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

ABSTRACT 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 PD‐L1 ≥ 50% group ( n = 26) more often had solid histology (62% vs. 8%), solid nodules on computed tomography (96% vs. 52%), and larger tumors (median 42.0 vs. 27.5 mm). Among 68 patients evaluable from t 0 , 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.