EGFR-Mutant Non–Small Cell Lung Cancer With Small Cell Transformation: Clinicopathological Features, Treatment Landscape, and Biomarker Profiles

Introduction Transformed small-cell lung cancer (tSCLC) is a clinically important resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in EGFR -mutant non-small-cell lung cancer. This study characterized clinical features, treatment outcomes, and biomarker profiles in patients with tSCLC. Methods Data from 45 patients with EGFR -mutant NSCLC who developed tSCLC between 2014 and 2023 were analyzed. Demographic characteristics, treatment history, DLL3 and B7-H3 expression were collected. Objective response rate, progression-free survival (PFS), and post-transformation survival (PTS) were assessed. Spatial transcriptomic profiling was performed in selected cases. Results Most patients were women (60%) and never-smokers (75.6%). Exon 19 deletion was the predominant EGFR mutation (57.8%). Median PFS and PTS were 3.3 and 9.2 months, respectively. Etoposide plus platinum (EP) was the predominant first-line regimen (69.8%), with 23.2% of the patients receiving EP plus immune checkpoint or tyrosine kinase inhibitors. EP-based combination regimens yielded a numerically higher objective response rate and a significantly longer PFS than did EP alone (7.5 vs. 2.8 months, p=0.002). PTS was longer with EP-based regimens than with other regimens (10.4 vs. 6.4 months, p=0.035). DLL3 and B7-H3 were expressed in 87.5% and 66.7% of tumors, respectively, without prognostic significance. Multivariable analysis identified brain metastasis and liver progression at transformation as adverse prognostic factors. Spatial transcriptomic analysis revealed neuroendocrine lineage reprogramming, stromal depletion, and immune exclusion. Conclusions tSCLC remains an aggressive resistance phenotype with poor outcomes. EP-based combination strategies may provide clinical benefit, while frequent DLL3 expression supports further evaluation of targeted therapies.