University of California, Davis Cancer Center, 4501 X St, Suite 3016, Sacramento, CA, USA.
J Clin Oncol. 2011 Aug 1;29(22):2965-71. doi: 10.1200/JCO.2011.35.0660. Epub 2011 Jun 27.
This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone.
Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS).
One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm.
The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.
本三期临床试验旨在检验新型血管破坏剂 ASA404（vadimezan）与一线含铂化疗药物联合应用是否能提高晚期非小细胞肺癌（NSCLC）患者的生存率，与单纯化疗相比。
入组患者为晚期 IIIB 或 IV 期 NSCLC 患者，按性别和肿瘤组织学分层，随机分为 1:1 组，接受紫杉醇（200mg/m2）联合卡铂（曲线下面积 6.0），或联合 ASA404（1800mg/m2），每 3 周静脉给药一次，共 6 个周期，随后进行 ASA404 或安慰剂维持治疗。主要终点为总生存期（OS）；次要终点包括总缓解率（ORR）和无进展生存期（PFS）。
1299 例患者被随机分配。中期分析时因无效而停止试验。最终分析时，ASA404 组（n=649）和安慰剂组（n=650）的 OS 无差异：中位 OS 分别为 13.4 和 12.7 个月（风险比 [HR]，1.01；95%CI，0.85 至 1.19；P=0.535）。同样，在组织学（鳞癌或非鳞癌）和性别（男性或女性）亚组中也未见 OS 差异。两组的中位 PFS 均为 5.5 个月（HR，1.04；P=0.727），ORR 均为 25%（P=1.0）。ASA404 组和安慰剂组的不良事件（AE）总体发生率相当。3/4 级中性粒细胞减少（27%比 19%）和输注部位疼痛（10%比 0.5%）在 ASA404 组更为常见。
尽管 ASA404 联合卡铂和紫杉醇耐受性良好，但未能提高晚期 NSCLC 的一线疗效。
