalation of the nuclear arms race has been successful. I hope thatSTATUSin& HISTORY medicine we can follow this PICKED UP FROM: example.

Maybe if we learn to negotiate, APPLIED TO: we won’t be so mad.

EDITOR: ART DIRECTOR:

—Jon C. White, MD

Dr. White is chief of Surgical Services, VAMC, and professor of surgery, George Washington University, Washington, DC.

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Money for Drugs

Part 2 of a Three-Part Series

Should Physicians Be Paid for Pharmaceutical Development and Clinical Investigations?

Cooperation Is Crucial for Lifesaving Medications Marjorie Powell, JD Senior Assistant General Counsel Pharmaceutical Research and Manufacturers of America Washington, DC

P

hysicians play a vitally important role in conducting clinical trials of potential new medicines and helping to explain new treatments and how they work to other health care providers.

Collaborations between biopharmaceutical research companies and physicians at respected research institutions have been critical to the development of clinical trials of new medicines for years.

some of the nation’s best physician clinicians and researchers. This finite pool of talented physicians is precisely the dynamic, experienced expertise companies want, and need, to conduct their clinical trials. Importantly, extensive safeguards exist to protect the interests of patients, help avoid biased clinical trial results and maintain the highest standards of medical research ethics.

FDA regulations are in place and detailed guidelines have been provided by the NIH and the medical schools themselves to help assure that clinical research is conducted in a way that protects all participating patients. At the University of Missouri School of Medicine, for example, all clinical tests of new medicines are reviewed and approved

In the end, the contentions of our critics distort the value of company–physician interactions and worse, threaten to jeopardize patient care.

The United States leads the world in the development of new medicines, and most of the drugs that U.S. companies have created are still on the market today saving and enhancing the lives of millions of patients and helping to control the costs of surgery and hospitalization.

Clinical trials are crucial to determining the safety and effectiveness of new medicines, and are an essential part of the increasingly expensive 10- to 15-year drug development and approval process. Biopharmaceutical companies often turn to physicians at respected academic medical centers, including the University of Missouri School of Medicine, the University of Kansas Medical Center and the Washington University School of Medicine in St. Louis, to conduct their clinical research.

The clinical testing database of the National Institutes of Health (NIH) shows that in the arena of new cancer medicine development alone, these three respected institutions are conducting nearly 70 trials of potential new anticancer drugs in collaboration with biopharmaceutical companies.

University medical centers attract

by an institutional review board and all faculty members are required to submit conflict-of-interest reports that disclose all outside activities and relationships, including involvement in clinical trials of new medicines being developed by biopharmaceutical companies.

The Pharmaceutical Research and Manufacturers of America (PhRMA), meanwhile, provides its “Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results”

Has Medicine Lost Its Moral Compass?

Art Gale, MD Internist Barnes-Jewish Hospital Missouri Baptist Medical Center St. Louis, MO

T

wo former editors of The New England Journal of Medicine (NEJM), Marcia Angell, MD, and Jerome Kassirer, MD, wrote separate books, both published in 2005, on how financial conflicts of interest involving physicians and the pharmaceutical industry have undermined the validity of clinical research and compromised the integrity of the medical profession.

be a “consultant” in name only.

Dr. Angell also discusses at length the role of contract research organizations that establish networks of practicing physicians who perform clinical studies. There are approximately 1,000 such organizations. They receive revenues of about $7 billion annually from their drug company clients. In 2001, these organizations offered bounties to physicians that averaged about $7,000 per patient enrolled. In one trial, physicians were offered $12,000 per patient and another $30,000 on enrollment of a sixth patient.

Many of the drugs tested are already approved, so-called postmarketing or Phase IV studies.

With decreasing reimbursement from managed care and increasing profession-

How can physicians believe anything that they are told by so-called experts when they learn that clinical guidelines are based on flawed research that may not be independent and objective?

Dr. Angell’s book is titled “The Truth about Drug Companies” (Random House Trade Paperbacks; 2005) and Dr. Kassirer’s book is “On the Take” (Oxford University Press, USA; 2005). Each work takes a slightly different approach. Dr. Angell focuses mainly on drug companies, whereas Dr. Kassirer’s book focuses mainly on physicians.

Both authors document the wellknown practices drug companies use to entice physicians to prescribe their products. These include gifts, dinners at expensive restaurants and payments to

al liability premiums, one can understand why so many doctors enroll their patients in these trials. A physician can make much more money from clinical trials than from seeing patients. And the work is a lot easier. Many critics view these studies as just excuses to pay doctors to put patients on a company’s already approved drug.

The authors reserve their harshest criticism for their colleagues in academia.

As former editors of one of the world’s premier medical journals, Drs. Angell and Kassirer have reviewed hundreds of articles submitted for publication and are eminently qualified to analyze clinical investigators and the conflicts of interest that affect their research.

Dr. Angell writes, “Until the 1980s, researchers were largely independent of the companies that sponsored their work. Now, however, companies are involved in every detail of the research ... even whether to publish the results.”

She thoroughly documents the financial relationship between academic medical centers, especially her own (Harvard) and the drug companies.

Harvard is hardly unique. Two-thirds of academic medical centers hold

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to help ensure that clinical research sponsored by biopharmaceutical companies is carefully conducted and meaningful research results are published for health care professionals and patients. Revisions to the principles, put in place nearly two years ago, call for increased transparency about clinical tests for physicians and their patients and improved disclosure to better manage potential conflicts of interest in medical research.

Some critics, who ignore the many effective efforts to protect the integrity of clinical trial data, insist that only tests conducted by the NIH are truly unbiased. They overlook a key fact: NIH officials have repeatedly acknowledged that their institutes are not equipped to conduct the thousands of clinical tests needed for the development of new medicines every year.

The NIH and its grantees conduct vitally important basic research that can be used by biopharmaceutical companies to help develop new medicines. But actual drug development, including preclinical and clinical testing, is the expensive and time-consuming responsibility of our nation’s innovative drug companies, which must spend tens of billions of dollars annually to get the job done.

In 2010, America’s biopharmaceutical research companies spent a record $67.4 billion on research and development. And various estimates show that clinical trials account for 45% to 75% of total pharmaceutical development costs. Our drug development and approval process today, one that

is carefully monitored by the FDA, is working well. And perhaps the best evidence of the system’s success is the progress that has been made in the fight against disease that can be, in large part, attributed to new medicines. For example, the development of new heart disease and stroke medicines has helped to reduce deaths from these two major killers by nearly 30%. New anticancer drugs, meanwhile, have contributed to an increase in cancer survivors from 3 million in 1971 to 11.7 million in 2007.

Physicians learn about new medicines from a range of sources, including firsthand experience, medical journals, continuing medical education programs and discussions with biopharmaceutical company representatives and fellow physicians at company-sponsored meetings. PhRMA agrees with the American Medical Association, which in Congressional testimony said, “There is a clear need for interactions between physicians and the pharmaceutical industry to ensure the free flow of valid scientific information. When the information is accurate and complete, physicians have the necessary tools to make the right prescribing decisions.”

When physicians meet with biopharmaceutical company representatives or attend events at which fellow physicians explain medicines and how they work, they are given the latest FDA-regulated information about the benefits, risks and appropriate uses of drugs. At physician speaker forums, health care providers can discuss this important information

with a peer who has firsthand knowledge and expertise in the therapeutic area being discussed. That interaction helps to improve knowledge and patient care.

It is, of course, vitally important to guarantee that sound scientific data are presented and that materials contain legitimate information. Strict federal regulations and self-imposed stringent industry standards are already in place to ensure the accuracy of discussions and documents offered during industry–physician interactions. The FDA requires that materials be “truthful, accurate and consistent with product labeling” approved by the agency. Companies are held accountable for the presentations of their speakers. Biopharmaceutical research companies and PhRMA have launched a number of wide-ranging efforts to help guarantee compliance with federal rules and industry standards. For example, the PhRMA Code on Interactions with Healthcare Professionals says company decisions to hire physicians as speakers should be based on the doctors’ medical knowledge, expertise in a particular therapeutic area, communication skills, faculty and medical society affiliations, participation in clinical trials and reputation.

For their part, the many biopharmaceutical companies adhering to the PhRMA Code conduct periodic reviews of speakers to determine if they are complying with FDA regulations and their own ethical compliance policies. The speakers may be fired if they violate federal rules or company policies. Biopharmaceutical research companies are also committed to transparency in their relationships

with health care professionals. PhRMA and its members supported recent Congressional transparency efforts, including enactment of the Physician Payment Sunshine Act. Several companies have voluntarily released information about payments to doctors before implementation of the Sunshine Act. When the law is fully implemented in 2014, drug companies will be required to provide a thorough listing of payments or other transfers of value to physicians and teaching hospitals to the U.S. Department of Health and Human Services, which will post the information on a federal Web site. Additionally, the PhRMA Code, which was strengthened in July 2008, requires that health care providers serving on committees that establish clinical guidelines or formularies must disclose to the committees their speaking and consulting arrangements with biopharmaceutical companies.

In the end, the contentions of our critics distort the value of company–physician interactions and worse, threaten to jeopardize patient care. Allegations that the promotional efforts of biopharmaceutical companies unduly influence physician prescribing and help to drive up health care costs are contradicted by a simple fact: 78% of the prescriptions written today are for generic drugs, not brand-name medicines.

The educational programs of biopharmaceutical firms help to make physicians aware of appropriate, often newly FDAapproved, medicines and their proper uses. Their arsenal of weapons to treat and prevent disease is growing, and that means better patient care.

equity in companies that sponsor some of their research.

The academic medical centers reap huge profits from these arrangements. They also receive major gifts and endowments from the drug companies. But there is a price to pay. In Dr. Angell’s view, researchers become little more than “hired hands” of the pharmaceutical industry. She concludes “all of this makes a mockery of the traditional role of researchers as independent impartial scientists.”

Both authors cite a particularly egregious example of authors’ financial ties to drug companies. These ties were so extensive that there was insufficient room to publish them in print. Instead, they had to be published on NEJM’s Web site, where they consumed three single-spaced typewritten pages!

Conflicts of interest extend even to the venerable National Institutes of Health (NIH). In 1995, the director of the NIH, Harold Varmus, MD, “quietly rescinded

the policy that barred NIH directors from accepting consulting fees and stock options from companies.” As a result, directors of various institutes have earned hundreds of thousands of dollars in “consulting” fees. For example, the deputy director of the NIH Laboratory of Immunology, whose salary was $179,000 in 2003, earned $1.4 million in consulting fees over 11 years and received stock options valued at $865,000. Other senior scientists with ties to industry included the director of the National Institute of Arthritis, a director of the National Institute of Diabetes and Digestive and Kidney Disease and the former director of the National Human Genome Research Institute.

When these revelations were published, a former acting director of the NIH opined that none of these revelations compromised the public interest because NIH scientists are “highly ethical people with enormous integrity.” Dr. Kassirer quotes the current director of

NIH, Elias Zerhouni, MD, who found no evidence that “medical decisions had been influenced by company payments to agency officials.” After Congress promised a full investigation, Dr. Zerhouni changed his mind and said that NIH top scientists were no longer accepting consulting fees or stock options.

The conflict of interest in clinical research is so pervasive that, as editor of the NEJM, Dr. Kassirer had difficulty finding independent authors to write review articles. In the late 1990s, he stated, “We occasionally had to reject five or six prominent authors before we found one who had no conflicts.” His successor at NEJM solved this problem by changing the policy because he found it too difficult to find authors who were free of such conflicts.

What do all the conflicts of interest have to do with the practice of medicine? The answer is: a lot. Probably their most important effect is through the development of clinical guidelines— guidelines that practicing physicians are

supposed to follow in treating patients.

The government and industry now are promoting “evidence-based medicine.” But has anyone asked where the “evidence” comes from? It often comes from the same conflicted studies by the same conflicted clinical investigators just described. How can physicians believe anything that they are told by so-called experts when they learn that clinical guidelines are based on flawed research that may not be independent and objective?

Dr. Kassirer cites two physicians, one the dean of Cornell Medical School in New York City and the other chief of cardiovascular medicine at Brigham and Women’s Hospital in Boston, as examples of experts who are promoting stricter guidelines for blood lipid levels. Both have financial ties to Pfizer. Dr. Kassirer asked one of the physicians, Peter Libby, MD, of Brigham Hospital, why he lent his distinguished name to brochures and Web sites that

Editor’s Note: This article was originally published in Missouri Medicine, September/October 2011;108:18-22.

see COMPASS, page 12 

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Soros’ Donations to Campaign Against Physicians Receiving Research Funds Should Be Disclosed

M

uch of the agitprop generated in the media and fourth estate originates from the Center on Medicine as a Profession (CMAP). “CMAP was established in October 2003 at the Columbia College of Physicians and Surgeons through a joint agreement by the Institute on Medicine as a Profession (IMAP)

John C. Hagen III, MD Ophthalmologist Editor, Missouri Medicine: The Journal of the Missouri Medical Association Kansas City, MO

and Columbia University. In February 2003, George Soros, chairman of the Open Society Institute, generously funded the establishment of IMAP with a gift of $7.5 million. CMAP carries out IMAP’s programmatic agenda.”1 This connection with Soros, a financier who is spending many billions of

dollars attempting to reshape the world into his view of a leftist utopia, is rarely to never disclosed by Soros-compensated physicians doing his bidding, nor the journalists that use CMAP for source material and physician quotes. This is disingenuous, hypocritical and completely undermines CMAP credibility.

