一项随机、双盲、安慰剂对照、III 期临床试验，评估厄洛替尼联合或不联合 c-Met 抑制剂替沃扎尼（ARQ 197）治疗既往治疗过的 IIIB/IV 期非鳞状非小细胞肺癌且携带野生型表皮生长因子受体的亚洲患者（ATTENTION 研究）。
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).
机构信息
Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki
Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume.
出版信息
Ann Oncol. 2015 Oct;26(10):2066-72. doi: 10.1093/annonc/mdv288. Epub 2015 Jul 7.
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.
TRIAL REGISTRATION NUMBER
NCT01377376.
背景
一项先前的随机 II 期研究表明，在先前接受过治疗的非鳞状非小细胞肺癌（NSCLC）患者中，表皮生长因子受体（EGFR）酪氨酸激酶抑制剂厄洛替尼联合 c-Met 抑制剂替沃替尼可延长无进展生存期（PFS）。在亚组分析中，野生型 EGFR（WT-EGFR）患者的生存获益大于激活型 EGFR 突变患者。在此，这项 III 期研究比较了接受厄洛替尼联合替沃替尼（替沃替尼组）或厄洛替尼联合安慰剂（安慰剂组）的亚洲非鳞状 NSCLC 患者中 WT-EGFR 患者的总生存期（OS）。
方法
计划招募 460 名 NSCLC 患者随机分配至替沃替尼或安慰剂组。主要终点为 OS。次要终点为 PFS、肿瘤反应和安全性。采集组织进行生物标志物分析，包括 c-Met 和 HGF 表达。
结果
在 307 名患者随机分组后，根据安全审查委员会基于两组间间质性肺病（ILD）发生率的不平衡建议停止入组。替沃替尼组有 14 例（3 例死亡）和安慰剂组有 6 例（0 例死亡）发生ILD。在入组患者中，替沃替尼组和安慰剂组的中位 OS 分别为 12.7 个月和 11.1 个月[风险比（HR）=0.891，P=0.427]。替沃替尼组和安慰剂组的中位 PFS 分别为 2.9 个月和 2.0 个月（HR=0.719，P=0.019）。替沃替尼组常见的≥3 级不良事件为中性粒细胞减少症（24.3%）、白细胞减少症（18.4%）、发热性中性粒细胞减少症（13.8%）和贫血（13.2%）。
结论
由于替沃替尼组 ILD 发生率增加，该研究提前终止。尽管由于提前终止，本研究缺乏统计学效力且未显示 OS 改善，但我们的结果表明，替沃替尼联合厄洛替尼可能改善 WT-EGFR 非鳞状 NSCLC 患者的 PFS，优于厄洛替尼单药治疗。
试验注册号
NCT01377376。
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