PD ‐ L1 Expression and Histopathological Features in EGFR ‐Mutated Non‐Small Cell Lung Cancer: Implications for Immune Checkpoint Inhibitors After EGFR ‐Tyrosine Kinase Inhibitors Resistance

BACKGROUND: Epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) responds well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), yet optimal therapy after resistance remains uncertain. Although immune checkpoint inhibitors (ICIs) show limited overall efficacy, heterogeneity in response by programmed cell death ligand 1 (PD-L1) expression exists. METHODS: We retrospectively evaluated 90 patients with advanced/recurrent EGFRm NSCLC treated with first-line EGFR-TKIs (October 2018-October 2023). Clinicopathological and radiologic features were compared by PD-L1 tumor proportion score (< 50% vs. ≥ 50%). The primary analysis evaluated overall survival from first progression (post-progression OS/PPS) using a time-varying Cox model with start-stop intervals, modeling ICI as a time-dependent exposure ICI(t) and testing the ICI(t) × PD-L1 interaction. RESULTS: , the ICI(t) × PD-L1 interaction was significant (Wald p = 0.015; likelihood-ratio p = 0.036). Stratum-specific adjusted ICI effects suggested a detrimental association in PD-L1 < 50% (hazard ratio [HR]: 3.11, 95% confidence interval [CI]: 0.94-10.30) but favorable association in PD-L1 ≥ 50% (HR: 0.457, 95% CI: 0.138-1.512). In exploratory analyses of 22 ICI-treated patients, PD-L1 ≥ 50% showed higher response rates (64% vs. 9%) and longer time to treatment failure (3.4 vs. 1.4 months). CONCLUSIONS: High PD-L1 expression in EGFRm NSCLC is associated with more aggressive morphologic features and modifies the association between post-progression ICI and survival. These findings support PD-L1-informed selection after EGFR-TKI failure, while prospective confirmation is needed.