Reference 1. http://www.cmap.columbia.edu/index.shtml

Money for Drugs As Research and Development has increased, the number of drugs approved by the FDA has decreased, 1996-2006.

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promote lipid-lowering drugs. Dr. Libby replied that it is a way to spread an educational message that he believes in. He believes that by disclosing all of his financial conflicts of interests he can maintain his “independence, objectivity and reputation.” According to Dr. Kassirer, Dr. Libby “asserts that he exploits a corrupt system in a way that benefits patients.” Apparently, Dr. Libby and other “distinguished” researchers hold to the discredited tenet that the end justifies the means.

On a more personal level, when drug reps come into our offices, they present studies that show why their drug is the best. Most of these studies are sponsored by drug companies and are conducted

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by, to quote Dr. Angell again, “hired hands,” and therefore are suspect. When I asked a drug rep recently whether his company sponsored a study he was citing, he replied, “Of course, what did you expect?”

Most practicing physicians are well aware that they cannot always take the word of the drug reps at face value. So why make a big fuss about it? The facts are that the pharmaceutical industry spends far more on marketing than on research. Their marketing is effective or they wouldn’t spend so much money on trying to influence physicians. The ultimate cost of all these suspect drug studies is borne by our patients—often our Medicare patients, who can least afford the drugs that are being promoted.

Drs. Angell and Kassirer do not deny that many products of the pharmaceutical

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industry have improved the lives of patients. Nor do they deny the importance of the researchers, often physicians, in developing these products. But Dr. Kassirer believes that pharmaceutical companies, in their lust for profits, have crossed the line between “advancing the cause of science and the betterment of patient care on the one hand and the pecuniary interests of physicians on the other. Too many physicians have become mere tools of industry’s promotional and marketing efforts. Others have engaged in pseudoscientific studies and published biased articles that foster industry’s goals over patient goals.”

The final sentence in Dr. Angell’s book sums it up: “Nowadays, even the most distinguished and apparently unbiased academics may be on the pharmaceutical industry’s payroll. If they are, you need

to be especially skeptical about their pronouncements.”

As we enter the third millennium, is this the kind of reputation we want our profession to have? Do we want future generations to look back and say we were, in Dr. Kassirer’s words, “on the take”? If we have lost our moral compass, we need to regain it.

In their concluding chapters, Drs. Angell and Kassirer make specific recommendations on ways that the pharmaceutical industry and the medical profession can reclaim the high ground.

But they have a healthy skepticism that this can be accomplished. Their books are more directed to the public than to doctors or drug companies. They believe that the public needs to learn the facts. The message is clear: If we as a profession do not police ourselves, the public eventually will.

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HEMATOLOGIC DISEASE

Clinical Oncology News • March 2012

Multiple Myeloma

CEREBLON continued from page 1 

Presenting the findings at the ASH meeting, Dr. Zhu, who works in the laboratory of Keith Stewart, MD, in the Division of Hematology-Oncology at Mayo Clinic in Scottsdale, Ariz., indicated that the importance of CRBN to this class of IMiDs not only explains the previously unknown mechanism of the antitumor effects but may also provide guidance for selecting candidates for treatment.

The investigators used cell lines with varying degrees of CRBN gene expression to verify that the presence of CRBN was critical to the antitumor effects of IMiDs (abstract 127). The CRBN shRNA lentiviral expression constructs were employed to lower CRBN levels in a series of human-derived myeloma cell lines. Cell lines with CRBN levels that were reduced or eliminated demonstrated resistance to lenalidomide (Revlimid, Celgene), although they remained sensitive to other anticancer drugs, such as melphalan, dexamethasone and

bortezomib (Velcade, Millennium).

In another experiment, the investigators evaluated CRBN expression by quantitative polymerase chain reaction in samples of 10 patients with multiple myeloma who had become resistant to lenalidomide therapy. According to Dr. Zhu, in eight of the 10 patients, there was a 20% to 90% reduction in the CRBN expression level at the time of drug resistance compared with baseline cell samples.

This not only reinforced the importance of CRBN depletion in resistance but raised the possibility that CRBN expression may serve “as a potential biomarker to predict response to immunomodulatory drugs,” reported Dr. Zhu, who noted that the importance of CRBN appears to be shared by all agents in this class, including the investigational agent pomalidomide (Celgene).

“This is an important finding,” said Shaji Kumar, MD, a hematologist and associate professor of medicine at Mayo Clinic in Rochester, Minn., who was not affiliated with the study. “Once validated, the key will be the development of a

clinical test which will allow us to determine the patients who will benefit and thus get us closer to the personalized medicine paradigm.”

The presence of CRBN appears to be critical for IMiD efficacy—cancer cells that do not express CRBN will not respond to this class of IMiD. However, even if CRBN is present, IMiD response is not guaranteed, which suggests that there are mechanisms of IMiD resistance other than CRBN depletion.

“We demonstrate here that CRBN is essential for immunomodulator activity and preliminary data support that low levels of CRBN predict for poor drug response,” Dr. Zhu said. She said future studies would focus on identifying CRBN downstream molecules that associate with antimyeloma effects of IMiDs, which may lead to development of new drugs with more specific antimyeloma activities.

Co-investigator Robert Orlowski, MD, professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center in Houston, who chaired the session during which the

results were presented, said that the clinical implications of the findings are significant. Dr. Orlowski indicated that progress in understanding the mechanisms of any anticancer therapy make take clinical practice closer to the goal of targeting specific tumors rather than simply treating the type of cancer.

“These data raise the possibility that we could personalize therapy with immunomodulatory drugs by screening each patient’s plasma cells for expression of cereblon, and treating only those patients whose myeloma is susceptible to these drugs” based on the CRBN levels, Dr. Orlowski said. “Even more exciting is the possibility that we could find ways to turn cereblon expression on, which could allow more patients to benefit from immunomodulatory drugs, including those whose disease has progressed on prior therapy.”

—Ted Bosworth

not impossible—that a commercial sponsor would support such a study? Pragmatically speaking, from the point of view of the sponsor, the potential market is quite small, and even if a Phase II trial were initiated, such an effort would, optimistically, take “a number of years to complete.” Furthermore, the only realistic study end point, “objective response rate,” would today almost certainly not satisfy requirements for “regulatory marketing approval.”

However, what if an individual oncologist, following a thorough discussion with an individual patient and based on this provocative, although solely preclinical report, wished to treat the patient with the combination of oxaliplatin and dasatinib? Would, or should, a third-party insurer be willing to consider such an approach in the recognized absence of alternatives known to realistically provide even a modest chance for clinical benefit in this specific clinical setting?

In response to the first question, one might speculate an international effort could achieve sufficient support to complete the trial in a more efficient manner, and possibly the pharmaceutical manufacturer might be persuaded to make the agents available free of charge for study participants. However, neither of these activities would alter the current drug approval paradigm, in which a “favorable but not truly spectacular response rate” is unlikely to result in anything more than a call for a “well-designed randomized comparative trial.”

Finally, even if a group of investigators wished to conduct such a study, this conceptual approach to the development of a

research study effort would be of no relevance to the patients with this rare condition who might be seen long before such a trial is actually activated or ultimately completed and reported in the peerreviewed literature.

But since both of the agents examined in this preclinical model are commercially available, an oncologist and an individual patient could elect to use the drugs today. How many third-party payers would be willing to examine the details of this case, appreciate the fundamental fact that there is no existing effective treatment in this specific clinical setting, and therefore seriously consider payment for the costs of these agents rather than simply conclude that the combination is not included in any so-called “evidencebased guidelines for ovarian cancer”?

If such considerations were undertaken, one might reasonably permit the oncologist to administer a maximum of two cycles of the novel strategy—assuming acceptable toxicity and absence of disease progression following the first cycle—and then to re-evaluate for evidence of “clinical benefit.” If none were seen, this program would be discontinued. But if clinically relevant favorable effects were observed (e.g., shrinkage of measurable masses, decrease in malignant ascites, decline in serum tumor markers or improvement in cancer-associated pain), the treatment plan and the associated third-party payment for the care would be continued.

One might even argue that the outcome of such individual non-investigative experiences be posted in an easily identified, well-organized, condition-specific online

EDITORIAL BOARD COMMENTARY

Dr. Zhu reported no relevant financial conflicts of interest. Dr. Orlowski reported that he has a financial relationship with Celgene.

CLINICAL TRIALS

RARE CANCERS continued from page 1 

morphologic subtypes found in patients with advanced epithelial ovarian cancer.

Unfortunately, it is well recognized that women with these cancers who present with metastatic disease, or who develop recurrence if initially diagnosed at an “early stage,” experience a particularly poor prognosis compared with the far more common epithelial ovarian subtypes.1,2 And in striking contrast with serous ovarian cancers, primary mucinous ovarian malignancies are considered by many investigators to be inherently resistant to cisplatin or carboplatin-based chemotherapy.

In a recently reported provocative preclinical model, investigators demonstrated in a well-characterized mucinous ovarian cancer cell line that the concurrent administration of dasatinib with oxaliplatin could impressively overcome the resistance of the line to the platinum agent.3 Furthermore, the research suggested that the observation resulted from major dasatinib-induced inhibition of the effect by oxaliplatin on SRC kinase. And interestingly, in vivo experiments demonstrated a substantial enhancement associated with the antitumor effects of the two-drug combination in the mucinous cell line that was not observed in a serous ovarian cancer cell line.

So, the questions to be asked in this commentary are as follows: How should clinical investigators wishing to examine this novel concept proceed, knowing it is unlikely—although

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

database (with absolutely no accompanying patient-specific identifiers), so the oncology community would be aware of any clinically beneficial effects observed if colleagues had previously attempted to employ this novel approach in an individual patient with a metastatic mucinous ovarian cancer. If no treatment responses were observed, for example, in 10 or 15 patients, the lack of clinical relevance of this model would be clear. If treatment responses were noted in this rare condition, however, this experience could inform future patient management as well as future discussions with individual third-party insurers.

If only life were so simple.

References 1. Hess V, A’Hern R, Nasiri N, et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol.

2004;22:1040-1044, PMID: 15020606.

2. Winter WE 3rd, Maxwell GL, Tian C, et al.

Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:36213627, PMID: 17704411.

3. Matsuo K, Nishimura M, Bottsford-Miller JN, et al. Targeting SRC in mucinous ovarian carcinoma. Clin Cancer Res. 2011;17:5367-5378, PMID: 21737505.

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Clinical Oncology News • MARCH 2012

Community Oncology

Clinical Conundrums

Prepared by

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

A quiz for the community hematologist/oncologist

QUESTIONS

c. Temozolomide d. Vemurafenib

palpable right inguinal lymphadenopathy. Further imaging demonstrates one liver and two lung lesions. Magnetic resonance imaging of the brain is unremarkable. Liver lesion biopsy is consistent with melanoma. Two years ago, she was diagnosed with T3b (3 mm) N0M0 melanoma in the right lower leg.

After wide excision and a negative sentinel lymph node biopsy, she has been observed. The patient reports that she is interested in high-dose interleukin (IL)-2 therapy based on the excellent response her brother had when he was diagnosed with melanoma. All of the following statements about high-dose IL-2 are correct except: a. The median response duration is about 24 months. b. High-dose IL-2 should be avoided in patients with poor performance status. c. High-dose IL-2 should be avoided in patients with significant cardiopulmonary disease. d. The overall response rate is 16% and complete response rate is about 6% in highly selected patients.

All of the following are known side effects of vemurafenib except: a. QT prolongation b. Keratoacanthoma c. Squamous cell carcinoma d. Photosensitivity skin reactions e. Cataract

1. A 55-year-old woman presents with

2.

The patient presented in Question 1 has poor performance status precluding the administration of high-dose IL-2 therapy. She is not interested in participating in a clinical trial. The tissue obtained from the liver demonstrates BRAF V600 mutation. What would be the next best treatment option for her? a. Sorafenib b. Dartmouth regimen

3.

4.

The patient presented in Question 1 reports history of melanoma in multiple family members in addition to history of pancreatic cancer in a paternal uncle. She inquires about possible hereditary conditions associated with her condition. You report to her that 25% to 40% of the members of melanoma-prone families have a specific germline mutation.

