PD‐L1 expression is associated with inferior outcomes independent of EGFR subtype in advanced non–small cell lung cancer with uncommon EGFR mutations treated with first‐line second‐generation EGFR‐tyrosine kinase inhibitors

Abstract Background Second‐generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are key first‐line therapies for advanced non–small cell lung cancer (NSCLC) with uncommon EGFR mutations, with risk stratification mainly based on EGFR mutation subtypes. Emerging evidence suggests programmed death‐ligand 1 (PD‐L1) expression may affect EGFR‐TKI efficacy. This study compared associations of PD‐L1 expression and EGFR mutation subtypes with outcomes in patients receiving first‐line second‐generation EGFR‐TKI monotherapy. Methods This dual‐center retrospective real‐world study included 215 patients with advanced NSCLC harboring uncommon EGFR mutations. Efficacy was evaluated across mutation subtypes (L861Q, G719X, S768I, other single‐site, compound mutations). Stratified analyses by PD‐L1 expression were performed, with prognostic value explored in primary lung lesions and metastatic lymph nodes. Primary end points include progression‐free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results The median PFS for all patients was 14.07 months (ORR, 49.3%; DCR, 89.8%). No statistically significant differences in ORR, DCR, or median PFS were observed among uncommon EGFR mutation subtypes. In contrast, high PD‐L1 expression was significantly associated with shorter PFS. Furthermore, PD‐L1 expression (tumor proportion score TPS ≥1%) in primary lung lesions was associated with shorter PFS, whereas no similar association was observed in metastatic lymph nodes. Conclusion In advanced NSCLC with uncommon EGFR mutations, first‐line second‐generation EGFR‐TKI monotherapy shows no statistically significant efficacy differences across mutation subtypes. PD‐L1 expression is inversely associated with outcomes, with prognostic value differing between primary tumors and metastatic lymph nodes, highlighting the importance of tissue sampling site in risk stratification.