Revisiting Biomarker-Guided Therapy in EGFR-Mutant Non-Small Cell Lung Cancer with High PD-L1 Expression.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has historically been regarded as a therapeutically uniform entity, characterized by marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and limited responsiveness to immune-checkpoint inhibitors (ICIs). However, accumulating clinical and translational data suggest heterogeneity within EGFR-mutant NSCLCs. In particular, patients whose tumors express high levels of programmed death-ligand 1 (PD-L1) consistently experience inferior outcomes with EGFR-TKI monotherapy, including earlier progression and reduced response durability, even with third-generation EGFR-TKIs. This review synthesizes clinical, molecular, and immunologic evidence supporting the hypothesis that EGFR-mutant NSCLC with high PD-L1 expression may represent a biologically distinct phenotype. Key findings include data from retrospective cohorts, real-world analyses, and translational studies showing high PD-L1 expression to be associated with attenuated oncogene addiction, increased genomic complexity, tumor cell plasticity, and a dysfunctional but non-quiescent immune microenvironment. Notably, in this context, PD-L1 expression does not reliably predict benefit from ICIs but, rather, serves as a marker of aggressive tumor biology and early resistance to EGFR-TKI therapy. Lastly, we discuss the therapeutic implications of these observations, outlining the rationale for biomarker-informed, risk-adapted treatment strategies, including EGFR-TKI-based combinations, while emphasizing the need for careful integration of immunotherapy and prospective validation.