You are referring to germline mutation in which of the following genes? a. p53 b. BRAF V600 c. p16/CDKN2A

5. What percentage of patients with

melanoma has a family history of the disease? a. 40% b. 10% c. 60% d. 30%

6.

A 36-year-old woman is diagnosed with chronic phase chronic myelogenous leukemia (CML-CP). Two months previously she presented to her local emergency room with an upper respiratory infection. Routine blood tests revealed white blood cell count of 45,000/mcL

with a myeloid left shift but no circulating blasts; hemoglobin was 11.1 g/dL; and platelet count was 350,000/mcL. BCRABL fusion gene on bone marrow specimen was confirmed by polymerase chain reaction. She is started on imatinib 400 mg per day. According to the recently published data by Marin and colleagues, assessment of BCR-ABL1 transcript levels at three months is the only requirement for predicting outcome in this patient? a. True b. False

7.

According to National Comprehensive Cancer Network (NCCN) guidelines, which milestone should be attained at three-month intervals for the patient in Question 6 to continue the same dose (400 mg/day) of imatinib therapy? a. Complete cytogenetic response (CCyR) b. Complete hematologic response (CHR) c. Partial molecular response d. Complete molecular response

8.

The patient in Question 6 is unable to achieve CCyR at 12 and 18 months despite dose escalation of imatinib. The patient is 100% compliant with the medication. The BCR/ABL kinase domain mutation analysis demonstrates T315I mutation. Which of the following agents are believed to be effective against this particular mutation?

a. Dasatinib b. Nilotinib c. Ponatinib d. Omacetaxine mepesuccinate e. c and d f. a and c

9.

Proteasome-mediated protein degradation is critical to cell function and survival. Proteasome inhibition has demonstrated clinical activity in multiple myeloma, waldenstrom macroglobulinemia and certain types of lymphomas.

All of the following are second-generation proteasome inhibitors except: a. MLN9708 b. Carfilzomib c. Marizomib d. Perifosine

10. All of the following statements

about Akt pathway and its regulation are correct except: a. Akt has two isoforms. b. Activation of Akt is dependent on phosphatidylinositol 3-kinase (PI3K). c. More than 50 substrates of Akt have been identified. d. Akt regulates a variety of cellular processes, including proliferation, survival, motility, angiogenesis and metabolism/glucose homeostasis. e. Loss of expression or catalytic function of phosphatase and tensin homolog (PTEN) results in constitutive activation of Akt. for answers see CONUNDRUMS, page 16 

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PRN

Clinical Oncology News • March 2012

Community Oncology

CONUNDRUMS

‘The Latest, Plus Some’:

ANSWERS

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

1. Answer: a. The median response

T

continued from page 16 

duration is about nine months (two months to more than 106 months).

Atkins MB, Lotze M, Dutcher JP, et al. Highdose recombinant interleukin-2 therapy for patients with metastatic melanoma: analysis of 270 patients treated from 1985-1993. J Clin Oncol.

1999;17(7):2105-2116, PMID:10561265.

Answer: a. In this study the three2. Answer: d. Vemurafenib produces 6. month BCR-ABL transcript level (higher rapid responses with improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation.

The mutation must be detected and confirmed by an FDA-approved test prior to treatment.

Chapman PB, Hauschild A, Robert C, et al.

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516, PMID: 21639808.

Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819, PMID: 20818844.

3. Answer: e. Cataract is not a known

side effect of vemurafenib. A detailed skin exam and electrocardiogram should be obtained prior to initiation of therapy and at regular intervals during therapy. Patient should use sunblock to avoid skin reactions.

Chapman PB, Hauschild A, Robert C, et al.

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516, PMID: 21639808.

Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819, PMID: 20818844.

4.

Answer: c. The gene p16/CDKN2A, which is located on chromosome 9p21, is an important determinant of melanoma risk in high-risk melanomaprone families. The BRAF V600 is the most common somatic mutation in melanoma and is present in approximately 60% of the cases. Germline mutation in p53 (Li-Fraumeni syndrome) is not associated with increased risk for melanoma.

Haluska FG, Hodi FS. Molecular genetics of familial cutaneous melanoma. J Clin Oncol.

1998;16(2):670-682, PMID: 9469357.

Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;17;353(20):2135-2147, PMID: 16291983.

5. Answer: b.

Monzon J, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med. 1998;338(13):879, PMID: 9516223.

Goldstein AM, Tucker MA. Screening for CDKN2A mutations in hereditary melanoma. J Natl Cancer Inst. 1997;89(10):676-702, PMID: 9168176.

or lower than 9.84%) was the only independent predictor for overall survival (relative risk [RR], 7.33; P<0.001), progression-free survival (RR, 7.16; P<0.001), event-free survival (RR, 9.71; P<0.001) and c-CCyRS (RR, 0.431; P<0.001), which indicates that this measurement at three months is the most informative.

Of note, these data are applicable only to patients on frontline therapy with imatinib for CML-CP.

Marin D et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30(3):232-238, PMID: 22067393.

7.

Answer: b. Disease monitoring to assess the response to therapy and to detect early relapse is one of the key management strategies of CML. Achievement of certain goals at specific time points appears to be important for the outcome of patients with CMLCP. CHRs should be observed after three months of therapy, and major cytogenetic response and CCyRs should be documented at 12 and 18 months, respectively. The CHR is defined as complete normalization of peripheral blood counts with no immature blood cells, leukocyte count less than 10 × 109/L and the platelet count less than 450 × 109/L. Additionally, the patient should be free of signs and symptoms of the disease with the disappearance of splenomegaly.

National Comprehensive Cancer Network (NCCN) guidelines. www.nccn.org. Accessed February 12, 2012.

8. Answer: e. Recently, ponatinib

and omacetaxine mepesuccinate have shown promising activity and tolerability against T315I mutation. Ponatinib is orally administered and omace­ taxine mepesuccinate subcutaneously.

Recent Phase I and II data, with ponatinib and omacetaxine mepesuccinate, reported early and durable responses, respectively.

Cortes J, Talpaz M, Bixby D, et al. A phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: emerging see CONUNDRUMS, page 22 

he name Johns Hopkins has become synonymous with excellence in oncologic research and patient care, which is why Clinical Oncology News is pleased to provide reviews and commentaries from Johns Hopkins over the next three months.

Since its opening in 1973, the Sidney Kimmel Comprehensive

progression and recurrence, and determine surgical margins by revealing cancer cells invisible to the human eye. Research linking DNA methylation to the leukemia precursor myelodysplastic syndrome led to the first FDA-approved demethylating agent Photo credits Joe Rubino and Peter Howard/Text provided

by Sidney Kimmel Comprehensive Cancer Center

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Sidney Kimmel Comprehensive Cancer Center Director William Nelson, MD Cancer Center (HopkinsKimmelCancerCenter.org) has been a world leader in deciphering the mechanisms of cancer and new ways to treat it. The strengths of the research and treatment programs at Johns Hopkins were recognized early on by its being named a National Cancer Institute (NCI) “Center of Excellence.” Today, Johns Hopkins University’s science and engineering programs earn more federal research dollars than any other medical institution in the country.

The work by center investigators in cancer genetics and epigenetics deciphers the mechanisms of cancer initiation and progression. Pioneering research that defined cancer as a genetic disease was done at Johns Hopkins, leading to the first genetic tests for a hereditary colon cancer condition (ie, familial adenomatous polyposis) and a screening stool test for colon cancer. Investigators from Johns Hopkins were the first to map a cancer genome, deciphering the genetic blueprints for colon, breast, pancreatic and brain cancers. Of the 100 cancers for which all genes have been sequenced, 90 have been sequenced at the Kimmel Cancer Center. These discoveries paved the way for personalized therapies, and Kimmel Cancer Center investigators undertook the first use of personalized genome scanning to reveal the gene mutation that caused a patient’s inherited form of pancreatic cancer.

Working to understand the effects of methylation patterns on genes, the hallmark of epigenetic alterations, Johns Hopkins scientists used this molecular trail of evidence to develop broad-based cancer screening tests, monitor patients for cancer

and earned the team recognition from the NCI for the most outstanding research in its Specialized Programs of Research Excellence portfolio.

Kimmel Cancer Center researchers were among the first to develop therapeutic cancer vaccines, and the center includes a good manufacturing practice facility that produces vaccines for clinical trials. In recent clinical studies of a pancreatic cancer vaccine, a small number of patients were vaccinated two weeks prior to surgery, jump-starting their immune systems and allowing, for the first time, doctors to explore exactly how the immune system behaves within the pancreas. Other vaccines, for cervical cancer, prostate cancer and leukemia, also were developed at the center.

Researchers at Kimmel Cancer Center were among the first to perform bone marrow transplants to treat blood and immune-forming cancers, and were the first to perform haploid (half)-identical transplants, increasing the number of patients who might benefit from this curative therapy.

Breakthroughs managing graft-versus-host disease have made transplants possible in those patients who do not have identical donor matches.

The mission of the Kimmel Cancer Center is to go beyond the cutting edge in science and medicine to perform the most advanced research and translate discoveries into the very best cancer therapies. “The latest, plus some” is how Kimmel Cancer director William Nelson, MD, describes the center’s objective, observing that the state of the art is merely the starting point.

SOLID TUMORS

Clinical Oncology News • March 2012

Breast

Benefit in Adding Anti-HER2 Pertuzumab to Breast Cancer Regimen From Lancet Oncology

A

study published in the January issue of Lancet Oncology (2012; 13:25-32, PMID: 22153890) has determined that the addition of the novel anti-HER2 antibody pertuzumab (2C4/ Omnitarg, Genentech) to a regimen of trastuzumab (Herceptin, Genentech) plus docetaxel (Taxotere, Sanofi-aventis) is more effective than a regimen of trastuzumab plus docetaxel alone in the treatment of women with locally advanced inflammatory or early HER2positive breast cancer.

The Phase II NeoSPHERE [Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation] trial— published by an international team of

EXPERT INSIGHT Roisin Connolly, MBBS Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

I

ncreased expression of HER2 or amplification of the HER2/ neu gene had been associated with a worse prognosis when compared with other breast cancer phenotypes.1 A number of clinical trials have indicated that the addition of one year of trastuzumab to adjuvant chemotherapy regimens in HER2-positive breast cancer patients results in an approximately 50% reduction in breast cancer recurrence and 35% reduction in mortality.2-4 Phase II and III trials evaluating the use of trastuzumab and chemotherapy in the neoadjuvant setting have reported impressive pCR rates, a surrogate end point for survival that is commonly used in neoadjuvant studies. A non–anthracycline-based approach combining carboplatin, weekly paclitaxel and trastuzumab, for example, was associated with a pCR rate of 76%.5 The Phase II randomized NeoSPHERE trial investigated the addition of pertuzumab to trastuzumab and chemotherapy and has provided further evidence that dual blockade of the HER2 pathway is a valid concept. Pertuzumab is the first of a novel

researchers and funded through a partnership between Fondazione Michelangelo in Milan, Italy, and Hoffmann-La Roche, which owns Genentech (manufacturers of the study drug)—randomly assigned 417 treatment-naive women with HER2-positive breast cancer to four treatment groups: group A, in which 107 patients received four neoadjuvant cycles of trastuzumab (8 mg/ kg loading dose, followed by 6 mg/kg every three weeks) plus docetaxel (75 mg/m2, escalating if tolerated to 100 mg/m2, every three weeks); group B, in which 107 patients received pertuzumab (loading dose 840 mg, followed by 420 mg every three weeks) and trastuzumab plus docetaxel; group C, in which 107 patients received pertuzumab and

trastuzumab; and group D, in which 96 patients received pertuzumab plus docetaxel. Pathologic complete response (pCR) in the breast, as examined in the intent-to-treat population, was the study’s primary end point.

In group B, 45.8% of the patients achieved pCR compared with 29% in group A, 24% in group D and 16.8% in group C. Neutropenia was the most common adverse event (AE) of grade 3 or higher across all treatment groups, affecting 61 patients in group A, 48 in group B, one in group C and 52 in group D. Febrile neutropenia and leukopenia also were reported. Overall, the number of serious AEs was similar in groups A, B and D (20, 15 and 16 total serious AEs, respectively) but lower in group C (4

serious AEs). Two patients died during the neoadjuvant phase of the trial, with one death in group B resulting from fulminant hepatitis and the other in group D, a result of lung metastases and progressive disease.

