Introduction: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with anti-vascular endothelial growth factor receptor (VEGFR) agents have shown improved survival outcomes in recent studies. However, its efficacy related to survival outcomes as a first- or second-line agent and based on generations remains to be explored. This study estimated the survival outcomes of EGFR-TKIs plus anti-VEGFR in combination in defined populations of advanced non-small cell lung cancer (NSCLC) patients overall, as a first- or second line of treatment, with different generations of EGFR-TKIs and EGFR-TKIs plus bevacizumab combination as a subgroup. Methods: A literature search was conducted using PubMed, SCOPUS, Cochrane Library, and ClinicalTrials.gov databases through June 2023 to identify primary research reporting the survival outcomes of EGFR-TKIs in combination with anti-VEGFR agents in patients with advanced NSCLC. Studies that were single-arm, published in non-English languages, and had missing data on survival outcomes were excluded. A meta-analysis was conducted to generate pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). Methodological quality and risk of bias in studies were assessed using the Cochrane Handbook for Systematic Reviews of Interventions risk of bias tool. Results: A total of 20 randomized controlled trials were included in the qualitative synthesis, and 11 (2182 participants) were included in the meta-analysis. Patients’ median age ranged from 58 to 68 years; 36% to 70% of patients were female; most of them had IIIa/b to IV stage cancer. In meta-analyses, the EGFR-TKIs plus anti-VEGFR combination resulted in improved PFS (HR, 0.73; 95% CI: 0.61, 0.86;p< 0.00001) in patients with advanced NSCLC but had no impact on OS (HR, 0.93; 95% CI: 0.79, 1.10;p= 0.41). The first line of treatment and first-generation EGFR-TKIs with the combination also improved the PFS (HR, 0.64; 95% CI: 0.57, 0.71;p< 0.00001; HR, 0.63; 95% CI: 0.56, 0.71;p< 0.00001) respectively, however, had no impact on OS. Conclusions: Our meta-analysis indicated EGFR-TKIs with anti-VEGFR in combination not only improved overall PFS but also showed similar results to a first line and first-generation agent compared to EGFR-TKI alone.
引言：表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）联合抗血管内皮生长因子受体（VEGFR）药物在近期研究中显示出改善生存结局的效果。然而，其作为一线或二线治疗药物以及基于不同代际的疗效对生存结局的影响仍有待探索。本研究评估了EGFR-TKIs联合抗VEGFR药物在晚期非小细胞肺癌（NSCLC）特定患者群体中的总体生存结局，包括作为一线或二线治疗、使用不同代际EGFR-TKIs的情况，并以EGFR-TKIs联合贝伐珠单抗作为亚组进行分析。方法：通过检索截至2023年6月的PubMed、SCOPUS、Cochrane Library和ClinicalTrials.gov数据库，筛选报告晚期NSCLC患者接受EGFR-TKIs联合抗VEGFR药物治疗生存结局的原始研究。排除单臂研究、非英文发表及生存结局数据缺失的文献。采用荟萃分析计算总生存期（OS）和无进展生存期（PFS）的合并风险比（HR）及95%置信区间（CI）。使用Cochrane干预系统评价手册偏倚风险评估工具对研究方法学质量及偏倚风险进行评估。结果：共20项随机对照试验纳入定性分析，其中11项（2182名受试者）纳入荟萃分析。患者中位年龄58-68岁；女性占比36%-70%；多数患者为IIIa/b至IV期癌症。荟萃分析显示，EGFR-TKIs联合抗VEGFR治疗可改善晚期NSCLC患者的PFS（HR=0.73，95% CI：0.61-0.86，p<0.00001），但对OS无显著影响（HR=0.93，95% CI：0.79-1.10，p=0.41）。一线治疗及第一代EGFR-TKIs联合方案同样显著改善PFS（一线治疗：HR=0.64，95% CI：0.57-0.71，p<0.00001；第一代药物：HR=0.63，95% CI：0.56-0.71，p<0.00001），但均未对OS产生显著影响。结论：本荟萃分析表明，EGFR-TKIs联合抗VEGFR治疗不仅能改善总体PFS，且作为一线治疗及使用第一代药物时，相较于单用EGFR-TKI显示出相似的疗效优势。
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