Spatial Heterogeneity of PD-L1 Expression as a Biomarker for Third-Generation EGFR-TKI Response in Advanced EGFR-Mutant NSCLC

The association between the spatial heterogeneity of programmed cell death ligand 1 (PD-L1) expression and the efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) remains elusive. This retrospective study analyzed data from 4171 NSCLC patients with EGFR-sensitive mutations treated at Shanghai Chest Hospital from August 2019 to September 2023. Among them, 182 patients receiving third-generation EGFR-TKIs monotherapy as a first-line treatment were enrolled. Patients were categorized by biopsy sites into primary lung lesions (n = 112) and metastatic lymph nodes (n = 70). PD-L1 expression was stratified based on tumor cell proportion score (TPS): < 1%, 1%–49%, and ≥ 50%. The median progression-free survival (PFS) for the entire cohort was 18.33 months. In the PD-L1 TPS group, PFS was 18.87 months for TPS < 1%, 17.6 months for TPS 1%–49%, and 13.6 months for TPS ≥ 50%, with significant differences across groups (p = 0.026). Moreover, multivariate analysis identified smoking history [HR = 1.653, 95% CI (1.132–2.414), p = 0.009] and TPS ≥ 50% [HR = 2.069, 95% CI (1.183–3.618), p = 0.011] as independent risk factors. In primary lesions, the median PFS was 21.93 months for TPS < 1%, 18.57 months for TPS 1%–49%, and 10.17 months for TPS ≥ 50%, with significant differences (p < 0.001). However, PD-L1 expression in metastatic lymph nodes was not associated with PFS (p = 0.973). In advanced EGFR-mutant NSCLC, high PD-L1 expression may suggest reduced efficacy of third-generation EGFR-TKIs. The spatial heterogeneity of PD-L1 expression could influence its predictive accuracy for third-generation EGFR-TKI efficacy.