In their concluding remarks, the authors noted that “although pertuzumab plus docetaxel was efficacious, the combination of chemotherapy with both antibodies was more active than chemotherapy with either antibody alone.” They added that “data obtained from NeoSPHERE supported the conduct and informed the design of an ongoing adjuvant trial with pertuzumab, and illustrated the potential of the neoadjuvant approach in new drug development.”

class of HER2-targeted agents known as HER2 dimerization inhibitors. This agent binds to a distinct epitope on the extracellular domain of the HER2 receptor, blocking the interaction between HER2 and other HER family receptors.6 Dual blockade of intracellular signaling then leads to inhibition of cancer cell growth and death.7 Patients in this study were randomized to receive preoperative trastuzumab and docetaxel; trastuzumab, pertuzumab and docetaxel; trastuzumab and pertuzumab; or pertuzumab and docetaxel. The pCR rates were 29%, 46%, 17% and 24%, respectively. AEs were those expected with use of docetaxel and were lowest in the trastuzumab -pertuzumab –alone arm. No cardiac safety concerns were identified.

When patients were analyzed based on estrogen receptor (ER) status, a 63% pCR rate was observed in those with ER-negative disease treated with trastuzumab, pertuzumab and docetaxel and 27% pCR in those with ER-negative disease treated with trastuzumab and pertuzumab,8 correlating favorably with pCR rates obtained in prior studies evaluating dual blockade of the HER2 pathway.9 That such impressive results were obtained with a regimen incorporating docetaxel alone, as opposed to combination chemotherapy, should spark great interest with physicians and patients.

Even more interesting is the fact that a large proportion of women treated with

biological therapy alone obtained a pCR, a result that has caused great excitement in the breast oncology community.

There is a clear need to determine who these patients are up front as they could potentially be spared the added toxicity of chemotherapy. Clinical trials are currently being designed to try and answer this question. It must be noted, however, that 6.5% of women in the trastuzumab and pertuzumab group were deemed to have tumor progression during therapy and one-third did not respond to

2. Romond EH, Perez EA, Bryant J, et al.

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.

N Engl J Med. 2005;353:1673-1684; PMID: 16236738.

3. Piccart-Gebhart MJ, Procter M, LeylandJones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672; PMID: 16236737.

4. Slamon D, Eiermann W, Robert N, et al.

Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:12731283; PMID: 21991949.

5. Sikov WM, Dizon DS, Strenger R, et al. Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study.

J Clin Oncol. 2009;27:4693-4700; PMID: 19720916.

6. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317-328; PMID: 15093539.

the dual anti-HER2 regimen. Equally important, therefore, is the need to identify those women who will not respond to therapy and develop novel treatment approaches for these patients. In summary, breast cancer treatment strategies incorporating at least two anti-HER2 agents are likely to become a standard of care in the near future, but ongoing work is needed to personalize treatment approaches for breast cancer patients.

References 1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.

Science. 1987;235:177-182; PMID: 3798106.

7. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330-9336; PMID: 19934333.

8. Gianni L, Pienkowski T, Im Y-H, et al. Neoadjuvant pertuzumab (P) and trastuzumab (H): antitumor and safety analysis of a randomized phase II study (‘NeoSphere’). Presented at the San Antonio Breast Cancer Symposium 2010. Abstract S3-2.

9. Baselga J, Bradbury I, Eidtmann H, et al.

First results of the NeoALTTO trial (BIG 01-06 / EGF 106903): A Phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Presented at the San Antonio Breast Cancer Symposium 2010. Abstract S3-3.

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Clinical Oncology News • March 2012

Pancreatic

Prognostic Factors Elucidated in Pancreatic Neuroendocrine Tumors From the European Journal of Cancer

A

team of researchers from Verona, Italy, believes it has identified two “powerful” predictors of recurrence in patients with malignant pancreatic neuroendocrine tumors (pNETs).

In a study published online by the European Journal of Cancer (2011 Nov 28. [Epub ahead of print], PMID: 22129889), Boninsegna et al concluded that a lymph node ratio—defined as the ratio between the number of metastatic lymph nodes and the total examined lymph nodes—greater than 0.20 was an accurate prognostic indicator of recurrence in patients with this form of pancreatic cancer. Another indicator turned out to be a value of Ki67 greater

EXPERT INSIGHT Barish H. Edil, MD Assistant Professor of Surgery and Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

B

oninsegna et al have made a significant contribution to our understanding and classification of pNETs. The authors reviewed their experience from 1990 to 2008 and analyzed 57 patients who were resected with curative intent and found that lymph node ratio and Ki67 greater than 5% are the most powerful predictors of survival and recurrence after multivariate analysis. Their patients had a median overall survival of 190 months and DFS of 80 months.

There were several aspects of this study that make their contribution unique. First, all of these patients had surgery with curative intent allowing full assessment of tissue,

than 5% (the Ki67 proliferative index is a percentage based on the number of Ki67-positive cells in 2,000 tumor cells). Although the prognostic value of lymph node ratio had previously been identified in other pancreatic malignancies, including pancreatic ductal adenocarcinoma, its precise role in malignant pNETs had previously been in question.

The study looked at patients from the prospective database of the Surgical Department at Verona University.

The researchers reviewed clinical and pathologic data of all patients with resected malignant pNETs at the hospital from 1990 to 2008, performing both univariate and multivariate analyses. In all, 57 patients (with a

median age of 58 years) were included in the study. Of these, 29 had undergone pancreaticoduodenectomy and 28 had undergone distal pancreatectomy.

Thirty-six of the patients were diagnosed with lymph node metastases.

Median follow-up was 54 months.

Ultimately, recurrent disease was identified in 24 of the study participants, with two- and five-year disease-free survival (DFS) rates of 82% and 49%, respectively. Eightythree percent of the recurrent patients had liver involvement and the rest had local recurrence. However, the authors found that those with a lymph node ratio greater than 0.20 had two- and five-year disease-free survival rates around 40% compared with 89% and

54%, respectively, among those with a lymph node ratio at or less than 0.20 (P<0.001). Similarly, two- and fiveyear DFS rates for patients with a Ki67 greater than 5% were 64% and 21%, respectively, compared with 85% and 73% among patients with Ki67 at or less than 5% (P=0.002).

Currently, the authors note, both the TNM staging system proposed by the European Neuroendocrine Tumor Society and the World Health Organization (WHO) classification have established a Ki67 value of 2% as the cutoff for prognosis. The authors argue that a Ki67 cutoff of 5% was able to accurately predict recurrence of pancreatic endocrine tumors at the same stage; a 2% cutoff was not.

margins and lymph node status.

Additionally, syndromic patients were excluded, allowing for a more homogeneous study group. Finally, this is a rare example in the literature where recurrence and disease-specific death from pNETs were acknowledged in their analysis. I feel, as do the authors, that when discussing pNETs, differentiation between syndromic and sporadic patients is important.

Additionally, I believe that functional tumors also should be excluded to create the most homogeneous population possible. Three functional pNETs were included in the analysis.

Although this had minimal impact on their conclusions, breaking pNETs down into homogeneous groups may allow for better interpretation of the data in the future. I also was surprised at the overall resectability rate of 35% of operated patients. In the discussion, the authors compared this rate with Lo et al (World J Surg 1996;20:878-884; PMID: 8678966). However, Lo et al was written in 1996 and the preoperative imaging to determine resectability has greatly improved since then, so I would be curious why the authors’ resectability

rate was not higher.

The incidence of pNETs is less than 0.25 to 1 in 100,000 people per year in the United States; however, the incidence doubled in the past 20 years.

Because these tumors are rare, their natural history and prognosis have been difficult to elucidate. Additionally, the heterogeneity in pathology and clinical presentation creates a difficult landscape to interpret the data of past literature. In fact, pNETs were believed to be benign neoplasms instead of neoplasms with a spectrum of indolence and malignancy. The history of staging and naming of pNETs also has undergone great changes. The WHO in 2000, later modified in 2004 and 2010, implemented categorization of these tumors into five general histologic groups and also recommended a separate grading system based on Ki67 staining. In 2006-2007, the European Neuroendocrine Tumor Society designed another staging and grading system based on stage with the TNM format and grading system and Ki67. Although grade was not directly included in the staging system, there was recognition that both were

important. In 2010, the American Joint Committee on Cancer created a staging system with the TNM format similar to exocrine pancreas malignancies, and grade was recorded separately due to its prognostic value. This has unfortunately created potential confusion and difficulty in communication in understanding and staging pNETs. Looking at our unpublished experience of 326 patients at The Johns Hopkins Hospital we have found, as have the authors, that Ki67 is a significant predictor of patient outcomes. However, we find that grade tends to have a more fluid predictive value instead of relying on strict cutoffs to determine prognosis.

Staging and understanding the natural history of pNETs will require further study to determine which patients will be treated systemically, particularly as therapies improve primarily in medical oncology.

Therefore, continued contributions such as that by Boninsegna et al are important in identifying important prognostic characteristics of this rare tumor.

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Clinical Oncology News • March 2012

Colorectal

Reduced Survival in CRC With Peritoneal Carcinomatosis Confirmed From Journal of Clinical Oncology

P

eritoneal carcinomatosis is associated with a 30% reduction in overall survival (OS) and a significant reduction in progression-free survival (PFS) among patients with metastatic colorectal cancer (CRC), a new study has confirmed.

Published in the Jan. 20 issue of the Journal of Clinical Oncology (JCO, 2012;30:263-267, PMID: 22162570), this study by Franko et al of 2,095 patients with metastatic CRC was initially presented at the 47th annual meeting of the American College of Clinical Oncology in June 2011. With funding from the National Institutes of Health, the Southwest Oncology Group, the Eastern Oncology Cooperative Group and Cancer and Leukemia Group B, the team of researchers performed a pooled

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

analysis of patients enrolled in two prospective, randomized trials of chemotherapy in the colorectal setting coordinated by the North Central Cancer Treatment Group. The majority of patients (n=1,646) had been previously enrolled in the N9741 trial and thus had been randomized to receive irinotecan (Camptosar, Pfizer), fluorouracil (5-FU) and leucovorin (IFL); irinotecan and oxaliplatin (Eloxatin, Sanofi-aventis) (IROX); or infusional fluorouracil, leucovorin and oxaliplatin (FOLFOX). The remainder (n=455), from the N9841 trial, had been randomized to receive either irinotecan or FOLFOX as second-line therapy following

F

ranko et al address important and previously undescribed questions regarding disease behavior of metastatic CRC patients with pcCRC in the Journal of Clinical Oncology. Patients with pcCRC may have a different disease behavior and sensitivity to chemotherapy, but this has never been studied systematically. This analysis uses patients enrolled in two large cooperative group trials, N9741 and N9841. N9741 was a trial testing IFL versus FOLFOX versus IROX in untreated metastatic CRC,

prior 5-FU treatment. Six patients were eliminated from the final analysis due to missing data on metastatic sites.

Of the patients making up the final study sample, 364 had peritoneal carcinomatosis CRC (pcCRC). These patients had similar characteristics—age and gender—to those in the non-pcCRC group, but they differed significantly when compared for median OS (12.7 vs. 17.6 months; P<0.001) and PFS (5.8 vs. 7.2 months; P=0.001).

“The unfavorable prognostic indicators” remained even after the researchers adjusted the data for age, performance status, liver metastases and other factors.

Of note, among patients treated with first-line FOLFOX included in the analysis, median OS was 15.7 months for patients with pcCRC compared with 20.9 months for FOLFOX patients with non-pcCRC metastases (P=0.003); however, the authors emphasize that the regimen remains superior to IFL and IROX regimens in patients with CRC regardless of the carcinomatosis status. In the second-line therapy group, there was no significant difference in prognostic indicators between patients treated with irinotecan or FOLFOX. The authors don’t believe that these findings indicate that carcinomatosis status should have any bearing on treatment selection. However, they do stress that additional research on “bimodality treatment combining surgery and alternative chemotherapy delivery routes may be warranted.”

while N9841 tested single-agent irinotecan versus FOLFOX in patients previously treated with 5-FU. Their results show that at the time of enrollment in the studies, patients with and without pcCRC had similar age and performance status but were less likely to have lung or liver metastases.

The pooled analysis showed that 17% of patients had pcCRC. These patients had significantly shorter OS (12.7 vs. 17.6 months; P<0.001) and PFS (5.8 vs. 7.2 months; P=0.001). This is a retrospective,

pooled analysis and evaluates multiple regimens that are now not considered standard of care for patients with CRC. Still, the findings are important to help describe disease behavior in a sizable subset of these patients. In the future, it will be important to determine if there are molecular markers that may predict this disease behavior as well as develop a better understanding of the best regimen for these patients among the standard of therapy today.

Prostate

Denosumab Helpful in Preventing Bone Metastases in Prostate Cancer From Lancet

T

argeting of the bone microenvironment with the monoclonal antibody denosumab (Xgeva, Amgen) has shown promise in the prevention of bone metastases in men with castration-resistant prostate cancer, a new study has found.

The results of a randomized, placebocontrolled trial, published in the Jan. 7 issue of the journal Lancet (2012;379:3946, PMID: 22093187), demonstrated that denosumab, which binds to and inactivates receptor activator of nuclear factor k-B ligand (RANKL; a mediator in osteoclast formation), increased bone metastasis–free survival by a median of 4.3 months compared with placebo. This Phase III study included 1,432 men with

nonmetastatic castration-resistant prostate cancer who were determined to be at high risk for bone metastasis based on a prostate-specific antigen (PSA) of 8 mcg/L or higher or PSA doubling time of 10 months or less, or both. The research was funded by Amgen, which manufactures the study drug.

The study participants, drawn from 319 centers in 30 countries, were randomized on a 1-to-1 ratio to receive either subcutaneous denosumab 120 mg or subcutaneous placebo every four weeks. The randomization was stratified based on PSA eligibility criteria and participant history of previous or ongoing chemotherapy for prostate cancer. This was a masked trial, meaning that neither patients nor investigators were aware of the group to which

they had been assigned.

In the final analysis, median bone metastasis–free survival in the denosumab group was 29.5 months compared with 25.2 months in the placebo group (P=0.028). Additionally, denosumab also delayed the time to first bone metastasis (33.2 months) among study participants compared with placebo (29.5 months; P=0.032). However, overall survival was actually slightly higher in the placebo group (44.8 months) than in the denosumab group (43.9 months; P=0.91). On this latter point, the authors note that the study design mandated that participants discontinue the study drug once they developed bone metastases; approximately 80% of the deaths in the denosumab group

occurred in participants who had discontinued treatment with the drug.

In general, incidence of adverse events (AEs) and serious AEs were similar between the two groups. However, osteonecrosis of the jaw occurred in 5% of the patients on the study drug, whereas no incidents were reported in the placebo group. Additionally, 12 incidents (2% of patients) of hypocalcemia were reported in the denosumab group compared with two in the placebo group.

Still, the authors conclude that their findings “provide clinical evidence for the important role of the bone microenvironment and RANKL signaling in development of bone metastases in men with prostate cancer” as well as the benefits of therapy using denosumab.

SOLID TUMORS

Clinical Oncology News • March 2012

Colorectal

Biomarkers for Poor Response to EGFR Colorectal Cancer Found From Annals of Oncology

A

team of researchers from Italy believes it may have identified several biomarkers that can predict lack of response to anti-epidermal growth factor receptor (EGFR) therapy in patients with K-RAS wild-type colorectal cancer (CRC).

Even in the absence of a mutation of the K-RAS gene, a significant number of patients with CRC fail to respond to anti-EGFR therapy, resulting, obviously, in poor treatment outcomes. Research to date has identified a potential role for human epidermal growth factor receptor-3 (HER-3), insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) in

EXPERT INSIGHT David Cosgrove, MBBCh Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

I

n this Annals of Oncology article, Scartozzi et al seek to identify molecular determinants of

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

T

his is the first study in patients with nonmetastatic prostate cancer to show a prolongation of bone metastasis–free survival in this setting.

This study, investigating the osteoclastinhibitory drug denosumab, comes on the heels of several other trials testing bone-targeting agents and their ability

predicting response, or lack thereof, to anti-EGFR therapy in this setting; however, no study has compared the four mutations as to their relative predictive ability.

The Italian study, which was accepted for publication in October 2011 in the journal Annals of Oncology and published online in November (2011 Nov 23. [Epub ahead of print], PMID: 22112971), attempted to do just that.

The researchers aimed to test the interaction between these gene mutations via mutational analysis to confirm “the relative ability of these variables to identify a subgroup” of K-RAS wildtype CRC patients “more likely to benefit from EGFR-targeted” therapies.

The team retrospectively analyzed tumor samples from 168 patients with

metastatic CRC who were treated with cetuximab (Erbitux, Bristol-Myers Squibb/Lilly) and irinotecan (Camptosar, Pfizer) for K-RAS mutation as well as HER-3, IGF-1 and NF-kB gene expression. The chromogenic in situ hybridization (CISH; Zymed Laboratories) process also was performed for EGFR GCN. The samples were compared for partial treatment response, overall survival (OS) and progression-free survival (PFS).

Overall, 90 patients (54%) in the study group were found to have K-RAS wildtype CRC. Of these patients, 46 (51%) were found to have HER-3–positive tumors, whereas 44 (49%) had HER3–negative tumors. Additionally, within the K-RAS wild-type group, 59 (65%) patients had IGF-1–positive tumors and

31 (35%) had IGF-1–negative tumors; and 48 (64%) patients had NF-kB–positive tumors, whereas 32 (36%) were NF-kB–negative.

Among these patients, the researchers were able to identify a role for the HER-3, IGF-1, NF-kB and EGFR GCN gene mutations in influencing the response to treatment and survival. For example, patients who were negative for HER-3, IGF-1 and NF-kB gene mutations were more likely to have partial response to anti-EGFR therapy and had higher PFS and OS rates than those who were positive for the mutations. Additionally, those whose tumors that tested 2.12 or higher on CISH EGFR GCN analysis demonstrated lower partial response, PFS and OS rates than those who tested 2.12 or lower.

resistance to anti-EGFR therapy in patients with K-RAS wild-type metastatic CRC. Although it is accepted that those tumors harboring a K-RAS mutation will not respond to anti-EGFR therapy, there has been no systematic analysis of why approximately 50% of K-RAS wild-type tumors exhibit a similar lack of response. This retrospective study assesses the relative effect of HER-3, IGF-1, NF-kB and EGFR GCN on response to anti-EGFR therapy in a population of patients with K-RAS wild-type CRC. Data were collected on 168 patients

with metastatic CRC who were treated with irinotecan and cetuximab, 90 of whom had K-RAS wild-type tumors.

The biological analysis was carried out on the primary tumor sample in these 90 cases, and clinical outcome data were available for all participants.

Immunohistochemical assessment of HER-3, IGF-1 and NF-kB was carried out using validated antibodies and scoring systems, and EGFR amplification was assessed via CISH. The results indicate that HER-3–negative tumors, IFG-1–negative tumors and high EGFR GCN tumors exhibit an increased

response rate to anti-EGFR–directed therapy and a prolonged OS, and HER-3–negative tumors and IGF-1– negative tumors have an improved PFS. NF-kB–negative tumors were not independently associated with an increased response rate, prolonged PFS or prolonged OS. As outlined by the authors, this data provides the foundation for the development of a molecular signature of EGFR resistance beyond the assessment of K-RAS, and prospective validation of these findings in future studies is certainly warranted.

to prevent or delay bone metastases in this patient population. Unfortunately, two prior placebo-controlled studies using bisphosphonate agents (clodronate and zoledronate), as well as two studies using endothelin-receptor antagonists (atrasentan and zibotentan) all failed to significantly improve bone metastasis– free survival compared with placebo.

In the present study, subcutaneous denosumab given at 120 mg every 4 weeks extended bone metastasis–free survival by a median of 4.2 months, while also improving time to first occurrence of bone metastasis. Although overall survival was not improved compared with placebo in this trial, patients were required to discontinue the study drug after development of metastases and therefore did not have any exposure to

denosumab after disease progression.

Additionally, it was impossible to control for the use of subsequent life-prolonging therapies for metastatic castration-resistant prostate cancer, of which there are now many.

Denosumab is already FDA-approved at the same dose and schedule (120 mg subcutaneously every 4 weeks) for the prevention of skeletal-related events in men with bone metastatic castration-resistant prostate cancer. It also has gained FDA approval at a different dose and schedule (60 mg subcutaneously every 6 months) for prophylaxis of osteopenia in men with nonmetastatic prostate cancer on androgen deprivation therapy and who are at high risk for fracture. Whether the FDA will expand the indications for denosumab to include

prevention of bone metastases is debatable, especially in view of the relatively small improvement in median bone metastasis–free survival (equivalent to one scanning interval), and the lack of a demonstrable survival benefit.

Nevertheless, the findings of this study lend some credence to the use of bone metastasis–free survival as a potential primary end point in subsequent trials of novel agents. However, because men with nonmetastatic prostate cancer are generally asymptomatic, the toxicity of any experimental agents tested in this patient population must be very low in order for such drugs to become accepted, begging the question of whether a 5% risk for osteonecrosis of the jaw is acceptable in this setting.

21

22

HEMATOLOGIC DISEASE

Clinical Oncology News • March 2012

CLL

NOTCH1 Mutations May Have Prognostic, Therapeutic Roles in CLL From Blood

F

ollowing up on findings demonstrating that NOTCH1 is recurrently mutated at presentation of chronic lymphocytic leukemia (CLL), an international team of researchers has identified a potential prognostic role for the proto-oncogene.

Based on two studies published last year, it is believed that NOTCH1 mutations occur in approximately 10% of CLL cases at diagnosis and that their frequency increases in advanced disease phases. However, until now, the effect of NOTCH1 on clinical outcomes has remained unknown.

In this study published in the Jan. 12 issue of the journal Blood

EXPERT INSIGHT Nilanjan Ghosh, MD, PhD Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

T

he prognostic relevance of NOTCH1 mutations in CLL was assessed in two cohorts of CLL patients. NOTCH1 mutations were not associated with TP53 abnormalities in a majority of cases. In multivariate analysis, NOTCH1 mutations were identified as independent predictors of OS. This study utilized a training cohort and a validation cohort. The training cohort consisted of 309 previously untreated CLL patients where samples were prospectively collected. The

(2012;119:521-529, PMID: 22077063), Rossi et al analyzed 539 cases of newly diagnosed CLL to identify the distribution of NOTCH1 mutations among wellestablished CLL genetic subgroups and their independent prognostic role. The “training cohort” of 309 patients was made up of a consecutive series of previously untreated patients who presented for initial evaluation at a single center. The 230 patients who made up the “validation cohort” were a retrospective series of previously untreated patients who presented at three institutions that were part of the same national CLL network.

NOTCH1 mutations were identified in 11% of those in the training group and 11.3% of those in the validation group.

The researchers found that the presence of NOTCH1 mutations led to a 3.77-fold increase in the hazard of death among these patients. After a median follow-up of six years, median overall survival (OS) in the training cohort was 13 years among those without NOTCH1 mutations, but only 3.5 years among those with them. In the validation cohort, these figures were 16 and 8.5 years, respectively. The researchers attributed the poor prognosis associated with NOTCH1 mutations to the shorter treatment-free survival and higher risk for Richter transformation among these patients, in addition to other factors.

Interestingly, TP53 gene disruption by mutation, deletion or both—which

has long been considered a key prognostic factor in patients with CLL— and NOTCH1 mutations appear to be mutually exclusive. The authors of the Blood article found that more than 90% of the study participants with NOTCH1 mutations were “devoid of TP53 disruption.”

The findings of this study demonstrate that the presence of NOTCH1 mutations may be of similar prognostic value as the presence of TP53 mutations in patients with CLL. The authors believe that NOTCH1 also may prove to be a viable therapeutic target in the treatment of CLL. NOTCH1 inhibitors are currently under development for the treatment of T-cell lymphoblastic leukemia, among other cancers.

validation cohort included a retrospective series of 230 previously untreated CLL patients who had samples collected during initial presentation and during clinical follow-up. NOTCH1 was analyzed by DNA Sanger sequencing. Multivariate analysis included NOTCH1 mutations, age, gender, Rai stage, IGVH gene mutations, trisomy 12, 11q22-q23 deletion and TP53 disruptions.

In the training cohort, NOTCH1 mutations occurred in 11% of cases.

NOTCH1-mutated cases preferentially had unmutated IGVH genes (76.5%; P<0.001), advanced Rai stage and trisomy 12 (44.1%; P<0.001). Univariate analysis of NOTCH1 mutations showed an increase in risk for death (hazard ratio [HR], 3.77; 95% confidence interval [CI] 2.14-6.66) and a significant shortening of OS (P<0.001). Multivariate analysis demonstrated that NOTCH1 mutations were an independent risk factor for OS (HR, 4.22; 95% CI, 2.15-8.28; P<0.001). These results were confirmed in the validation

cohort. NOTCH1-mutated patients also had a higher risk for developing Richter’s transformation.

NOTCH1 is a heterodimeric transmembrane protein. NOTCH1 signaling activates downstream anti-apoptotic mechanisms, which includes the nuclear factor-kB pathway. An oncologic role for NOTCH1 signaling has been previously established in T-cell acute lymphoblastic leukemia where more than half of the patients harbor NOTCH1 mutations. In B-cell chronic lymphocytic leukemia, NOTCH1 mutations occur in less than 20% of cases. Two studies have reported an increased frequency of NOTCH1 mutations in trisomy 12 CLL (42%-44%).

The majority of the NOTCH1 mutations are seen in IGVH-unmutated cases. In the present study, the investigators have provided insight into the prognostic importance of NOTCH1 mutations as an independent prognostic factor in a large cohort of CLL patients.

