Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer The SELECT-1 Randomized Clinical Trial
Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer The SELECT-1 Randomized Clinical Trial
复制标题
DOI：
10.1001/jama.2017.3438
复制
发表时间：
2017-05-09
影响因子：
120.7
通讯作者：
Vansteenkiste, Johan
中科院分区：
文献类型：
--
作者：
Janne, Pasi A.;van den Heuvel, Michel M.;Vansteenkiste, Johan
重要提示目前尚无专门批准的针对最常见的基因组定义的非小细胞肺癌（NSCLC）亚组KRAS突变型肺癌的靶向治疗。目的比较丝裂原活化蛋白激酶激酶（MEK）抑制剂司美替尼+多西他赛与多西他赛单药作为晚期KRAS突变型NSCLC二线治疗的疗效。2013年10月至2016年1月在25个国家的202个研究中心进行的随机临床试验。在3323例一线抗癌治疗后疾病进展的晚期NSCLC患者中，866例入组，510例随机分组。排除的主要原因是不合格。数据分析的截止日期为2016年6月7日。干预患者按1：1的比例随机分组，254例接受司美替尼+多西他赛治疗，256例接受安慰剂+多西他赛治疗。次要终点包括总生存率、客观缓解率、缓解持续时间、对疾病相关症状的影响、安全性和耐受性。（平均年龄61.4岁[SD，8.3];女性207例[41%]），505例患者（99%）接受治疗并完成研究（251例接受司美替尼+多西他赛; 254例接受安慰剂+多西他赛）。在数据截止时，447例患者（88%）发生了进展事件，346例患者（68%）死亡。司美替尼+多西他赛组的中位无进展生存期为3.9个月（四分位距[IQR]，1.5-5.9），安慰剂+多西他赛组为2.8个月（IQR，1.4-5.5）（差异为1.1个月;风险比[HR]，0.93 [95%CI，0.77-1.12]; P = 0.44）。司美替尼+多西他赛组的中位总生存期为8.7个月（IQR，3.6-16.8），安慰剂+多西他赛组为7.9个月（IQR，3.8-20.1）（差异为0.9个月; HR，1.05 [95%CI，0.85-1.30]; P = 0.64）。司美替尼+多西他赛组的客观缓解率为20.1%，安慰剂+多西他赛组为13.7%（差异为6.4%;比值比为1.61 [95%CI，1.00-2.62]; P = 0.05）。司美替尼+多西他赛的中位缓解持续时间为2.9个月（IQR，1.7-4.8; 95% CI，2.7-4.1），安慰剂+多西他赛为4.5个月（IQR，2.3-7.3; 95% CI，2.8-5.6）。司美替尼+多西他赛组3级或以上不良事件更常见（司美替尼+多西他赛组169例不良事件[67%] vs安慰剂+多西他赛组115例不良事件[45%];结论和相关性在既往接受过治疗的晚期KRAS突变型非小细胞肺癌患者中，与多西他赛单药治疗相比，多西他赛加用司美替尼不能改善无进展生存期。
IMPORTANCEThere are no specifically approved targeted therapies for the most common genomically defined subset of non-small cell lung cancer (NSCLC), KRAS-mutant lung cancer.OBJECTIVE To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC.DESIGN, SETTING, AND PARTICIPANTS Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016.INTERVENTIONS Patients were randomized 1: 1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel.MAIN OUTCOMES AND MEASURES Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability.RESULTS Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12]; P =.44). Median overall survivalwas 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30]; P =.64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62]; P =.05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%).CONCLUSIONS AND RELEVANCE Among patients with previously treated advanced KRAS-mutant non-small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone.