Evaluation of AZD2171, an oral, highly potent and selective VEGFR signaling inhibitor, in renal cell carcinoma (RCC): Combined results from two phase I studies

Abstract

3560 Background: Antiangiogenic agents have recently demonstrated promising activity in patients with advanced RCC. AZD2171 is an oral, highly potent and selective inhibitor of VEGFR-1, -2 and -3 tyrosine kinases, and is currently in Phase II/III development in NSCLC and CRC. Safety and efficacy results are presented for patients with RCC who participated in two Phase I dose-escalation studies of AZD2171 in advanced solid tumors. Methods: Patients with advanced recurrent metastatic RCC received once-daily oral AZD2171, either as monotherapy (Drevs et al. Proc Am Soc Clin Oncol 2005: abst 3002; completed) or in combination with gefitinib (van Cruijsen et al. Proc Am Soc Clin Oncol 2006: abst 3017; ongoing). All patients had received prior interferon-a ± interleukin-2/ 5-FU or radiotherapy. Results: Twenty-one patients received AZD2171, 4 as monotherapy (20 mg, n=1; 60 mg, n=3) and 17 as combination therapy (AZD2171 20–45 mg with gefitinib 250 or 500 mg). The adverse event (AE) profile in RCC patients was similar to that reported previously for all patients in these studies; hypertension, dysphonia, nausea, vomiting, diarrhea and fatigue were the most common AEs. The most common CTC grade 3 AEs were hypertension (n=5) and diarrhea (n=4). Reductions in plasma levels of sVEGFR-2 were observed in RCC patients when AZD2171 was administered as a monotherapy or in combination with gefitinib; the reductions in the combination study were dose- and time-dependent (sustained). Nineteen patients were evaluable for efficacy (RECIST): 2/3 monotherapy patients experienced tumor regression, one of which was confirmed as a partial response (duration of response [DR] 87 days); in the combination study, 6/16 (38%) patients achieved a partial response (median DR 6 months; 3/6 ongoing at data cut off) and 7/16 (44%) patients had stable disease (4/7 had a confirmed 10–30% reduction in maximum tumor diameter). Conclusion: AZD2171, both as monotherapy and in combination with gefitinib, showed encouraging antitumor activity and a manageable toxicity profile in patients with advanced RCC who had failed prior therapy. A randomized Phase II investigation of AZD2171 monotherapy (45 mg/day) vs placebo in patients with advanced RCC is ongoing. [Table: see text]