Although TP53 disruption has been

well established as a high risk factor in CLL, about 40% to 50% of highrisk CLL does not harbor TP53 abnormalities. This study demonstrates that NOTCH1 mutations are an independent adverse prognostic factor in CLL and mutually exclusive of TP53 disruption, although this should be confirmed in the setting of a prospective clinical trial. Because trisomy 12 is considered as an intermediate prognostic factor in CLL, the presence of NOTCH1 mutations may identify a high-risk subset within this group. IGVH-unmutated CLL carries a poor prognosis and the majority of CLL cases with NOTCH1 mutations also have unmutated IGVH. It will be interesting to see within the IGVH-unmutated group if NOTCH1mutated versus wild-type has any prognostic relevance. The investigators report a simple polymerase chain reaction technique for at least 80% of the NOTCH1 mutations, which increases its practical applicability.

epoxyketone that selectively and reversibly binds the proteasome resulting in sustained inhibition. Marizomib (NPI0052) is a novel, non–peptide-based proteasome inhibitor. Perifosine is an Akt inhibitor.

MM): long-term follow-up and subgroup analysis.

ASCO Meeting Abstracts. 2011;29(15 suppl):8027.

has three isoforms: Akt1 (also known as PKB-α), Akt2 (PKB-β), and Akt3 (PKB-γ). Akt1 and Akt2 are expressed in most tissue types; Akt3 expression is generally restricted to neuronal tissue and the testes. The three isoforms share more than 80% homology.

PRN

CONUNDRUMS continued from page 16 

safety and clinical response findings. ASH Annual Meeting Abstracts. 2010;116(21). Abstract 210.

Nanda N, Cortes J, Lipton JH, et al. Treatment of chronic phase (CP) myeloid leukemia (CML) patients who harbor the BCR-ABL T315I mutation with subcutaneous omacetaxine results in improved survival compared to historical data.

Haematologica. 2011;96(2S). Abstract 1012.

9.

Answer: d. MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome. Carfilzomib is a novel

Berdeja JG, Richardson PG, Lonial S, et al.

Phase 1/2 study of oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). ASH Annual Meeting Abstracts.

2011;118(21):479.

Siegel DSD, Martin T, Wang M, et al. PX171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R

Richardson PG, Spencer A, Cannell P, et al.

Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts.

2011;118(21):302.

Richardson PG, Wolf JL, Jakubowiak AJ, et al.

Perifosine plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma patients previously treated with bortezomib: final results of a phase I/II trial. ASH Annual Meeting Abstracts.

2011;118(21):815.

10. Answer: a. Akt is a member of

the AGC family of protein kinases. Akt

Davies MA. Regulation, role, and targeting of Akt in cancer. J Clin Oncol. 2011:29(35)4715-4717, PMID: 22025159.

Bellacosa A, Testa JR, Moore R, Larue L. A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther. 2004;3(3):268-275, PMID: 15034304.

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24

SOLID TUMORS

Clinical Oncology News • MARCH 2012

Breast

Zoledronic Acid Debate in Breast Cancer Continues SABCS studies largely positive, although not unanimous San Antonio—Long-term results of the ABCSG-12 trial and subanalyses of two recently presented Phase III trials provide further evidence that bisphosphonates can improve survival in breast cancer patients with low estrogen levels. The results of the studies, presented at the recent San Antonio Breast Cancer Symposium (SABCS), have convinced some doctors of the low estrogen hypothesis, but for others the water is still very murky.

“Before I sprinkle this stuff around, I want a randomized prospective trial in whatever population they claim it works,” said Steven Vogl, MD, a medical oncologist in New York City. He pointed out that the drugs are not without side effects, such as osteonecrosis of the jaw, and that zoledronic acid (Zometa, Novartis) is “expensive.”

Four trials now support the hypothesis that bisphosphonates have value as an anticancer agent. And a year ago a subanalysis of the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial demonstrated that zoledronic acid can improve disease-free survival (DFS) in postmenopausal breast cancer patients.

“Mounting evidence suggests that bisphosphonates will become established as efficacious in adjuvant therapy of postmenopausal women with early-stage breast cancer,” said James Ingle, MD, a professor of oncology at Mayo Clinic in Rochester, Minn., who served as a discussant for the trials at SABCS. Bisphosphonates have multiple potential anti-tumor effects in bone, researchers said. They include reducing the release of bone-derived tumor growth factors, modifying levels of circulating tumor cells, affecting tumor vasculature and having direct effects on tumor cells themselves.

“We believe we can effectively silence dormant tumor micrometastases with this treatment,” said Michael Gnant, MD, a professor of surgery at the Medical University of Vienna, who led the ABCSG-12 trial (abstract S1-2) by the Austrian Breast and Colorectal Cancer Study Group.

ABCSG-12 According to Dr. Ingle, the long-term results of ABCSG-12 provide level 1 evidence of the benefit of zoledronic acid in the specific population studied.

In the study, 1,803 premenopausal patients with endocrine receptor–positive early breast cancer who received goserelin to shut down their ovarian function were randomized to receive either tamoxifen with or without zoledronic acid or anastrozole with or without zoledronic acid. The treatment duration was three years.

After a seven-year follow-up, investigators identified a 28% relative reduction in the risk for relapse in patients

who received zoledronic acid (P=0.01).

Earlier analyses also had shown similar improvements in DFS: 26% after 48 months (P=0.01), 32% at 62 months (P=0.008) and 27% after 76 months (P=0.02). Overall survival (OS) seven

currently treated with goserelin.

“There is a study called SOFT [Suppression of Ovarian Function Trial] where they are trying to add ovarian ablation to tamoxifen,” said Dr. Vogl.

“If that study is positive, we may have

‘We believe we can effectively silence dormant tumor micrometastases with this treatment.’

—Michael Gnant, MD

‘Sub-analyses are suspect. This is interesting, but we need to study it some more.’ years out also was increased with zoledronic acid (hazard ratio [HR], 0.64; 95% confidence interval, 0.39-0.96; P=0.033).

The absolute difference was about 4% in progression-free survival and 1.6% in OS, according to Dr. Ingle.

Dr. Gnant said that the four- to fiveyear post-treatment follow-up suggests that zoledronic acid may have “a sustained anticancer effect.”

Although the evidence from ABCSG-12 seems solid, few women with breast cancer in the United States are

— Steven Vogl, MD

a large number of such patients, but if it’s not, nobody is going to be treating a patient like this except in Austria.”

According to Catherine Van Poznak, MD, a medical oncologist at the University of Michigan, doctors cannot conclude from the ABCSG-12 results that biphosphonates will increase survival in postmenopausal women.

“It is likely that there was a low estrogen environment in the end organs [in ABCSG-12],” she said. “Little more than that can be said about this study’s

population’s similarities to postmenopausal women.”

ZOFAST The Zometa-Femara Adjuvant Synergy Trial (ZOFAST) trial involved 1,065 women with stage I to IIIa hormone receptor–positive breast cancer who were postmenopausal or amenorrhoeic due to cancer treatment. Eligible patients had a bone mineral density (BMD) T score of at least two standard deviations below normal. All patients received letrozole (Femara, Novartis) for five years.

Patients were randomized to receive zoledronic acid immediately and for the duration of the trial or to delay the start of the drug until their BMD T score decreased to more than 2 standard deviations below normal, they had a clinical nontraumatic fracture or they had an asymptomatic fracture detected via x-ray when they were assessed at 36 months. The median age was less than 60 in both arms.

Zoledronic acid increased patients’ BMD, the study’s primary end point.

“We can see the benefit in the immediate therapy group occurring early on, when bone turnover or bone loss is at its greatest, and continuing out to the fiveyear time point, with a net difference of 10% favoring the immediate zoledronic acid group,” said Richard de Boer, MD, of the Royal Melbourne Hospital in Australia, who presented the study (SABCS abstract S1-3).

With a follow-up of five years, patients who received immediate zoledronic acid had a 34% improvement in DFS (HR, 0.66; P=0.0375), the secondary end point, resulting in a 3.6% absolute difference. An exploratory analysis of DFS and OS showed that women who had been postmenopausal for at least five years or were older than 60 had greater benefits.

“As per the improved disease-free survival results seen in both the Austrian and AZURE trials, these data support the hypothesis that the anti-cancer potential of zoledronic acid might best be realized in a low-estrogen environment,” said Dr. de Boer.

NSABP-34 In the National Surgical Adjuvant Breast and Bowel Project (NSABP)-34 trial (abstract S2-3), investigators compared adjuvant clodronate with placebo in 3,323 patients with early-stage breast cancer who had received systemic chemotherapy and/or tamoxifen or no therapy. Clodronate, importantly, is not approved in the United States.

Only 3% of patients had received no

SOLID TUMORS

Clinical Oncology News • MARCH 2012

25

Breast

prior adjuvant therapy, and 78% were positive for the estrogen and/or progesterone receptor. Patients were stratified by age—younger than 50 years or 50 years and older—and roughly 65% of patients were older than 50 years. The study failed to show that clodronate improved DFS, the study’s primary end point (HR, 0.91; P=0.27). In the overall study population, the only secondary end point that was improved was non-bone metastasis–free interval (HR, 0.743; P=0.046).

In a subanalysis however, secondary end points were improved in women aged 50 years or older who received clodronate. These included recurrence-free interval (HR, 0.76; P=0.05), bone metastasis–free interval (HR, 0.61; P=0.024), and non-bone metastasis–free interval (HR, 0.63; P=0.015).

Breaking patients into age groups of younger than 50 years, between 50 and 59 years and older than 60 years, Alexander H. G. Paterson, MD, a professor of medicine and oncology at the University of Calgary in Alberta, Canada, who led the study, showed a stepwise increasing benefit for clodronate in older patients in terms of skeletal metastases and nonskeletal metastases.

“Similar beneficial results in older

than 2 and a life expectancy of at least 10 years.

At a median follow-up of 39 months, investigators did not identify an GAIN improvement in DFS (P=0.59) or OS However, not all studies presented at (P=0.8) in patients who received ibanSABCS bolstered the claim that bisphos- dronate. There were no statistically sigphonates can improve survival in a low- nificant differences in subgroup analyses estrogen environment. The first interim based on hormone receptor or menoresults from the GAIN (German Adju- pausal status. Although not statisticalvant Intergroup Node Positive) trial ly significant, the HR of 0.75 in women (abstract S2-4) were negative. The study aged 60 years and older was identical to showed that the bisphosphonate iban- the HR of postmenopausal women in the dronate (Boniva, Roche) did not increase AZURE trial. The interim futility boundsurvival in women with node-positive, ary for chemotherapy was not crossed, primary breast cancer, whether or not and these data were not reported. they had low estrogen levels.

“The GAIN study demonstrated FILE SLUG that GAIN included 3,023 patients who adjuvant ibandronate improves neiCurrent file: CMEzone qtrpg.indd 1st PROOF LAYOUt APPROVED were first randomized between two dif- ther DFS nor OS inInItIALs node-positive earAnD DAtE ferent dose-dense chemotherapy regily breast cancer after treatment with Full name of project MAX sign-off mens (epirubicin, paclitaxel and cyclo- dose-dense chemotherapy,” said Volker senior Editor phosphamide [ETC]) or to the same Möbus, MD, head of the Department of style chges fr. prev. (XeloCopy Editor at Klinikum three drugs plus capecitabine Obstetrics and Gynecology da, Roche). After completing chemoFrankfurt Höchst in Frankfurt, GermaRevision # R2 sales therapy, patients were then random- ny. He pointed out that GAIN was quite Layout Date/time March 12, 2012 10:55 AM Production ized to either the oral drug ibandronate different from the other three studies Date/time Creative 50 mg per day for two Editorial years or observa- in that all patients received dose-dense tion. Patients aged 65trimyears or youngchemotherapy.

COMMENTS: size Half Vertical er were eligible for the trial if they had Color specs 4C untreated primary breast cancer, no dis- Weighing the Evidence In recent years, some oncologists tant metastases, an Eastern Cooperative Oncology Group (ECOG) status of less have been prescribing bisphosphonates

postmenopausal women are seen in other studies involving bisphosphonates,” Dr. Paterson said.

We’re in a

position

off-label to treat breast cancer, and the new studies may sway more doctors to do so.

“The anticancer effects of adjuvant zoledronic acid are now well established in endocrine-responsive patients,” said Dr. Gnant.

Dr. Paterson added that “inhibition of osteoclast function with bisphosphonates has an effect on cancer growth in older women, and little effect in premenopausal women.”

For other doctors, however, the jury is still out. “Subanalyses are suspect,” said Dr. Vogl. “This is interesting, but we need to study it some more. But if they study it some more, Novartis will have lost its patent protection by the time that study PROOF 1 12/10 FInAL OK comes out.

