To evaluate the feasibility, toxicity, and efficacy of oral gefitinib (ZD1839, Iressa) in patients with refractory non-small-cell lung cancer (NSCLC) treated in a community-based setting. One hundred twenty-four patients with advanced, refractory NSCLC received treatment with gefitinib 250 mg orally each day. Ninety-six percent of patients had received >or= 1 previous chemotherapy regimens and 79% had received previous platinum and taxane therapy. Patients were evaluated for response after 6-12 weeks of daily gefitinib therapy; patients with objective response or stable disease continued gefitinib until disease progression occurred. Gefitinib was well-tolerated in these patients with advanced, refractory NSCLC. There were no grade 4 toxicities, and grade 3 skin toxicity and diarrhea were observed in only 4% and 2% of patients, respectively. Nine of 120 evaluable patients (8%) had partial responses to treatment; however, 54 patients (45%) had no evidence of progression at first reevaluation, and a total of 35 patients (29%) reported improvement in lung cancer-related symptoms while receiving gefitinib. Median survival for the entire group was 6.5 months, with a 1-year survival rate of 35%. Gefitinib is active and very well-tolerated in patients with advanced, refractory NSCLC. Although the major response rate was low, nearly 50% of patients derived substantial palliative benefit from gefitinib therapy. The median survival of 6.5 months achieved in this large group of relatively unselected patients is unprecedented in the third-line treatment setting, and compares favorably to other available second-line treatment including docetaxel. A therapeutic trial of gefitinib should be considered in all patients with refractory NSCLC.