免疫检查点抑制剂治疗非小细胞肺癌患者有效性及安全性的Meta分析

Efficacy and safety of immune checkpoint inhibitors in the treatment of non-small cell lung cancer: a Meta-analysis

目的:评价程序性细胞死亡蛋白1(programmed cell death protein-1,PD-1)以及程序性细胞死亡蛋白配体1(programmed cell death protein ligand 1,PD-L1)免疫治疗ⅢB/Ⅳ期及复发进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的有效性和安全性。方法:计算机检索PubMed、EMbase、e Cochrane Library和Web of Science数据库,对PD-1/PD-L1免疫治疗ⅢB/Ⅳ期及复发进展期NSCLC患者的有效性和安全性,以及与患者肿瘤细胞中PD-L1表达水平、性别、年龄、病理类型、吸烟状态、表皮生长因子受体(epidermal growth factor receptor,EGFR)及K-ras突变状态间的关系进行Meta分析。结果:共纳入8项随机对照试验(randomized controlled trial,RCT),4 207例ⅢB/Ⅳ期及复发进展期NSCLC患者。Meta分析结果显示,PD-1/PD-L1免疫治疗组的客观缓解率(objective response rate,ORR)[相对危险度(relative risk,RR)=1.30,95%可信区间(condence interval,CI):1.02～1.67,P=0.04]、无进展生存期(progression-free survival,PFS)[风险比(hazard ratio,HR)=0.83,95%CI:0.72～0.97,P=0.02]和总生存期(overall survival,OS)(HR=0.72,95%CI:0.66～0.78,P<0.000 01)均高于或长于化疗组。亚组分析结果表明,肿瘤细胞中PD-L1表达水平大于50%(HR=0.58,95%CI:0.44～0.76,P=0.000 1)、有吸烟史(HR=0.72,95%CI:0.58～0.88,P=0.001)、EGFR野生型(HR=0.67,95%CI:0.60～0.75,P<0.001)及K-ras突变型(HR=0.65,95%CI:0.43～0.97,P=0.03)患者免疫治疗更能延长OS。免疫治疗组总的治疗相关不良反应事件发生率低于化疗组(RR=0.80,95%CI:0.76～0.85,P<0.000 01)。结论:PD-1/PD-L1免疫治疗ⅢB/Ⅳ期及复发进展期NSCLC患者较化疗有更好的疗效,肿瘤细胞中PD-L1表达水平高、有吸烟史、EGFR野生型及K-ras突变型患者更能在免疫治疗中生存获益。

Objective： To evaluate the efficacy and safety of programmed cell death protein-1（PD-1） and programmed cell death protein ligand 1（PD-L1） immunotherapy for the patients with recurrent and advanced（stage ⅢB/Ⅳ） non-small cell lung cancer（NSCLC）.Methods： Electronic databases including Pub Med, EMbase, The Cochrane Library and Web of Science were searched. The Meta-analysis was conducted to analyze the efficacy and safety of PD-1/PD-L1 immunotherapy as well as its relationships with PD-L1 expression level, gender, age, pathological type, smoking status, epidermal growth factor receptor（EGFR） and K-ras mutation status in the patients with recurrent and advanced（stage ⅢB/Ⅳ） NSCLC.Results： A total of 8 randomized controlled trials（RCTs） and 4 207 patients with recurrent and advanced（stage ⅢB/Ⅳ） NSCLC were enrolled. Meta-analysis showed that the objective response rate（ORR） [relative risk（RR） = 1.30, 95% confidence interval（CI）： 1.02-1.67, P = 0.04], progression-free survival（PFS） [hazard ratio（HR） = 0.83,95% CI： 0.72-0.97, P = 0.02] and overall survival（OS）（HR = 0.72, 95% CI： 0.66-0.78, P〈0.000 01） of patients in PD-1/PD-L1 immunotherapy group were higher or longer than those in chemotherapy group. Subgroup analysis showed that the patients with high expression level of PD-L1（more than 50%）（HR = 0.58, 95% CI： 0.44-0.76, P = 0.000 1）, smoking history（HR = 0.72, 95% CI： 0.58-0.88, P = 0.001）, EGFR wild type（HR = 0.67, 95% CI： 0.60-0.75, P〈0.001） and K-ras mutation（HR = 0.65, 95% CI ： 0.43-0.97, P = 0.03） in immunotherapy group achieved significant benefits in improving OS. The rate of total treatment-related adverse effects in immunotherapy group was lower than that in chemotherapy group（RR = 0.80, 95% CI： 0.76-0.85, P〈0.000 01）.Conclusion： PD-1/PD-L1 immunotherapy is more effective than chemotherapy in the treatment of patients with recurrent and advanced（stage ⅢB/Ⅳ） NSCLC. The patients who have higher expression level of PD-L1 in tumor cells, smoking history, EGFR wild type and K-ras mutation may achieve significant survival benefits.