Gefitinib Fails to Stem Malignant Mesothelioma

September 1, 2003

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

ST. LOUIS, MISSOURI-Gefitinib (ZD1839, Iressa) was not activeagainst malignant mesotheliomain a phase II study testing the novelagent in 43 patients with unresectabledisease.Investigator Ramaswamy GovindanMD, assistant professor, Divisionof Medical Oncology, WashingtonUniversity in St. Louis, told ONI thatresults from the multicenter Cancerand Leukemia Group B investigationwere disappointing (ASCO abstract2535). There were no complete responsesand only one patient had apartial response. While 21 patients hadstable disease, 16 progressed and 5died within 2 months of registeringfor the study. Median failure-free survivalwas 1.7 months, and median survivalwas 6.8 months, on the low endfor malignant mesothelioma.Dr. Govindan said that the groupundertook the study because gefitinibhad been active against malignantmesothelioma cell lines in vitro. Theagent is an HER1/epidermal growthfactor receptor (HER1/EGFR) tyrosinekinase inhibitor, and EGFR amplificationis a common feature of thedisease.Of 28 patients in the study forwhom immunohistochemistry wasavailable, all but one showed EGFRexpression. EGFR levels for 10 patientswere at 2+, and 17 reached 3+,an echelon Dr. Govindan characterizedas "an intense expression." Yet hereported, "EGFR expression did notseem to correlate with any benefit."All patients in the study had measurabledisease less than 4 months afterradiation therapy. None had priorcytotoxic therapy or another treatmenttargeting EGFR. With only four females,the population was overwhelminglymale. The group's median agewas 72, as all but seven patients wereage 60 or older. Epithelial disease wasdiagnosed in 34 patients, and all casesbut 1 were pleural in origin.The patients received a fixed oraldose of 500 mg of gefitinib once a dayin 21-day cycles that continued as longas the patient did not progress or haveto discontinue because of adverseevents. The treatment was generallywell tolerated. Diarrhea and nauseawere the most common adverse events.Only two patients had a grade 3 rash,a common side effect that other studieshave suggested might be a biomarkerfor response to EGFR agents.Might Some Patients Benefit?
Dr. Govindan said the investigatorsplan to analyze the data to seewhether a subset of patients might bemore likely to respond to gefitinib."[For the overall] group it's not active,but we still don't know which patientsare likely to benefit," he said.Commenting on various lung cancertrials, Alex Adjei, MD, PhD, of theMayo Clinic in Rochester, Minnesota,noted, "Single-agent Iressa unfortunatelyhas no role [in malignant mesothelioma]."He said it might still beworth investigating as a maintenancetherapy after other treatments.