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Abstract：
Background: The synergistic effects of antiangiogenic inhibitor bevacizumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) therapy were encouraging in patients with EGFR-mutant advanced NSCLC, though some controversy remains. The specific subgroup of patients who might benefit most from the EGFR-TKI and bevacizumab combination therapy is yet to be determined. Methods: Randomized clinical trials (RCTs) that had compared the clinical efficacy of EGFR-TKI and bevacizumab combination therapy with EGFR-TKI monotherapy in treating EGFR-mutant advanced NSCLC patients published before 23 December 2022 were searched in the Cochrane, PubMed and Embase. We performed a meta-analysis for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events with a grade equal or more than 3 (grade≥3 TRAEs). Subgroup analyses of PFS and OS stratified by clinical characteristics and treatment were conducted. Results: We included 10 RCTs involving 1520 patients. Compared with EGFR-TKI monotherapy, addition of bevacizumab to EGFR-TKI resulted in a significantly higher PFS (hazard ratio (HR) = 0.74, 95% confidence interval (95% CI): 0.62-0.87)) and ORR (risk ratio (RR) = 1.07, 95% CI: 1.01-1.13). However, no significant difference in OS (HR = 0.96, 95% CI: 0.83-1.12) was noticed. Patients with EGFR-mutant advanced NSCLC receiving combination therapy showed PFS improvement regardless of gender (male or female), Eastern Cooperative Oncology Group performance status (0 or 1), baseline central nervous system (CNS) metastasis (presence or absence) and EGFR mutation type (19del or 21L858R). Subgroup analyses showed that, with the treatment of bevacizumab and EGFR-TKI, patients who ever smoked achieved significantly better OS and PFS benefits (HR = 0.68, 95% CI: 0.48-0.95; HR = 0.59, 95% CI: 0.46-0.74, respectively), and those aged <75 years and the Asian population had significantly prolonged PFS (HR = 0.69, 95% CI: 0.52-0.91; HR = 0.71, 95% CI: 0.58-0.87; respectively). The superiority of EGFR-TKI and bevacizumab combination therapy against EGFR-TKI monotherapy in improving PFS was more significant in the erlotinib regimen subgroup. The risk of grade≥3 TRAEs was remarkably higher in the combination therapy group (HR = 1.73, 95% CI: 1.39-2.16). Conclusion: Addition of bevacizumab to EGFR-TKI therapy provided significantly better PFS and ORR for EGFR-mutant advanced NSCLC patients, though with higher risk of grade≥3 TRAEs. Patients who ever smoked, aged <75 years, and Asian population might benefit more from the combination regimen. Systematic Review Registration: This systematic review and meta-analysis was registered in the PROSPERO database (CRD42023401926).
摘要：
背景：抗血管生成抑制剂贝伐单抗和表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）治疗在EGFR突变的晚期NSCLC患者中的协同作用令人鼓舞。尽管仍有一些争议。可能从EGFR-TKI和贝伐单抗联合治疗中受益最大的患者的具体亚组尚未确定。方法：在Cochrane上搜索了在2022年12月23日之前发表的比较EGFR-TKI和贝伐单抗联合治疗与EGFR-TKI单药治疗EGFR突变型晚期NSCLC患者的临床疗效的随机临床试验（RCT）。PubMed和Embase。我们对总生存期(OS)进行了荟萃分析，无进展生存期（PFS），客观反应率（ORR），和治疗相关的不良事件，其等级等于或大于3级（≥3级TRAEs）。根据临床特征和治疗进行PFS和OS的亚组分析。结果：我们纳入了10个RCTs，涉及1520例患者。与EGFR-TKI单药治疗相比，在EGFR-TKI中加入贝伐单抗可显著提高PFS(风险比(HR)=0.74,95%置信区间(95%CI):0.62~0.87)和ORR(风险比(RR)=1.07,95%CI:1.01~1.13).然而,OS无显著差异(HR=0.96,95%CI:0.83-1.12)。EGFR突变的晚期NSCLC患者接受联合治疗后，无论性别（男性或女性）均显示PFS改善。东部肿瘤协作组的表现状态（0或1），基线中枢神经系统（CNS）转移（存在或不存在）和EGFR突变类型（19del或21L858R）。亚组分析显示，贝伐单抗和EGFR-TKI治疗，曾经吸烟的患者获得了明显更好的OS和PFS益处（HR=0.68，95％CI：0.48-0.95；HR=0.59，95％CI：0.46-0.74），年龄<75岁和亚洲人群的PFS显着延长（分别为HR=0.69，95％CI：0.52-0.91；HR=0.71，95％CI：0.58-0.87）。EGFR-TKI和贝伐单抗联合治疗对EGFR-TKI单药治疗改善PFS的优越性在厄洛替尼方案亚组中更为显著。在联合治疗组中，≥3级TRAE的风险明显更高（HR=1.73，95％CI：1.39-2.16）。结论：贝伐单抗联合EGFR-TKI治疗对EGFR突变型晚期NSCLC患者的PFS和ORR显著改善。尽管具有更高的≥3级TRAE风险。曾经吸烟的病人，年龄<75岁，亚洲人群可能从联合治疗方案中获益更多。系统评价注册：该系统评价和荟萃分析已在PROSPERO数据库（CRD42023401926）中注册。
