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March 8, 2005 • Volume 2 / Number 10 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Featured Article

Gefitinib Use Plummets Following ISEL Trial Results

More than 85 percent of clinical oncologists who treat lung cancer patients have modified their care patterns based on the results of a clinical trial that showed the targeted agent gefitinib (Iressa) failed to improve survival compared with placebo. At a meeting of the Food and Drug Administration (FDA) Oncology Drugs Advisory Committee last week, officials from the drug's manufacturer, AstraZeneca PLC, reported the data, along with additional market research on gefitinib use since the company issued a "Dear Doctor" letter on Dec. 17, 2004 and other communications describing the trial's overall survival results.

"Physicians are aware of the [trial] results and are no longer selecting Iressa as their EGFR inhibitor of choice," said Carolyn Fitzsimons, an executive director with AstraZeneca. "They are choosing erlotinib (Tarceva)."

In the Iressa Survival Evaluation in Lung cancer (ISEL) trial, gefitinib was tested as a second- or third-line therapy in nearly 1,700 patients with advanced non-small-cell lung cancer (NSCLC). AstraZeneca officials presented further data from ISEL during the advisory committee meeting, including subset analyses revealing a significant survival advantage with gefitinib in never smokers and patients of "Asian ethnicity."

These latter findings are consistent with previous studies of gefitinib, and represent a "real effect of the drug," argued AstraZeneca's Dr. Kevin Carroll. Many committee members agreed that some patients clearly benefit from gefitinib. Several others commented that the trial, while it did not meet its primary endpoint, was, as one member put it, "as close to a positive trial as you can get."

As for the subset analyses - which were not a prespecified component of the trial - a negative result in the overall population can cloud the accuracy of subsequent subset analyses, said Dr. Janet Dancey, a senior investigator in the NCI Cancer Therapy Evaluation Program. "The more subset analyses that are done, the more likely is the chance that positive results will be seen," she said. "However," she continued, "there are data from other studies which also show benefit in these subgroups, raising the probability that the beneficial effects seen in never smokers and patients with East Asian ethnicity are true."

The ISEL trial was one of several post-market trials required of AstraZeneca under the accelerated approval mechanism used by FDA to approve gefitinib in May 2003 - an approval granted solely based on the agent's ability to shrink tumors in a small percentage of patients. The follow-up studies - one has been abandoned; the other, which is pitting gefitinib against docetaxel, is ongoing - were required to show whether gefitinib could extend survival. Although gefitinib fell short in ISEL, both erlotinib and pemetrexed (Alimta) have proven in clinical trials to improve survival in patients with advanced lung cancer who have previously received chemotherapy.

The committee generally agreed that AstraZeneca had done a good job of communicating the preliminary ISEL results to the oncology community, including the "Dear Doctor" letter, which advised clinicians "to consider other treatment options in the recurrent [NSCLC] patient population." According to AstraZeneca's market research, 78 percent of clinical oncologists were familiar with the letter and 86 percent said they had modified their treatment practice as a result.

Dr. Richard Pazdur, director of FDA's Division of Oncology Drug Products, said the agency will not make a decision on gefitinib's fate in the marketplace until the final ISEL data are reviewed. The final trial data, including an analysis of survival in relation to EGFR expression and mutation status - potential indicators of patient response to the drug - will be available by June, AstraZeneca officials said.

By Carmen Phillips