Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599

LBA4 Background: The results of a randomized phase II trial of PC +/- bevacizumab (A) suggested improved activity for the combination of PCA when compared to PC alone (Johnson DH, et al JCO 2004). Grade 5 hemoptysis was seen in the PCA arms & multivariate analysis suggested squamous cell histology to be a significant risk factor. Methods: The primary endpoint of this randomized trial was to compare the effects of the addition of A to PC on overall survival in patients (pts) with previously untreated non-squamous NSCLC. Secondary endpoints included response rate, time to progression, and tolerability. Correlative studies consisted of pre & post-treatment circulating VEGF, VCAM, E-selectin & bFGF as prognostic & predictive markers. Other eligibility criteria included ECOG PS 0 or 1, & adequate hematologic, renal, & hepatic function. Pts with brain metastases were excluded. Pts were randomized to receive P 200 mg/m2 + C AUC=6 on day 1 every 3 wks or PC + A 15mg/kg day 1 (PCA) every 3 weeks. Pts on PCA continued bevacizumab after 6 cycles until progressive disease or intolerable toxicity. With at least 842 pts entered & a total information of 650 deaths, this study was designed to have 91% (80.5%) power to detect a 30% (25%) improvement in median survival from 8 months on PC to 10.4 (10.0) months on PCA with an overall one-sided type I error of 2.5%. Interim analyses were planned. Results: This study opened in 7/01, was suspended for a planned toxicity evaluation from 2–8/02. Accrual was completed in 4/04 with 444 pts assigned to PC & 434 to PCA. 10% were stratified as non-measurable, 11% having prior RT, 75% as prior weight loss < 5%, and 14% as stage IIIB. The 1st interim analysis was conducted at 48% information using data available as of 9/7/04. Results: The 2nd interim analysis of overall survival will take place in 3/05. If the criteria for early stopping are met (+/-), then the interim study results will be released for presentation. Conclusions: To be reached if the data is available in 1st quarter of 2005.