A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)
A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)
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DOI：
10.1093/annonc/mdv072
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发表时间：
2015-05-01
影响因子：
50.5
通讯作者：
Jaenne, P. A.
中科院分区：
文献类型：
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作者：
Blumenschein, G. R., Jr.;Smit, E. F.;Jaenne, P. A.
背景：25% 的非小细胞肺癌 (NSCLC) 中检测到 KRAS 突变，并且尚未批准针对该亚群的靶向治疗。 Trametinib 是 MEK1/MEK2 的选择性变构抑制剂，在 KRAS 突变 NSCLC 中表现出临床前和临床活性。我们报告了一项在晚期 KRAS 突变 NSCLC 患者中比较曲美替尼与多西他赛的 II 期试验。 患者和方法：先前接受过一种铂类化疗且经组织学证实的 KRAS 突变 NSCLC 的合格患者以 2:1 的比例随机分配至曲美替尼（每天一次口服 2 mg）或多西他赛（每 3 周静脉注射 75 mg/m(2)）。允许疾病进展后交叉至另一臂。主要终点是无进展生存期（PFS）。该研究在对 92 例 PFS 事件进行中期分析后提前终止，结果显示曲美替尼与多西他赛对 PFS 的比较跨越了无效界限。 结果：129 名 KRAS 突变 NSCLC 患者被随机分组；其中，86名患者接受曲美替尼治疗，43名患者接受多西他赛治疗。曲美替尼组的中位 PFS 为 12 周，多西他赛组为 11 周（风险比 [HR] 1.14；95% CI 0.75-1.75；P = 0.5197）。虽然数据尚不成熟，但曲美替尼组的中位总生存期为 8 个月，而多西他赛组未达到（HR 0.97；95% CI 0.52-1.83；P = 0.934）。曲美替尼组有 10 例 (12%) 部分缓解 (PR)，多西他赛组有 5 例 (12%) 部分缓解 (P = 1.0000)。 ≥ 20% 的曲美替尼患者中最常见的不良事件 (AE) 是皮疹、腹泻、恶心、呕吐和疲劳。 Trametinib 组中最常见的 3 级治疗相关 AE 是高血压、皮疹、腹泻和乏力。结论：在既往接受过 KRAS 突变阳性 NSCLC 治疗的患者中，Trametinib 显示出与多西他赛相似的 PFS 和缓解率。
Background: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.Patients and methods: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2:1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.Results: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in >= 20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.Conclusion: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.