Background Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. Results A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. Conclusion The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. Trial identifier Clinicaltrials.gov NCT01750281.

中文翻译：

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SELECT-2：一项 II 期、双盲、随机、安慰剂对照研究，旨在评估司美替尼联合多西他赛作为晚期或转移性非小细胞肺癌患者二线治疗的疗效。

背景 在之前的一项针对 KRAS 突变晚期非小细胞肺癌 (NSCLC) 患者的 II 期试验中，司美替尼联合多西他赛提供了临床益处。II 期 SELECT-2 试验调查了司美替尼联合多西他赛治疗晚期或转移性 NSCLC 患者的安全性和有效性。患者和方法 一线抗癌治疗后疾病进展的患者被随机分配（2:2:1）接受 selumetinib 75 mg bid 加多西他赛 60 或 75 mg/m2（SEL + DOC 60；SEL + DOC 75），或安慰剂加多西他赛 75 mg/m2 (PBO + DOC 75)。患者最初是独立于 KRAS 突变状态入组的，但该方案被修改为仅包括中央证实的 KRAS 野生型 NSCLC 患者。主要终点是无进展生存期（PFS；RECIST 1.1）；统计分析比较了每个 selumetinib 组与 PBO + DOC 75 的 KRAS 野生型和总体（KRAS 突变体或野生型）群体。结果共有212例患者被随机分组​​；69% 是 KRAS 野生型。与 PBO + DOC 75 相比，任一 selumetinib 组的总体或 KRAS 野生型人群的 PFS 或总生存期均无统计学意义的改善。与 PBO + DOC 75 相比，SEL + DOC 60、SEL + DOC 75 的总体人群中位 PFS分别为 3.0、4.2 和 4.3 个月，HRs：1.12 (90% CI: 0.8, 1.61) 和 0.92 (90% CI: 0.65, 1.31)。在总体人群中，与 PBO + DOC 75 (14%) 相比，SEL + DOC 75 (33%) 的客观缓解率 (ORR；研究者评估) 更高；优势比：3.26（90% CI：1.47, 7.95）。总体而言，SEL + DOC 的耐受性概况与历史数据一致，未发现新的或意外的安全问题。结论未达到主要终点（PFS）。SEL + DOC 75 的较高 ORR 并未转化为整体或 KRAS 野生型患者群体的 PFS 延长。与单独使用多西紫杉醇相比，在 KRAS 野生型患者中使用 SEL + DOC 未观察到临床益处。没有报告意外的安全问题。试验标识符 Clinicaltrials.gov NCT01750281。与单独使用多西紫杉醇相比，在 KRAS 野生型患者中使用 SEL + DOC 未观察到临床益处。没有报告意外的安全问题。试验标识符 Clinicaltrials.gov NCT01750281。与单独使用多西紫杉醇相比，在 KRAS 野生型患者中使用 SEL + DOC 未观察到临床益处。没有报告意外的安全问题。试验标识符 Clinicaltrials.gov NCT01750281。