In L858R-mutated NSCLC, ICI combinations improve progression-free survival versus chemotherapy in TKI-resistant patients.

The application of immune checkpoint inhibitors (ICIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following tyrosine kinase inhibitor (TKI) resistance remains controversial. Prior studies often obscured immunobiological heterogeneity by analyzing exon 19 deletions and L858R mutations in aggregate. This study conducts the first meta-analysis specifically focusing on the EGFR L858R subtype to systematically evaluate ICI efficacy (monotherapy vs. combinations) in the post-TKI setting. We systematically searched PubMed, EMBASE, Cochrane, and Web of Science (up to January 1, 2026) for studies on ICI-treated EGFR-mutated NSCLC. Prospective or retrospective studies explicitly reporting L858R data were selected. Primary endpoints included progression-free survival (PFS) and objective response rate (ORR); the secondary endpoint was overall survival (OS). Given that our meta-analysis includes both randomized controlled trials and single-arm studies, we explicitly stratified analyses by study design. RCTs provide comparative estimates, whereas single-arm studies are descriptive and exploratory; pooled results from single-arm studies should not be interpreted as definitive evidence of efficacy. Pooled hazard ratios (HRs) were calculated using a random-effects model, stratified by treatment modality. Seventeen studies involving 1, 154 patients were included. Compared with chemotherapy, ICI-based treatments significantly improved PFS [HR = 0.63, 95% confidence intervals (CI):0.44-0.90, P = 0.01]. Subgroup analysis revealed significant disparities: ICI monotherapy failed to confer a PFS benefit (HR = 1.68, 95% CI:0.94-2.99, P = 0.08), whereas combination therapies were effective. Exploratory analyses from non-comparative single-arm studies supported these trends, showing higher ORR and PFS for combination regimens than for monotherapy. Notably, the “ICI plus anti-angiogenic agents plus chemotherapy” regimen exhibited the optimal PFS benefit (HR = 0.50, P For EGFR-TKI-resistant, L858R-mutated NSCLC, ICI monotherapy appears ineffective. Conversely, ICI-based combinations—particularly the four-drug regimen incorporating anti-angiogenic agents—significantly delay disease progression and improve response rates. Future research should prioritize prospective studies and novel agents, such as antibody-drug conjugates, to improve long-term survival. https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420261278330.