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.

Prognostic Impact of Organ-Specific Metastasis in Non-Small-Cell Lung Cancer

Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74–3.37, p < 0.001; 1.94 and 1.19–3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.