EGFR exon 20-altered NSCLC in China: molecular heterogeneity and real-world outcomes with sunvozertinib.

Abstract

Purpose: EGFR exon 20 alterations are uncommon and heterogeneous in non-small cell lung cancer (NSCLC), with reduced sensitivity to conventional EGFR tyrosine kinase inhibitors. This study aimed to characterize their molecular spectrum, clinical relevance, and real-world outcomes.

Patients and methods: We retrospectively analyzed 50 patients with NSCLC harboring EGFR exon 20 alterations confirmed by next-generation sequencing. Mutation spectrum, structural distribution, co-occurring genomic alterations, clinicopathological features, treatment patterns, and overall survival (OS) were evaluated. Associations between molecular features, sunvozertinib exposure, and OS were assessed using Kaplan-Meier survival analysis and Firth penalized Cox regression.

Results: EGFR exon 20 alterations showed marked molecular heterogeneity, with multiple mutation subtypes and structural subclasses. Co-occurring genomic alterations were frequent, and TP53 was the most common concomitant alteration. TP53 co-mutation was associated with inferior OS. Exploratory Kaplan-Meier analysis suggested shorter OS for far-loop than near-loop variants, although the subgroups were small and imbalanced. Among non-surgical patients, sunvozertinib exposure was associated with longer OS in unadjusted analysis, but this association did not remain statistically significant after multivariable adjustment.

Conclusion: This study provides real-world evidence of the molecular and clinical heterogeneity of EGFR exon 20-altered NSCLC. TP53 co-mutation was associated with poorer OS. Exploratory analyses suggested a possible survival difference according to loop location and a potentially favorable association between sunvozertinib exposure and OS among non-surgical patients, although the adjusted results varied across models and were limited by the small number of survival events. These findings highlight the potential relevance of molecular stratification but require validation in larger prospective cohorts.