BATTLE-ing Lung Cancer

[Christine]

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Conquest Magazine

Fall 2007

MD Anderson Cancer Center

In a novel project matching drugs to molecular targets in lung cancer, M. D. Anderson

investigators are engaging in an intensive and ongoing interrogation of the tumors themselves.

The underlying premise of the landmark package of clinical trials — known collectively as the Biomarker-based Approaches of Targeted Therapy for Lung Cancer Elimination — is to let the biology of a patient’s tumor teach physicians how to treat that tumor. A major step toward individualized therapy, BATTLE examines four treatment options against biomarkers representing four molecular pathways that fuel lung cancer, and relies heavily on core biopsies of patients’ tumors before and during the trial.

Despite the approval of new drugs in recent years, lung cancer remains stubbornly difficult to treat and is the leading cause of death due to cancer, says Edward Kim, M.D., assistant professor in M. D. Anderson’s Department of Thoracic/Head and Neck Medical Oncology and BATTLE clinical trial principal investigator.

“We have no targeted therapies for lung cancer,” he says. “There’s been a tunnel vision approach to research, with clinical trials focusing on a single drug and a single biomarker. Those trials are costly, and often they don’t pan out. We’re broadening our approach.”

In the BATTLE study, patients with previously treated, advanced non-small cell lung cancer are randomly assigned to one of four treatment options.

They are evaluated eight weeks after treatment begins. If the cancer remains stable or has improved, they stay on the first treatment. Patients whose disease has progressed may drop out of their initial study arm and enter one of the other studies of a drug that targets a different molecular pathway.

As the four clinical trials progress under the BATTLE umbrella, investigators evaluate disease progression and changes in the genomic profiles of the tumors after treatment via follow-up biopsies. Information from early patients in the trial gradually influences which treatment may be best for later patients, a unique adaptive randomization study design that learns as it goes.

“Patient accrual is like a ramp,” Kim explains. “As the statistical model learns from each patient enrolled in the study, assignment to a treatment arm becomes more targeted and less random. As we learn more about which biomarkers respond best to which drugs, more patients will go on a treatment arm favoring that biomarker.”

As the trial progresses, the number of patients enrolled in a treatment arm may increase or decrease, or a treatment arm might be discontinued.

Using this approach, investigators are trying to “understand the biologic properties of tumor tissue, to detect a dominant tumor progression pathway and then to give the right agent to block that molecular pathway, seeing whether it correlates with tumor response,” says Waun Ki Hong, M.D., head of M. D. Anderson’s Division of Cancer Medicine and director of the BATTLE program.

All four treatment regimens have shown some activity against lung cancer and are taken in pill form. They are erlotinib (Tarceva®), vandetanib (Zactima™), sorafenib (Nexavar®), and a combination of erlotinib and bexarotene (Targretin®).

Tarceva and other new medications approved by the U.S. Food and Drug Administration in recent years to treat lung cancer have been shown to slightly increase overall patient survival. Biomarkers are needed to predict which patients are likely to benefit from the drugs.

“Tarceva won’t be any more effective in lung cancer than it already is, which is a little bit, unless we know who to give it to, at what dose and at what time,” says Roy Herbst, M.D., Ph.D., professor in the Department of Thoracic/Head and Neck Medical Oncology and BATTLE clinical trial co-principal investigator.

As of mid-September, 75 patients were enrolled in BATTLE and assigned to one of the four clinical trials. The team expects to begin selective randomization this fall, with patients statistically nudged toward specific treatment arms. A total of 250 patients will be enrolled.

Research Nurse Christine Alden meets with potentially eligible patients to explain the trial and, in particular, to review the need for multiple biopsies and the possible risks and discomforts of that procedure.

Interested patients return a week later to review the trial and give their informed consent to join. Next, they meet with interventional radiology to arrange for a biopsy the next day. Two weeks after the biopsy, patients have a return appointment, are randomized to one of the four treatment options and leave with the medication that day.

After eight weeks, another biopsy is performed, adds Ignacio Wistuba, M.D., associate professor in the Department of Pathology. Typically, “many biologic and biomarker studies are done only in specimens taken from the tumor before treatment. We think, however, it will be useful to do these studies in real-time so we can learn what’s happening after treatment because the tumor changes during therapy.”

Defeating lung cancer has never been easy, but it’s one battle investigators hope to win.

— Scott Merville