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

Authors: A. B. Sandler, R. Gray, J. Brahmer, A. Dowlati, J. H. Schiller, M. C. Perry, D. H. Johnson


Background: Platinum-based chemotherapy doublets remain the standard of care for patients with stage IIIb (pleural effusion) & stage IV NSCLC. The results of a randomized phase II trial of PC ± bevacizumab (B) suggested improved activity for PCB compared to PC alone (Johnson, DH et al., JCO, 2004). Gr 5 hemoptysis was seen in the PCB arms; central tumor location & squamous histology were risk factors.

Methods: The primary endpoint was to compare the effects of the addition of B to PC on overall survival in patients (pts) with previously untreated non-squamous NSCLC. Secondary endpoints included response rate, time to progression, & tolerability. Correlative studies included plasma VEGF, VCAM, E-selectin, & basic fibroblast growth factor.

Eligibility criteria: ECOG PS 0 or 1, & adequate hematologic, renal, & hepatic function, no brain metastases. Pts were randomized to receive P 200 mg/m2 + C AUC=6 on day 1 every 3 wks or PC + B 15mg/kg day 1 (PCB) every 3 weeks. Pts on PCB continued B after 6 cycles until progressive disease or intolerable toxicity. With 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 PCB with an overall one-sided type I error of 2.5%.

Results: From 7/01 - 4/04, 444 pts were assigned to PC & 434 to PCB. 14% were stage IIIB. This 2nd planned interim analysis was conducted with 469 of a planned 650 deaths (72.2%) for full analysis. Response rate (10% vs. 27%, p<0.0001); progression-free survival (4.5 mo. vs. 6.4 mo., p<0.0001); & median survival (10.2 mo. vs. 12.5 mo., p = 0.0075) all favoring PCB. Both regimens were well tolerated with selected toxicities: (PC vs. PCB): grade 4/5 neutropenia (16.4% vs. 24%); gr - thrombosis/embolism (3% vs. 3.8%); & hemorrhage (1.0% vs 4.1%). There were 11 treatment-related deaths (arm PC: 2; arm PCB: 9); 5 due to hemoptysis, all on arm B.

Conclusions: The addition of B to PC in pts with NSCLC (non-squamous) provides a statistically & clinically significant survival advantage with tolerable toxicity. PCB is ECOG's new treatment standard in this patient population.