Randomized phase III placebo-controlled trial of carboplatin/paclitaxel (CP) with or without the vascular-disrupting agent vadimezan (ASA404) in advanced non-small cell lung cancer (NSCLC).

7502 Background: Vascular disruption of established tumor blood vessels is a unique anti-neoplastic strategy. In a randomized phase II trial in patients (pts) with advanced NSCLC, the vascular disrupting agent ASA404 (vadimezan) in combination with CP was found to improve several efficacy parameters including overall survival (OS). A global, double-blind, placebo-controlled phase III trial of frontline CP with or without ASA404 in advanced NSCLC was therefore conducted to validate these results. Methods: Pts with stage IIIB or IV NSCLC - stratified by sex and histology – with no prior systemic therapy for metastatic disease, good performance status (0 or 1), and acceptable end-organ function, were randomly assigned to Paclitaxel 200 mg/m2 and Carboplatin (AUC 6) +/- ASA404 (1,800 mg m2), given IV every 3 weeks for 6 cycles. Primary endpoint was OS. Secondary endpoints included response rate (RR) and progression-free survival (PFS). 1200 patients were required, based on a hazard ratio (HR) of 0.80, corresponding to a median OS of 9 vs. 11.24 months (CP+placebo vs. CP+ASA404, respectively). Results: A total of 1,299 pts were randomized. Baseline demographics were well balanced. Median age was 61 years, 62% were male, and 40% had PS=0. The trial was stopped for futility at interim analysis by the independent data safety monitoring committee. HR for OS was 1.01 (95% CI: 0.85, 1.19; p=0.535). Median OS was 13.4 (ASA404 + CP) vs. 12.7 months (placebo + CP). No difference in OS was seen in the histologic (squamous or non-squamous) and sex strata. Median PFS was 5 months in both arms (HR=1.04; p=0.7). Overall RR was comparable (25%) between the arms, as was the rate of adverse events (AEs). The most commonly reported AEs were neutropenia, alopecia, nausea, and fatigue. Grade 4 neutropenia (27% vs. 19%) and infusion site pain (10% vs. 0.5%) were more frequent in the ASA404 arm. Conclusions: Median OS was greater than 12.5 months with CP alone, exceeding a priori assumptions. The addition of ASA404 to CP, although generally well-tolerated, failed to improve efficacy in pts with advanced NSCLC.