A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study)
A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study)
复制标题
DOI：
10.1093/annonc/mdv288
复制
发表时间：
2015-10-01
影响因子：
50.5
通讯作者：
Nakagawa, K.
中科院分区：
文献类型：
--
作者：
Yoshioka, H.;Azuma, K.;Nakagawa, K.
背景资料：先前的一项随机II期研究表明，在表皮生长因子受体（EGFR）酪氨酸激酶抑制剂厄洛替尼的基础上添加c-Met抑制剂tivantinib可能会延长既往接受过治疗的非鳞状非小细胞肺癌（NSCLC）患者的无进展生存期（PFS）。在亚组分析中，野生型EGFR（WT-EGFR）患者的生存获益大于EGFR激活突变患者。在此，本III期研究比较了接受厄洛替尼加tivantinib（tivantinib组）或厄洛替尼加安慰剂（安慰剂组）的WT-EGFR的亚洲非鳞状NSCLC患者的总生存期（OS）。主要终点为OS，次要终点为PFS、肿瘤缓解和安全性。收集组织进行生物标志物分析，包括c-Met和HGF expression.Results：招募停止时，307例患者被随机分组，以下安全审查委员会的建议，基于组间间质性肺病（ILD）的发病率不平衡。tivantinib组和安慰剂组分别有14例患者（3例死亡）和6例患者（0例死亡）发生ILD。在入组患者中，tivantinib组和安慰剂组的中位OS分别为12.7和11.1个月[风险比（HR）= 0.891，P = 0.427]。tivantinib组和安慰剂组的中位PFS分别为2.9和2.0个月（HR = 0.719，P = 0.019）。tivantinib组中常见的≥ 3级不良事件为中性粒细胞减少（24.3%）、白细胞减少（18.4%）、发热性中性粒细胞减少（13.8%）和贫血（13.2%）。结论：由于tivantinib组ILD发生率增加，本研究提前终止。尽管这项研究由于提前终止而缺乏统计学把握度，并且没有证明OS的改善，但我们的结果表明，在携带WT-EGFR的非鳞状NSCLC患者中，tivantinib联合厄洛替尼可能比厄洛替尼单药改善PFS。
Background: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group).Methods: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression.Results: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade >= 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%).Conclusions: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR.