Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.

CONTEXT: More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. OBJECTIVE: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. INTERVENTION: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). MAIN OUTCOME MEASURES: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). RESULTS: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). CONCLUSIONS: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.

A phase II trial of weekly i.v. KW-2170 in advanced castrate-resistant prostate cancer.

AIM: KW-2170 is a novel pyrazoloacridone derivative that intercalates nucleic acids. It has promising in vitro properties against prostate and other cancers and is active in vivo against doxorubicin-resistant cell lines. We wished to investigate its activity and toxicity profile in this Phase II trial in androgen independent prostate cancer. METHODS: Overall 44 men were recruited to this multicenter, open label, non-randomized study, with 35 evaluable for prostatic specific antigen (PSA) response. RESULTS: Five patients had a PSA fall greater than 50% (overall RR 14.3%, 95% CI 4.8-30.3%). Overall median survival was 16 months. In the evaluable group (n = 35), median survival was 18.9 months. The drug was very well tolerated, with the most common toxicities being hematological (anemia, leucopenia, thrombocytopenia), alopecia, fatigue, and nausea. However, most of these were National Cancer Institute Grade 1 or 2; Grade 3 neutropenia occurred in only 11% of patients, and there was no Grade 4 neutropenia. Quality of life as measured by the FACT-P scale was not compromised. CONCLUSION: KW-2170 is a very well tolerated chemotherapy agent. It has a relatively low PSA response rate, and did not meet the pre-specified criteria for further studies.