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

Abstract

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.

Keywords: EGFR; NSCLC; PD‐L1; heterogeneity; third‐generation EGFR‐TKIs.

FIGURE 1

Flow chart of the study. NSCLC, non‐small cell lung cancer; EGFR, epidermal growth factor receptor; PD‐L1, programmed cell death‐ligand 1; TKIs, tyrosine kinase inhibitors.

FIGURE 2

Response rate across different groups. (A) ORR for all patients, patients in the primary lung lesion group, and those in the lymph node group. No statistically significant difference was observed across the three groups. (B) DCR for all patients, patients in the primary lung lesion group, and those in the lymph node group. No statistically significant difference was observed among the three groups. DCR, disease control rate; LN, lymph node; ORR, objective response rate; TPS, tumor cell proportion score.

FIGURE 3

Kaplan–Meier estimates of PFS. (A) PFS for all patients. A statistically significant difference in median PFS was observed among the three groups. (B) PFS in the primary lung lesion group. A statistically significant difference in median PFS was noted among the three groups. (C) PFS in the lymph node group. No statistically significant differences in median PFS were observed among the three groups. OS, overall survival; PFS, progression‐free survival; TPS, tumor cell proportion score.

FIGURE 4

Univariate Cox regression analysis of PFS. EGFR, epidermal growth factor receptor; PFS, progression‐free survival; TPS, tumor cell proportion score.

FIGURE 5

Paired analysis of PD‐L1 expression in same‐site biopsies before and after third‐generation EGFR‐TKIs treatment. No statistically significant difference was observed in PD‐L1 expression before and after treatment. EGFR‐TKIs, epidermal growth factor receptor‐tyrosine kinase inhibitors; PD‐L1, programmed cell death‐ligand 1.