背景:在酪氨酸激酶抑制剂(TKI)耐药的化疗中添加免疫检查点抑制剂的作用,表皮生长因子受体(EGFR)突变型非小细胞肺癌(NSCLC)仍未知.我们进行了一项荟萃分析,以全面评估化学免疫疗法组合的作用,有或没有血管内皮生长因子(VEGF)抑制,在抗TKI中,EGFR突变非小细胞肺癌。
方法:我们系统地搜索了PubMed/MEDLINE和2018年至2024年之间的重要年度会议的会议记录,以确定评估化学免疫疗法组合并包括EGFR突变NSCLC患者的随机研究。六个随机,III期试验(CheckMate-722,KEYNOTE-789,ORIENT-31,IMpower150,IMpower151和ATTLAS)纳入荟萃分析.比较无进展生存期(PFS)和总生存期(OS)结局,我们从每项研究中提取了EGFR突变亚组的PFS和OS的风险比(HR)和95%置信区间(CI).我们使用具有逆方差加权的固定效应模型来估计化学免疫疗法组合(有和没有VEGF抑制剂)与对照组的PFS和OS的总体效应大小。
结果:共纳入1772例EGFR突变型NSCLC患者。在化疗中加入程序性死亡配体1[PD-(L)1]抑制剂可显著改善PFS(HR0.77,95%CI0.67-0.88,P=0.0002)。当同时利用PD-(L)1和VEGF抑制时,这种效果更大(PFS:HR0.62,95%CI0.52-0.73,P<0.0001)。化疗+PD-(L)1组合的合并OSHR为0.86(95%CI0.75-1.00,P=0.0429),PD-(L)1/VEGF双重抑制的合并OSHR为0.98(95%CI0.79-1.22,P=0.8463)。
结论:尽管PFS有所改善,当将PD-(L)1和VEGF抑制剂添加到化疗中时,最明显,两种策略均未导致OS的临床上有意义的改善.我们的结果不支持在TKI耐药中广泛使用化学免疫疗法组合,EGFR突变肺癌。癌基因驱动的NSCLC迫切需要新的免疫治疗方法。
BACKGROUND: The role of adding immune checkpoint inhibitors to chemotherapy in tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) remains unknown. We carried out a meta-analysis to comprehensively assess the role of
chemoimmunotherapy combinations, with and without vascular endothelial growth factor (VEGF) inhibition, in TKI-resistant, EGFR-mutant NSCLC.
METHODS: We systemically searched PubMed/MEDLINE and the proceedings of key annual meetings between 2018 and 2024 to identify randomized studies that evaluated
chemoimmunotherapy combinations and included patients with EGFR-mutant NSCLC. Six randomized, phase III trials (CheckMate-722, KEYNOTE-789, ORIENT-31, IMpower150, IMpower151, and ATTLAS) were included in the meta-analysis. To compare progression-free survival (PFS) and overall survival (OS) outcomes, we extracted hazard ratio (HR) and 95% confidence interval (CI) for PFS and OS for EGFR-mutant subgroups from each study. We used the fixed effects model with inverse variance weighting to estimate the overall effect sizes for PFS and OS for
chemoimmunotherapy combinations (with and without VEGF inhibitors) versus control arms.
RESULTS: A total of 1772 patients with EGFR-mutant NSCLC were included. Adding programmed death-ligand 1 [PD-(L)1] inhibitors to chemotherapy significantly improved PFS (HR 0.77, 95% CI 0.67-0.88, P = 0.0002). This effect was greater when both PD-(L)1 and VEGF inhibition were utilized (PFS: HR 0.62, 95% CI 0.52-0.73, P < 0.0001). The pooled OS HR was 0.86 (95% CI 0.75-1.00, P = 0.0429) with the chemotherapy + PD-(L)1 combinations and 0.98 (95% CI 0.79-1.22, P = 0.8463) with dual PD-(L)1/VEGF inhibition.
CONCLUSIONS: Despite modest improvements in PFS, most pronounced when both PD-(L)1 and VEGF inhibitors are added to chemotherapy, neither strategy led to clinically meaningful improvements in OS. Our results do not support the broad use of
chemoimmunotherapy combinations in TKI-resistant, EGFR-mutant lung cancer. Novel immunotherapy approaches are urgently needed for oncogene-driven NSCLC.