A randomized double-blind phase IIa dose-finding study of ZD6474 in Japanese patients with NSCLC

Abstract

7067 Background: ZD6474 is a once-daily oral therapy that selectively inhibits key signaling pathways in cancer by targeting vascular endothelial growth factor receptor (VEGFR)-dependent tumor angiogenesis, and epidermal growth factor receptor (EGFR)- and RET-dependent cancer cell proliferation and survival. ZD6474 was evaluated as monotherapy in an ongoing randomized, double-blind, parallel-group, Phase IIa, dose-finding, multicenter study in Japan. Methods: Patients with locally advanced or metastatic (stage IIIB/IV) or recurrent non-small-cell lung cancer (NSCLC), after failure of one or two platinum-based chemotherapy regimens, were eligible for this study. Patients were randomized to receive ZD6474 100, 200 or 300 mg/day in a 1:1:1 ratio, with stratification according to sex, histology (adenocarcinoma vs other histology) and smoking status (smoker vs non-smoker). Tumor response was assessed every 4 weeks for the first 24 weeks of treatment and then every 8 weeks until progressive disease (PD) or withdrawal due to any reasons other than PD. The primary objective was the objective response rate, as evaluated by RECIST. Secondary objectives included disease control rate, tolerability and safety. Adverse events (AEs) were assessed using CTC version 3.0. Results: A total of 53 patients (34 males/19 females, median age 60 years [range 30–78], 35 adenocarcinomas and 33 smokers) with a WHO PS status of 0 (n = 20) or 1 (n = 33) were recruited from eight centers between December 2004 and September 2005. Among 53 patients, 6 partial responses (PR; 11%, 2 males/4 females, 6 adenocarcinomas, 2 smokers/4 non-smokers) have been confirmed and disease control (PR or stable disease≥ 8 weeks) has been observed in 27 patients (51%). The most common AEs were rash and diarrhea, and asymptomatic QTc prolongation was also observed. One patient died due to drug-related interstitial lung disease. Conclusions: In this ongoing trial, ZD6474 has demonstrated antitumor activity as monotherapy in patients with refractory NSCLC, with 11% experiencing a PR and 51% having disease control. The tolerability profile of ZD6474 was consistent with that seen previously. [Table: see text]