Novartis has some InItIALs AnD DAtE REV 1 12/17interest in it [being approved] now.” REV 2 REV 3 —Kate O’Rourke REV 4 REV 5 6 Dr. Paterson is REV a consultant for REV 7 Roche and GlaxoSmithKline, Amgen, Nicomed and has received REV 8 a grant for a clinical trial involving denosumab.

Dr. Gnant REV 9

disclosed relationships with AstraZeneca, Novartis, Pfizer, Sanofi, Roche, Schering and Amgen. Dr. Möbus disclosed relationships with Amgen, Novartis and Roche. Dr. de Boer disclosed a relationship with Novartis. Drs. Ingle and Dr. Vogl have no relevant disclosures.

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SOLID TUMORS

Clinical Oncology News • March 2012

Breast

Tamoxifen for Breast Cancer in Men Causes High Adverse Events From Annals of Oncology

A

potentially troubling number of male patients undergoing treatment for breast cancer with tamoxifen discontinue therapy due to drug-related toxicities, a new study has revealed.

The study, published online by the journal Annals of Oncology (2011 Nov 15.

[Epub ahead of print], PMID: 22085764), may be the largest to examine tamoxifen-related toxic effects and their effect on treatment among male breast cancer patients. Because discontinuation of treatment while on tamoxifen has been associated with poorer outcomes, the study’s authors believe their findings highlight a disturbing trend and that the

EXPERT INSIGHT Robert S. Miller, MD Clinical Associate, Breast Cancer Program Oncology Medical Information Officer Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

T

his paper by Pemmaraju and colleagues from MD Anderson is a retrospective review from 1999 to 2009 of 64 stage I, II or III male breast cancer patients who were treated with tamoxifen, presumably in the adjuvant setting. The authors sought to identify the toxicities experienced and the frequency of tamoxifen discontinuation in this cohort, a population not well characterized because of the rarity of the diagnosis. The most common AEs were weight gain, sexual dysfunction and hot flashes. One of the limitations of the study is that all AEs were selfreported, and the paper does not use a standardized toxicity scale, such as the National Cancer Institute’s Common Terminology Criteria for Adverse

issue warrants further study.

The authors, from the University of Texas MD Anderson Cancer Center in Houston, reviewed the therapeutic histories of 126 male breast cancer patients treated at the center between 1999 and 2009. In all, 64 met the study’s inclusion criteria. Patients included in the analysis had received tamoxifen therapy for breast cancer (stages I, II or III) and had at least one follow-up visit after starting therapy. A Cancer Center Support Grant from the National Cancer Institute funded the study, in part.

The authors found that 53% of the patients experienced one or more adverse event (AE) while on tamoxifen, predominantly weight gain (22%) and

sexual dysfunction (22%). Within the study population, 13 patients (20.3%) discontinued therapy as a result of a drugrelated AE. Four of these patients experienced a thromboembolic event and were directed to discontinue treatment by their physician; three patients reported sexual dysfunction. The median time to discontinuation was 49 months.

Most of the patients (54.7%) who met the inclusion criteria were suffering from stage II breast cancer at the time of treatment; 29.7% and 15.6% were suffering from stage I and III breast cancer, respectively. Median age at diagnosis for the study population was 61 years; patients in the study ranged in age from 30 to 79 years.

These results confirm similar findings in a much smaller study by Anelli et al (Cancer 1994;74:74-77, PMID: 8004585), which reported a similar rate of treatment discontinuation (20.8%) and a higher incidence of drug-related AEs (62.5%) in a study population of only 24 patients.

Unfortunately, as the authors in the present study note, the mechanisms of action leading to these treatment discontinuations remain poorly understood. As all men with breast cancer have hormone receptor–positive tumors and thus will undergo treatment with anti-hormonal therapies such as tamoxifen, additional studies that further elucidate these mechanisms are vital to improving outcomes in this patient population.

Events. Of note, 13 of the 64 patients (20%) discontinued tamoxifen because of AEs, with the most common reasons being thromboembolic events, loss of libido, bone pain and neurocognitive deficits. Interestingly, in only 30% of cases was tamoxifen discontinued at the direction of the physician, so in 70% the decision to discontinue was made by the patient due to AEs. The authors do not indicate if there were any nonclinical reasons for discontinuation, such as an inability to afford the medication.

This paper makes an important contribution to the literature because it represents the largest published series to date on the topic of tamoxifen-related side effects in males. The fact that one in five male patients stopped taking tamoxifen at a median time from start of therapy of approximately four years suggests that a substantial number might not be receiving optimal adjuvant therapy, possibly risking a poorer outcome. Additionally, the study notes that 62.5% of tamoxifentreated patients experienced at least one AE attributable to the drug, negatively impacting quality of life, and that may have increased the chance of premature discontinuation.

These findings should be compared

with the literature on adherence to endocrine therapy in female breast cancer patients, and Pemmaraju et al cite some of this earlier work. For example, Hershman et al (J Clin Oncol 2010; 28:41204128, PMID: 20585090) examined automated pharmacy records from Kaiser Permanente of Northern California for 8,769 women with early-stage breast cancer treated with tamoxifen and/or aromatase inhibitors. They found substantial rates of nonadherence and discontinuation, with only 49% completing the full duration on the recommended schedule. In another series of 961 women with breast cancer aged 65 and older, Owusu and colleagues (J Clin Oncol 2008;26:549555, PMID: 18071188) also showed a 49% discontinuation rate for tamoxifen, and they found that older age, breast-conserving therapy without radiotherapy and increasing comorbidities predicted tamoxifen nonadherence. Given that these two series were larger and more rigorous, since they examined pharmacydispensing records, it seems likely that the actual rate of tamoxifen discontinuation in male patients may be higher than the 20% reported by Pemmaraju, because I suspect that men are no less likely than women to experience tamoxifen AEs

impacting quality of life.

This paper also reminds us that, because male breast cancer is a rare disease (2,140 estimated cases in American men in 2011), there are no real treatment guidelines and few alternatives to the current paradigms. Men intolerant of adjuvant tamoxifen have few options, since orchiectomy and luteinizing hormone-releasing hormone agonists have considerable toxicity, and there is little evidence supporting their use, despite similarities between male breast cancer and breast cancer in postmenopausal women. Likewise, aromatase inhibitors have been inadequately studied and should be used in men with great caution because it is biologically plausible that they may increase circulating testosterone and indirectly increase estrogen levels.

Further advances in this field will come from a greater understanding of the biology of breast cancer in men and what if any differences exist between the disease in men and women. Until such findings come to light, entering all newly diagnosed male patients on disease registries so that outcomes can be systematically tracked is the best next step.

Melanoma

Risk Factors for CNS Metastases in Melanoma Identified From American Journal of Clinical Oncology

A

new study, published in the December 2011 issue of the American Journal of Clinical Oncology (2011;34:603-610, PMID: 21150567), has identified several potential patient-related risk factors independently associated with the

development of central nervous system (CNS) metastases from the time of diagnosis of advanced surgically unresectable (stage III/IV) metastatic melanoma.

The study, which was jointly funded by Chiron Corporation and a cancer center support grant from the National Institutes of Health, analyzed 922 chemotherapy-naive patients from 12

consecutive studies performed at the University of Texas MD Anderson Cancer Center in Houston over a 15-year period ending in 2002. Ultimately, 740 patients were included in the final analysis—653 who had enrolled in studies of therapies of advanced systemic metastases at the center plus an additional 87 patients with advanced melanoma who developed CNS

metastases culled from three separate adjuvant and neoadjuvant studies.

Of these patients, 329 developed CNS metastases. In analyzing the data for these patients, the authors, led by Agop Bedikian, MD, confirmed the results of an earlier study (J Clin Oncol 2004;22:1293–1300, PMID: 15051777), which found that elevated serum lactate

SOLID TUMORS

Clinical Oncology News • March 2012

Breast

Everolimus Plus Exemestane Improves PFS in Advanced Breast Cancer From The New England Journal of Medicine

A

study published online by The New England Journal of Medicine (2011 Dec 7. [Epub ahead of print], PMID: 22149876) has found that the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor, Novartis), when combined with the aromatase inhibitor exemestane (Aromasin, Pfizer), improves progression-free survival (PFS) in patients with hormone receptor (HR)–positive advanced breast cancer, when compared with exemestane plus placebo.

Authored by an international team of researchers as well as representatives of Novartis, which manufactures

EXPERT INSIGHT Vered Stearns, MD Associate Professor of Oncology Johns Hopkins University School of Medicine Co-Director, Breast Cancer Program Breast Cancer Research Chair in Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

I

n BOLERO-2 (Breast Cancer Trials of Oral Everolimus), 724

everolimus, the study reviewed and analyzed treatment data pooled from the sponsor’s data management systems. The Phase III randomized trial was comprised of 724 female patients with HR-positive advanced breast cancer, gathered from 189 hospital centers in 24 countries. All of the enrolled patients experienced recurrence or progression after undergoing therapy with a nonsteroidal aromatase inhibitor (either letrozole or anastrozole) either in the adjuvant setting or in order to treat advanced disease (or both). The participating patients were randomized according to a 2-to-1 ratio, so that 485 patients ultimately received the study drug and 239 received the placebo.

The study’s primary end point was

PFS. At the interim analysis, median PFS was 6.9 months among patients receiving combination therapy and 2.8 months for patients receiving placebo plus exemestane (P<0.001); median PFS was 10.6 and 4.1 months, respectively (P<0.001). At the study’s cutoff date (February 2011), 47% of the patients in the combinationtherapy group were still receiving treatment compared with 29% in the placebo group. Disease progression was the primary reason for treatment discontinuation in both groups, although 19% of the patients in the combination-therapy group discontinued treatment compared with 4% in the placebo group.

Median treatment duration in the combination group was 17.4 weeks and in the placebo group was 12 weeks. The

authors note that this longer treatment period may have contributed to the higher rate of discontinuation. In all, 23% of the patients in the combination-therapy group experienced “serious adverse events,” with stomatitis and rash being the most commonly reported.

The authors conclude that, although the addition of everolimus led to an improvement in clinical outcomes within the study groups, this benefit “should be weighed against the side effects observed with [the drug].” They advocate careful monitoring of patients with HR-positive advanced breast cancer undergoing treatment with everolimus and recommend further study to elucidate the drug’s potential clinical benefits.

women with HR-positive metastatic breast cancer, whose disease progressed on a nonsteroidal aromatase inhibitor, were randomly assigned the steroidal aromatase inhibitor exemestane with or without the mTOR inhibitor everolimus. Women assigned to the combination arm enjoyed superior PFS compared with those receiving exemestane alone (10.6 and 4.1 months, respectively, using central review, hazard ratio, 0.36; 95% confidence interval, 0.27-0.47; P<0.001). Although women in the combination arm were more likely to report grade 3 or 4 adverse events, including stomatitis, anemia,

dyspnea, hyperglycemia, fatigue and pneumonitis, overall quality of life was not different between the groups. Overall survival data were not mature at the time of study publication.

The superiority of the combination is statistically and clinically significant. The single-arm data suggest that the transition onto a steroidal aromatase inhibitor buys little time for most women meeting the trial’s criteria before the next step, chemotherapybased therapy. Because everolimus is an oral agent that is already in clinical use, it is anticipated that clinicians will be comfortable adopting the regimen and

recommending it to their patients.

Future studies should help identify the women who are most likely to require the combination earlier in the course of therapy. Predictive markers of benefit may include prior treatments; for example, it is possible that the combination is more active in women who have acquired hormone resistance as opposed to de novo resistance, or the presence of specific activated pathways in tumor tissues. Until additional data are available, clinicians should be cautious and apply the treatment only to women who meet this trial’s criteria.

discovered that patients with M1b and M1c disease were significantly more likely to develop CNS metastases than those with stage III/M1a disease.

Furthermore, the study confirmed the findings of multiple earlier studies, which found that those whose primary melanomas are located centrally (the head and neck, trunk or abdomen) are more likely to develop CNS metastases than those

whose primary tumor site is in the limbs.

Additionally, the researchers found that patients with melanoma of unknown origin were at greater risk for CNS metastases than patients whose primary tumor site is in the limbs, and that those with skin melanomas were more likely to develop CNS metastases than those with uveal melanomas.

The authors conclude that, despite

their study’s possible limitations (including potential bias stemming from patient selection, treatment time and response assessment), the “increased knowledge of risk factors for CNS metastasis should open new areas for research” into improving the poor treatment outcomes associated with this diagnosis in patients with advanced unresectable melanoma.

and revealed several previously unidentified predictive factors. The results of this important study might inform how we monitor a patient’s disease and affect the way we counsel patients about the likely course of their illness.

