INTRODUCTION We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel as second-line treatment for small-cell lung cancer (SCLC). METHODS In this double-blind study, patients with relapsed/refractory SCLC were stratified by relapse type (sensitive versus resistant/refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo/paclitaxel (28-day cycles). Primary endpoint was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS 178 patients were enrolled (89 in each arm). Median PFS with alisertib/paclitaxel versus placebo/paclitaxel was 3.32 versus 2.17 months (hazard ratio [HR]: 0.77; 95% CI: 0.557-1.067; p = 0.113 in intent-to-treat population, and HR: 0.71; 95% CI: 0.509-0.985; p = 0.038 applying corrected analysis). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (CDK6/RBL1/ RBL2/RB1) had significantly improved PFS (3.68 versus 1.80 months, HR: 0.395; 95% CI: 0.239-0.654; p = 0.0003) and overall survival (7.20 versus 4.47 months, HR: 0.427; 95% CI: 0.259-0.704; p = 0.00085) with alisertib/paclitaxel versus placebo/paclitaxel. A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. Incidence of grade ≥3 drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve (14%) versus 11 (12%) patients died on-study, including 4 versus 0 treatment-related deaths. CONCLUSIONS Efficacy signals were seen with alisertib/paclitaxel in relapsed/refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

中文翻译：

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紫杉醇加 Alisertib 与紫杉醇加安慰剂作为小细胞肺癌二线治疗的随机 II 期研究：主要和相关生物标志物分析

引言 我们评估了 Aurora A 激酶抑制剂 alisertib 加紫杉醇作为小细胞肺癌 (SCLC) 的二线治疗。方法在这项双盲研究中，复发/难治性 SCLC 患者按复发类型（敏感与耐药/难治）和脑转移进行分层，并按 1:1 随机分配至 alisertib/紫杉醇或安慰剂/紫杉醇（28 天周期）。主要终点是无进展生存期（PFS）。评估了肿瘤组织中 c-Myc 表达（预先指定）和循环肿瘤 DNA 中的遗传改变（回顾性）与临床结果的关联。结果 招募了 178 名患者（每组 89 名）。alisertib/紫杉醇与安慰剂/紫杉醇的中位 PFS 分别为 3.32 个月和 2.17 个月（风险比 [HR]：0.77；95% CI：0.557-1.067；在意向治疗人群中 p = 0.113，HR：0.71；95% CI：0.509-0.985；p = 0.038 应用校正分析）。在 140 名遗传改变患者中，细胞周期调节基因突变 (CDK6/RBL1/RBL2/RB1) 患者的 PFS 显着改善（3.68 个月 vs 1.80 个月，HR：0.395；95% CI：0.239-0.654；p = 0.0003）和总体alisertib/紫杉醇与安慰剂/紫杉醇的生存率（7.20 与 4.47 个月，HR：0.427；95% CI：0.259-0.704；p = 0.00085）。具有 c-Myc 表达的一部分患者显示使用 alisertib/紫杉醇显着改善 PFS。alisertib/紫杉醇组 3 级以上药物相关不良事件的发生率为 67%（58 名患者），而安慰剂/紫杉醇组为 22%（25 名患者）。12 名 (14%) 与 11 名 (12%) 患者在研究中死亡，包括 4 名与 0 名治疗相关死亡。结论 alisertib/紫杉醇在复发/难治性 SCLC 中观察到了疗效信号。细胞周期调节因子中的 c-Myc 表达和突变可能是 alisertib 疗效的潜在预测生物标志物；进一步的前瞻性验证是有必要的。