一线EGFR-TKIs联合血管生成抑制剂治疗晚期EGFR突变非小细胞肺癌的疗效分析

Efficacy analysis of first-line EGFR-TKIs combined with angiogenesis inhibitors in the treatment of advanced EGFR mutated non-small cell lung cancer

目的:比较一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)联合血管生成抑制剂对比EGFR-TKIs单药治疗晚期EGFR突变非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效和安全性。方法:对PubMed、Embase、Web of Science和Cochrane Library数据库以及欧洲医学肿瘤学会(ESMO)、美国临床肿瘤学会(ASCO)中会议摘要进行了全面的文献检索。检索时间截止至2020年11月13日。使用STATA V.14.0对相关数据进行统计分析。结果:本meta共纳入6个II/III期RCTs(11篇文章),包括1537例符合分析条件的NSCLC患者。结果表明,与EGFR-TKIs单药组相比,联合血管生成抑制剂组患者的无进展生存期(progression-free survival,PFS)显著延长(HR=0.62,95%CI 0.54~0.70,P<0.001)。然而,联合治疗并不能改善患者的总生存期(overall survival,OS)(P=0.536)、客观缓解率(objective response rate,ORR)(P=0.186)和疾病控制率(disease control rate,DCR)(P=0.918)。联合治疗组发生grade3+不良事件(RR=1.80,95%CI 1.46~2.22,P<0.001)和严重不良事件(RR=1.48,95%CI 1.22~1.81,P<0.001)的风险较EGFR-TKIs单药组增加。其中联合治疗组患者蛋白尿、高血压和腹泻的发生显著增加。此外,亚组分析结果表明,联合治疗组中Ex19del(HR=0.62,95%CI 0.51~0.75,P<0.001)和Leu858Arg(HR=0.62,95%CI 0.51~0.75,P<0.001)突变的NSCLC患者获益相当。结论:一线EGFR-TKIs联合血管生成抑制剂可以显著延长晚期EGFR突变NSCLC患者的PFS。尽管联合组不良反应发生率增加,但毒性尚可耐受和管理。联合治疗可作为晚期EGFR突变NSCLC患者一线选择。

up to November 13,2020.STATA version 14.0 was used for statistical tests.Results:There were six phase II/III randomized controlled trails(RCTs)from 11 articles,encompassing 1537 patients eligible for meta-analysis.The results suggested that EGFR-TKIs plus angiogenesis inhibitors had remarkably prolonged progression-free survival(PFS)[hazard ratio(HR)=0.62,95%confidence interval(CI)0.54~0.70,P<0.001].However,the combination group failed to improve overall survival(OS)(P=0.536),objective response rate(ORR)(P=0.186),and disease control rate(DCR)(P=0.918).The risk of overall grade 3 or higher adverse events[risk ratio(RR)=1.80,95%CI 1.46~2.22,P<0.001]and serious adverse events(RR=1.48,95%CI 1.22~1.81,P<0.001)were significantly increased in the combination group.Among them,the incidence of proteinuria,hypertension and diarrhea in the combination group was significantly increased.In addition,subgroup analysis showed that patients with exon 19 deletions(HR=0.62,95%CI 0.51~0.75,P<0.001)and exon 21 Leu858Arg mutation(HR=0.62,95%CI 0.51~0.75,P<0.001)had similar benefits in the combination group.Conclusion:EGFR-TKIs plus angiogenesis inhibitors as the first-line treatment can prolong PFS of advanced NSCLC patients with EGFR mutations.Although the incidence of AEs in the combination group increased,the toxicity could be tolerable and manageable.Thus,the combination therapy can be used as the first-line option for advanced patients with EGFR mutations.