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Spatial Heterogeneity of PD-L1 Expression as a Biomarker for Third-Generation EGFR-TKI Response in Advanced
Yidan Zhang1, Yingqi Xu1, Hongping Jin1
1Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
High programmed cell death ligand 1 (PD-L1) expression in primary tumors of non-small cell lung cancer may reduce the effectiveness of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Spatial heterogeneity of PD-L1 impacts its predictive value.
Area of Science:
- Oncology
- Translational Research
- Molecular Diagnostics
Background:
- The efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is crucial.
- The role of programmed cell death ligand 1 (PD-L1) expression, particularly its spatial heterogeneity, in predicting treatment response remains unclear.
- Understanding PD-L1 expression across different biopsy sites is essential for optimizing NSCLC treatment strategies.
Purpose of the Study:
- To investigate the association between spatial heterogeneity of PD-L1 expression and the efficacy of third-generation EGFR-TKIs in EGFR-mutant NSCLC.
- To evaluate the impact of PD-L1 tumor cell proportion score (TPS) from primary lesions versus metastatic lymph nodes on progression-free survival (PFS).
- To identify independent risk factors influencing PFS in patients receiving first-line third-generation EGFR-TKIs.
Main Methods:
- Retrospective analysis of 4171 NSCLC patients with EGFR-sensitive mutations treated at Shanghai Chest Hospital (August 2019 - September 2023).
- Included 182 patients receiving first-line third-generation EGFR-TKIs monotherapy, categorized by biopsy site (primary lung lesions vs. metastatic lymph nodes).
- PD-L1 expression stratified by TPS (<1%, 1%-49%, ≥50%); multivariate analysis performed to identify risk factors for PFS.
Main Results:
- Median PFS for the cohort was 18.33 months.
- Higher PD-L1 TPS (≥50%) in primary lesions was associated with significantly shorter PFS (10.17 months) compared to lower TPS (<1%: 21.93 months; 1%-49%: 18.57 months; p<0.001).
- PD-L1 expression in metastatic lymph nodes showed no significant association with PFS (p=0.973); smoking history and high PD-L1 TPS (≥50%) were independent risk factors for reduced PFS.
Conclusions:
- High PD-L1 expression in primary EGFR-mutant NSCLC lesions may indicate reduced efficacy of third-generation EGFR-TKIs.
- Spatial heterogeneity of PD-L1 expression, specifically the difference between primary tumors and lymph nodes, can influence its predictive accuracy.
- Biopsy site selection for PD-L1 assessment is critical for accurate prediction of treatment response in NSCLC patients receiving EGFR-TKIs.