The study also underscores the need for investigational, multimodality treatment protocols that include patients with melanoma metastatic to the CNS. The FDA’s 2011 approvals of ipilimumab (Yervoy) and vemurafenib

(Zelboraf )—both of which have activity in the brain—represent a sea change in melanoma therapy. Those and other emerging therapies have armed clinicians and researchers with increasingly effective tools against melanoma in even the most advanced stages. Just as the key to curative regimens may lie with the potential synergy of combinatorial therapy, so too might we prevent the spread of disease into the CNS by using some of the same strategies.

Melanoma

dehydrogenase levels at the time of diagnosis of unresectable stage III/IV melanoma were a significant risk factor for the development of CNS metastases. Additionally, they confirmed that “the presence of visceral tumor metastasis” is associated with a high risk for the development of CNS metastases, a finding that echoed those of several previous studies. The authors also EXPERT INSIGHT Evan Lipson, MD Instructor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

W

hile the prognosis for patients with metastatic melanoma is often grave, involvement of the CNS makes the disease particularly challenging to treat and adds an additional degree of morbidity. Bedikian and colleagues performed a retrospective study of 740 patients with advanced melanoma in order to identify factors associated with the development of brain metastases. Their results confirmed the findings of multiple published studies

27

28

HEMATOLOGIC DISEASE

Clinical Oncology News • March 2012

CLL

BRAF V600E Mutation May Be Hairy Cell Leukemia Biomarker

incidence of BRAF V600E mutation in a large series of diverse lymphoid disorders. PCRs were performed on 240 patients with mature B-cell lymphoid neoplasms, including 62 with HCL, one with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia and 57 with B-cell chronic lymphoproliferative disorders.

According to the authors, the BRAF V600E mutation was identified in all 62 cases of HCL included in the study population. In 61 of these

cases, researchers were able to extract genomic DNA from bone marrow biopsies, with hairy cell infiltration ranging from 15% to 95%. In the remaining case, the authors report, DNA was derived from peripheral blood biopsy, with 2% of hairy cells detected by flow cytometry immunophenotyping.

The mutation was identified in only two of the remaining 178 patients who had other forms of B-cell neoplasms.

However, the authors note that despite the positive PCR findings, the mutations in these two cases could not be

detected through Sanger sequencing, indicating that they may have been “associated with a small subclone.” The two cases also had significantly different clinical characteristics.

The study’s findings echo those of other similar research efforts that used either another PCR approach (Blood 2012;119:192-195, PMID: 22028477) or a high-resolution melting analysis (Br J Haematol 2011;155:609-612, PMID: 21910720), respectively. However, that the researchers in the Blood study were able to successfully analyze DNA extracted via bone marrow biopsy is key, because this, as the authors note, “often represents the only available material containing hairy cells in patients with hairy cell leukemia.”

They conclude that with their customized PCR approach, BRAF V600E mutation is reliable as a molecular marker for the diagnosis of this mature B-cell neoplasm.

lymphoid disorders. They developed an allele-specific PCR for this mutation and tested 240 B-cell lymphoid disorders.

The BRAF V600E mutation was detectable in 100% of the HCL cases but absent in the HCL variant as well as the splenic marginal zone lymphoma and Waldenström macroglobulinemia cases. Two patients with B-cell chronic lymphoproliferative disorders had the BRAF V600E mutation detectable by PCR but DNA sequencing did not reveal the mutation. The investigators conclude that in addition to clinical and morphologic features, the BRAF V600E mutation is a reliable molecular marker for the diagnosis of HCL. The BRAF V600E mutation is frequently present in melanoma, papillary thyroid cancer and colon cancer.

In 2011, Tiacci et al first identified the BRAF V600E mutation (by DNA sequencing) in 47 of 47 cases with HCL; none of the 195 other B-cell lymphoproliferative disorders harbored this mutation. The investigators of the current study confirm this finding, that within B-cell lymphoproliferative disorders, the BRAF V600E mutation may be specific to HCL. This mutation leads to constitutive kinase activation resulting in a 500fold greater kinase activity than wildtype BRAF. This causes constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. It is not clear if HCL is dependent on BRAF V600E for proliferation and survival.

Purine analogs such as cladribine

and pentostatin (Nipent, Hospira) have been widely used in the treatment of HCL, with significant numbers of patients achieving complete remission. However, relapses and resistance are not uncommon, and for patients who relapse or fail to respond to existing therapies, novel agents such as BRAF inhibitors should be tested. These agents have already shown promise in BRAF V600E–mutated melanoma, which led to the FDA’s approval of vemurafenib (Zelboraf, Genentech) in metastatic melanoma. If HCL cells are dependent on the BRAF V600E mutation for proliferation and survival, then it is likely that BRAF inhibitors will have a significant impact on the disease.

From Blood

T

he somatically acquired V600E mutation of the BRAF gene can potentially serve as a “reliable” molecular marker for hairy cell leukemia (HCL) and other mature B-cell neoplasms, a recent study concludes.

The study, which was published in the Jan. 5 issue of the journal Blood (2012;119:188-191; PMID: 22072557), was designed to expand on the findings of Tiacci et al (N Engl J Med 2011;364:2305-2315, PMID: 21663470), which identified five somatically acquired gene mutations in patients with HCL, including the V600E mutation in the BRAF gene. For this followup study, by Arcaini et al, researchers used a specially designed, allelespecific, oligonucleotide polymerase chain reaction (PCR) test to perform BRAF gene exon 15 sequencing. The PCR test attempted to establish the

EXPERT INSIGHT Nilanjan Ghosh, MBBS, PhD Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

T

he BRAF V600E mutation was detected in all of the 62 HCL cases but only in two of 178 cases of other B lymphoproliferative disorders. BRAF V600E can be considered a molecular marker for HCL. The investigators aimed at identifying the incidence of the BRAF V600E mutation in B-cell

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SOLID TUMORS

Clinical Oncology News • March 2012

Colorectal

REGORAFENIB continued from page 1 

Institute, Durham, N.C., who was not involved with the study. “The toxicity profile is acceptable, but does require dose adjustment and monitoring of the patient. This is likely to be a candidate for regulatory approval [this year].”

Regorafenib is the first small-molecule, multikinase inhibitor with proof of efficacy in CRC. “The vast majority of colorectal cancer patients with metastatic disease are in a palliative situation,” said principal investigator Axel Grothey, MD, professor of oncology at Mayo Clinic in Rochester, Minn. Thus, regorafenib could offer these patients a much-needed salvage option once the FDA approves the drug, according to Dr. Grothey, who presented the regorafenib Phase III data at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (abstract 385).

Standard treatments for mCRC include 5-fluorouracil plus leucovorin, capecitabine (Xeloda, Roche), oxaliplatin, irinotecan, bevacizumab (Avastin, Genentech), cetuximab (Erbitux, BMS/Imclone) and panitumumab (Vectibix, Amgen). Once patients have exhausted these therapies, many still have a good performance status, but no standard salvage therapy exists, Dr. Grothey noted.

Pathways to Approval Research demonstrating that compensatory pathways are activated during therapy with bevacizumab sparked the idea of using multitargeted agents after disease progression. Regorafenib

Table 2. Comparison of Selected Grade 3/4 Treatment-Emergent Adverse Events Regorafenib, %

Placebo, %

Hand-foot skin reactions

16.6

0.4

Fatigue

9.6

5.1

Hypertension

7.2

0.8

Diarrhea

7.2

0.8

Rash/desquamation

5.8

0

Anorexia

3.2

2.8

Mucositis

3.0

0

Thrombocytopenia

2.8

0.4

Regorafenib is the first small-molecule, multikinase inhibitor with proof of efficacy in colorectal cancer.

Once the FDA approves the drug, regorafenib could offer colorectal cancer patients with metastatic disease a much-needed salvage option. is a promising candidate because it inhibits multiple cell-signaling kinases: angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGR), and oncogenic (KIT, PDGFR, RET).

After regorafenib showed promise in a Phase I expansion trial of mCRC, a team of international researchers launched the Phase III CORRECT trial.

Patients were eligible if they had mCRC disease progression during or within three months after the last administration of approved standard therapy.

Those therapies included fluoropyramidine, oxaliplatin, irinotecan, bevacizumab. Patients with K-RAS wild-type

Table 1. Comparison of Selected TreatmentEmergent Adverse Events, All Grades Regorafenib, %

Placebo, %

Hand-foot skin reactions

46.6

7.5

Fatigue

47.4

28.1

Hypertension

27.8

5.9

Diarrhea

33.8

8.3

Rash/ desquamation

26.0

4.0

Anorexia

30.4

15.4

Mucositis

27.2

3.6

Thrombocytopenia

12.6

2.0

Fever

10.4

2.8

Nausea

14.4

11.1

Bleeding

11.4

5.5

Voice changes

29.4

5.5

Weight loss

13.8

2.4

mCRC were treated with cetuximab or panitumumab. Other eligibility criteria included an Eastern Cooperative Oncology Group Performance Status of 0 or 1 and a life expectancy of at least three months.

Involving 114 centers in 16 countries, the double-blind trial recruited 760 patients within the first 10 months—16 months ahead of schedule, demonstrating great interest in new treatment options. Patients were randomized in a 2-to-1 fashion to regorafenib (160 mg orally once daily) plus best supportive care (BSC) or placebo plus BSC. Placebo and regorafenib were given for three weeks on, one week off, until disease progression. Patient demographics and baseline disease characteristics were well balanced: Approximately 60% of patients had at least four lines of systemic therapy, and all patients had been treated with bevacizumab.

The median OS, the primary end point of the trial, was 6.4 months in patients receiving regorafenib and five months in patients receiving placebo (hazard ratio [HR], 0.77; P=0.0052). “We see a 23% reduction of death events on the trial, which I perceive as clinically meaningful,” said Dr. Grothey, who called regorafenib “a potential new standard of care.” The results come from a prespecified interim analysis after 74% of events were reported. The median progression-free survival (PFS) also was improved in the regorafenib arm (1.9 vs. 1.7 months; HR, 0.49; P<0.000001).

“The median PFS clearly does not reflect the efficacy of this drug in this patient population. The curves run together for about 50% of patients and

then spread out wide with a hazard ratio of 0.49,” said Dr. Grothey.

Delaying Tumor Progression Is Key The efficacy of regorafenib was driven by improvements in stable disease (44.8% vs. 15.3%) and progressive disease (49.5% vs. 80%), rather than complete responses, of which there were none, or partial response rate, which revealed only a minor improvement for regorafenib (1% vs. 0.4%; all P<0.000001). “The strength of this drug is clearly more in delaying tumor progression than in inducing tumor responses,” Dr. Grothey said.

Adverse events (AEs) were managed with dose delays and reductions (Tables 1 and 2). There were few grade 4 AEs. Patients discontinued therapy only slightly more often in the regorafenib arm because of treatment-related AEs (8.2% vs. 1.2%). The researchers are currently conducting biomarker analyses of plasma and tissue samples and analyzing quality-of-life data.

According to Dr. Hurwitz, the median OS improvement of 1.4 months “may be a reasonable representation of the likely benefit for the average patient,” and the Kaplan-Meier PFS curves suggest that there is a subset of patients who may derive more benefit.

Dr. Hurwitz pointed out that the dosing schedule of three weeks on, one week off leaves the door open as to what a continuous dosing strategy could achieve.

How this drug would fare in patients with a performance status of 2 or above also is not known, he said.

In both the regorafenib trial and in the recent Phase III trial of aflibercept (Zaltrap, Sanofi/Regeneron), the improvement in median OS was about 1.5 months, a small difference, noted Cathy Eng, MD, associate director of the Colorectal Center, Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston. “Have we set the bar high enough is the question,” Dr. Eng said. “In a setting of a heavily pretreated patient population, it will be interesting to see how the toxicities play out when you take it out in the real world.” She added that she is particularly concerned about how fatigue may affect a patient’s quality of life.

—Kate O’Rourke Dr. Grothey disclosed a consultant or advisory role for Bayer. Dr. Hurwitz disclosed a consultant or advisory role for Bristol-Myers Squibb and Genentech/Roche, honoraria from Roche, and research funding from Acceleron Pharma, Amgen, BMS, Cephalon, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, Threshold and Tracon. Dr. Eng has a consultant or advisory role for Genentech and received research money from the company.

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].

INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug.

QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.

Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].

Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available.

Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].

General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug 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 [see Use in Specific Populations].

Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.

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

Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 1 (<1) 3 (1.5) -

1 1

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

2 2 -

(1) (1)

22 20 8 4 3 4 1

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. 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.

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].

Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.

Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively.

N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.

The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].

Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and -hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and -hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug 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.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies.

Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis).

Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use There is no indication for use of FARESTON in pediatric patients.

Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Race The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].

Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days.

Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.

Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients.

Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.

Race – The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.

PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].

Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].

Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.

Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved.

2E Rev. 03/2011

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia.

Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com