Immune Checkpoint Inhibitors in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer: A Meta-Analysis Based on Eight Randomized Trials.

Abstract

The efficacy and safety of combination strategies involving immune checkpoint inhibitors (ICIs) in patients with advanced epidermal growth factor receptor (<i>EGFR</i>)-mutant non-small cell lung cancer (NSCLC) who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs) remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ICIs combined with chemotherapy with or without antiangiogenic therapy (C/A) versus C/A alone in the treatment of advanced NSCLC after resistance to EGFR-TKIs. We searched databases, including PubMed, Cochrane Library, Embase, Web of Science, and meeting abstracts. Hazard ratios (HRs) and 95% CI for median overall survival (OS) and median progression-free survival (PFS) were calculated. Risk ratios (RRs) and 95% CI were used as indicators of objective response rate (ORR) and adverse events (AEs). Eight RCTs involving 10 cohorts and 2,269 patients were included. Adding ICIs to C/A significantly improved PFS (HR, 0.67 [95% CI, 0.57 to 0.80]; <i>P</i> < .001), OS (HR, 0.89 [95% CI, 0.79 to 0.99]; <i>P</i> = .031), and ORR (RR, 0.80 [95% CI, 0.74 to 0.88]; <i>P</i> < .001) comparedwith C/A alone. Subgroup analyses showed that the benefits were more pronounced in patients with PD-L1 expression ≥50%, specific <i>EGFR</i> mutations (Leu858Arg), absence of Thr790Met mutation, and treatment with pemetrexed-platinum. No significant increase in grade 3 or higher AEs was observed, but rates of discontinuation and specific AEs (rash, hypothyroidism, and hypertension) were significantly higher in the ICI+C/A group. This meta-analysis suggests that the addition of ICIs to C/A may improve survival outcomes in patients with advanced NSCLC after resistance to EGFR-TKIs, particularly in selected subpopulations such as those with high PD-L1 expression or specific <i>EGFR</i> mutations. However, careful monitoring for specific AEs is warranted.