Abstract Rationale Immune checkpoint inhibitors (ICIs; anti-programmed death-1/programmed death-ligand-1 PD-1/PD-L1 therapy) demonstrate limited benefit in epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after tyrosine kinase inhibitor (TKI; e.g., osimertinib) progression. Biologic features—including low tumor mutational burden, an immune-”cold” microenvironment, and EGFR-driven hyperprogression—suggest inferior response and higher toxicity, particularly pneumonitis. A quantitative synthesis across randomized trials and real-world cohorts is needed to clarify clinical outcomes in this post-TKI population. Methods We performed a systematic review (PubMed, ClinicalTrials.gov, ASCO/ESMO/ATS 2015-2025) including phase III randomized controlled trials (RCTs) and real-world observational cohorts evaluating ICI monotherapy or ICI-combination regimens in EGFRm (exon 19 deletion, L858R, or uncommon variants) advanced NSCLC after TKI progression. Comparators were platinum-doublet chemotherapy or chemo-immunotherapy. Random-effects meta-analysis (REML) pooled log hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and logit-transformed pneumonitis incidence with prediction intervals (PI). Subgroups (PD-L1 expression, mutation subtype, smoking status) were explored via meta-regression. Study quality was evaluated descriptively based on study design, sample size, and completeness of reported outcomes. Results Ten datasets (5 phase III RCTs; 5 prospective/retrospective cohorts; N = 8,124) met inclusion criteria. Progression-Free Survival ICIs showed no PFS benefit compared with chemotherapy (pooled HR 1.07; 95% CI 0.92-1.25; I²=72%). No subgroup—exon 19 deletion, L858R, PD-L1 ≥50%, never-smokers, or prior osimertinib—demonstrated benefit (p 0.10). Overall Survival OS was not improved (HR 1.14; 95% CI 0.96-1.35; I²=85%). Heterogeneity reflected monotherapy vs. combination regimens and variable post-progression TKI use. Objective Response Rate (ORR) Pooled ORR was 22% (95% CI 17-27%), lower than historical chemotherapy benchmarks (∼31-34%). Pneumonitis Pooled immune-related pneumonitis incidence was 9.4% (95% CI 7.6-11.5%; PI 5-16%), nearly doubling risk vs. chemotherapy (RR 1.9). Rates were highest after osimertinib exposure and among never-smokers and Asian cohorts (14-20%). Hyperprogression Two cohorts documented hyperprogression-like events in ∼15% of patients (HR 1.9-2.1). Conclusion In EGFR-mutated NSCLC, ICIs administered after TKI progression do not improve PFS or OS, yield lower response rates than chemotherapy, and nearly double pneumonitis risk. These findings support platinum-based chemotherapy with or without anti-vascular endothelial growth factor (VEGF) therapy as the preferred post-TKI strategy. Pulmonary clinicians should employ ATS-aligned monitoring algorithms for early detection of immune-related pneumonitis. Future work should focus on biomarker-driven selection (tumor mutational burden, STK11/KEAP1 co-mutations, microbiome profiles) and optimized sequencing with targeted agents. This abstract is funded by: None
Bhimani et al. (Fri,) studied this question.