SELECT-2 研究：一项评估 selumetinib 联合多西他赛二线治疗晚期或转移性非小细胞肺癌患者的疗效的 II 期、双盲、随机、安慰剂对照研究。
SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer.
机构信息
Department of Medical Oncology, Gustave Roussy, Villejuif, France.
Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf (M.R.), Germany.
出版信息
Ann Oncol. 2017 Dec 1;28(12):3028-3036. doi: 10.1093/annonc/mdx628.
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.
背景
在先前的 II 期试验中，塞来替尼联合多西他赛为 KRAS 突变型晚期非小细胞肺癌（NSCLC）患者提供了临床获益。II 期 SELECT-2 试验研究了塞来替尼联合多西他赛治疗晚期或转移性 NSCLC 患者的安全性和疗效。
患者和方法
在一线抗癌治疗后疾病进展的患者被随机（2：2：1）分为塞来替尼 75mg，bid 加多西他赛 60 或 75mg/m2（SEL+DOC 60；SEL+DOC 75）或安慰剂加多西他赛 75mg/m2（PBO+DOC 75）。最初，患者独立于 KRAS 突变状态入组，但方案修订仅包括经中心确认的 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塞来替尼组与 PBO+DOC 75 用于 KRAS 野生型和总体（KRAS 突变或野生型）人群的结果。
结果
共有 212 名患者被随机分组；69%为 KRAS 野生型。与 PBO+DOC 75 相比，SEL+DOC 60 或 SEL+DOC 75 组在总体或 KRAS 野生型人群中均未观察到 PFS 或总生存期的统计学显著改善。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，HR：1.12（90%CI：0.8，1.61）和 0.92（90%CI：0.65，1.31）。在总体人群中，SEL+DOC 75 的客观缓解率（研究者评估）较高（33%），与 PBO+DOC 75（14%）相比；优势比：3.26（90%CI：1.47，7.95）。总体而言，SEL+DOC 的耐受性特征与历史数据一致，未发现新的或意外的安全性问题。
结论
主要终点（PFS）未达到。SEL+DOC 75 较高的客观缓解率并未转化为总体或 KRAS 野生型患者人群的 PFS 延长。与单独多西他赛相比，SEL+DOC 在 KRAS 野生型患者中未观察到临床获益。未报告意外的安全性问题。
试验标识符
Clinicaltrials.gov NCT01750281。
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