CHICAGO—ATTRACT-1, a global, double-blind randomized Phase 3 trial of carboplatin/paclitaxel (CP) coupled with the vascular-disrupting agent vadimezan (ASA404), although generally well-tolerated, did not demonstrate enhanced efficacy over placebo in patients with advanced non-small cell lung cancer (NSCLC), according to data presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.

Primo N. Lara, MD, University of California, Davis, Cancer Center, and colleagues explained that in an earlier Phase 2 randomized trial in patients with advanced NSCLC, that vadimezan in combination with CP did improve several efficacy parameters and that this Phase 3 study was conducted to validate those results. Patients with stage IIIB or IV NSCLC—stratified by sex and histology—with no prior systemic therapy for metastatic disease, good performance status (PS of 0 or 1), and acceptable end-organ function, were randomly assigned to paclitaxel 200mg/m2 and carboplatin AUC 6 with or without vadimezan 1,800mg/m2, given intravenously every three weeks for six cycles. The primary endpoint was overall survival (OS). Secondary endpoints included response rate (RR), progression-free survival (PFS), and safety. Twelve hundred (1,200) patients were required to determine a hazard ratio (HR) of 0.80, corresponding to a median OS of 9 months (CP + placebo) vs. 11 months (CP + vadimezan).

A total of 1,299 patients were randomized. Baseline demographics were well balanced. Median age was 61 years, 62.2% were male, and 40.3% had PS of 0. The trial was stopped due to lack of efficacy 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 (vadimezan + 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. The most commonly reported AEs were neutropenia, alopecia, nausea, and fatigue and were comparable between the two treatment groups. Grade 4 neutropenia (27% vs. 19%) and infusion-site pain (10% vs. 0.5%) were more frequent in the vadimezan arm.

Vascular disruption of established tumor blood vessels is a unique anti-neoplastic strategy. In a randomized Phase 2 trial in patients with advanced NSCLC, vadimezan in combination with CP was found to improve several efficacy parameters including OS. Study limitations of the Phase 2 trial, however, were a small sample size that may have caused an overestimation of treatment effect and the lack of a placebo-control, and blinding. ATTRACT-1 was designed to validate the results of the Phase 2 trial.  Dr. Lara concluded that median OS was greater than 12.5 months with CP alone and exceeded a priori assumptions, but the addition of vadimezan, despite being generally well tolerated, failed to improve efficacy.