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Gefitinib Fails to Stem Malignant Mesothelioma

Gefitinib Fails to Stem Malignant Mesothelioma

ST. LOUIS, MISSOURI- Gefitinib (ZD1839, Iressa) was not active against malignant mesothelioma in a phase II study testing the novel agent in 43 patients with unresectable disease. Investigator Ramaswamy Govindan MD, assistant professor, Division of Medical Oncology, Washington University in St. Louis, told ONI that results from the multicenter Cancer and Leukemia Group B investigation were disappointing (ASCO abstract 2535). There were no complete responses and only one patient had a partial response. While 21 patients had stable disease, 16 progressed and 5 died within 2 months of registering for the study. Median failure-free survival was 1.7 months, and median survival was 6.8 months, on the low end for malignant mesothelioma. Dr. Govindan said that the group undertook the study because gefitinib had been active against malignant mesothelioma cell lines in vitro. The agent is an HER1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, and EGFR amplification is a common feature of the disease. Of 28 patients in the study for whom immunohistochemistry was available, all but one showed EGFR expression. EGFR levels for 10 patients were at 2+, and 17 reached 3+, an echelon Dr. Govindan characterized as "an intense expression." Yet he reported, "EGFR expression did not seem to correlate with any benefit." All patients in the study had measurable disease less than 4 months after radiation therapy. None had prior cytotoxic therapy or another treatment targeting EGFR. With only four females, the population was overwhelmingly male. The group's median age was 72, as all but seven patients were age 60 or older. Epithelial disease was diagnosed in 34 patients, and all cases but 1 were pleural in origin. The patients received a fixed oral dose of 500 mg of gefitinib once a day in 21-day cycles that continued as long as the patient did not progress or have to discontinue because of adverse events. The treatment was generally well tolerated. Diarrhea and nausea were the most common adverse events. Only two patients had a grade 3 rash, a common side effect that other studies have suggested might be a biomarker for response to EGFR agents. Might Some Patients Benefit?
Dr. Govindan said the investigators plan to analyze the data to see whether a subset of patients might be more likely to respond to gefitinib. "[For the overall] group it's not active, but we still don't know which patients are likely to benefit," he said. Commenting on various lung cancer trials, Alex Adjei, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, noted, "Single-agent Iressa unfortunately has no role [in malignant mesothelioma]." He said it might still be worth investigating as a maintenance therapy after other treatments.

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