ROCKVILLE, Maryland-The United States Food and Drug Administration (FDA) has granted accelerated approval to Iressa tablets (gefitinib, AstraZeneca) as monotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) in patients whose disease has progressed despite treatment with platinum-based and docetaxel(Drug information on docetaxel) (Taxotere) chemotherapy. The Oncologic Drugs Advisory Committee (ODAC) recommended approval of Iressa on September 24, 2002, but the FDA delayed action for 3 months to analyze new Japanese data indicating Iressa was associated with an unexpected and often-fatal occurrence of interstitial lung disease (ILD). As a condition of approval, Astra- Zeneca agreed to conduct three phase IV postmarketing trials of Iressa (see box, Postmarketing Studies). Accelerated approval is granted to drugs that have shown indications of benefit in serious or life-threatening diseases over available therapies or, like Iressa, in conditions with no effective treatment. "An essential part of our accelerated approval process is the further study of the new treatment after it is on the market," said FDA commissioner Mark B. McClellan, MD, PhD. "In the case of Iressa, studies are needed to confirm clinical benefit, understand better which patients benefit, and evaluate long-term safety." Iressa's mechanism of action is not fully understood; it was designed to inhibit growth stimulatory signals by blocking several tyrosine kinases, including one associated with the HER1/ epidermal growth factor receptor. This blocking results in an inhibition of cancer cell proliferation and an increase in apoptosis. The drug is administered as a 250-mg tablet taken once a day. Phase II Trial The FDA approved Iressa on the basis of findings from a phase II trial that studied two doses of the drug in 216 patients in whom previous platinum- based and docetaxel chemotherapy had failed. In reviewing the data, ODAC concluded that the 10% Iressa response rate in these patients was reasonably likely to predict clinical benefit, but told the FDA that symptom improvement could not be adequately evaluated without a randomized, blinded study. For their review of Iressa, FDA medical officers accepted the 142 patients in the study who had refractory disease. Patients receiving the 250-mg dose had a 13.6% partial response rate, defined as a 50% or greater reduction in tumor size. Those who received the 500-mg dose did not have a higher response rate, but they did suffer more adverse side effects. The overall response rate for both doses was 10.6%. Duration of response ranged from 4.4 to 18.6+ months, with a median of 7 months. However, the response rate proved highly variable in different subpopulations, based on sex, smoking habits, and histology, ranging from 4.6% to 29.4%. Higher response rates were seen in women and patients with adenocarcinoma, and lower rates in men and smokers. Iressa's efficacy was accepted based on response rates, rather than a clinical benefit such as improved symptoms or increased survival. Two large randomized, controlled studies of the drug as a first-line treatment in combination with doublet platinum-based chemotherapy showed no benefit. Thus, the FDA did not approve its use with any other cancer drug. The most common adverse events associated with Iressa in the trial included diarrhea (48%), rash (43%), acne (25%), dry skin (13%), nausea (13%), and vomiting (12%). These side effects generally occurred in the first month of treatment and were usually mild to moderate. Iressa may harm the fetus if given to pregnant women. Rates of Interstitial Lung Disease Shortly after ODAC recommended Iressa's approval, FDA officials learned of reports that patients treated with the drug in Japan had suffered ILD, which consists of interstitial pneumonia, pneumonitis, and alveolitis. The agency extended its investigation of the drug, which included a comprehensive analysis of updated toxicity data from clinical trials and the Iressa expanded-access program, which involves some 23,000 patients. The FDA concluded that the ILD incidence was about 2% in Japan and 0.3% in the expanded- access program. The Iressa-associated ILD mortality rate is about 33%. "FDA believes this rare but serious toxicity of Iressa does not outweigh benefits demonstrated in patients with advanced NSCLC," the agency said.