Mutational landscape and tyrosine kinase inhibitor sensitivity in EGFR L833 and H835 mutated non–small cell lung cancer

Abstract Background Non–small cell lung cancer (NSCLC) patients with EGFR L833 and H835 mutations show potentially satisfying responses to EGFR tyrosine kinase inhibitors (TKI); however, investigations on their molecular and clinical characteristics are limited. Methods DNA sequencing data from 240 NSCLC patients with EGFR L833 and H835 mutations were analyzed, including 57 with EGFR‐TKI treatment records. An external cohort of 346 EGFR L858R‐mutated NSCLC patients was also evaluated for comparative molecular landscape analysis. Results In the study cohort, 98.3% of patients with EGFR L833 mutations and 100% with EGFR H835 mutations had concurrent EGFR mutations. A total of 97.5% of patients (78 of 80) with EGFR H835L mutations had concurrent L833V mutations, whereas the most frequent comutations of EGFR L833V were L858R (44.1%) and H835L (37.0%). Compared to EGFR L858R patients in the external cohort, those with EGFR L833V+H835L and L833V+L858R mutations had less frequent LRP1B , RB1 , TP53 mutations, CD4K amplifications, and mutations in the RTK‐RAS and cell‐cycle signaling pathways. Tumor mutational burden, chromosomal instability, and whole‐genome duplication rates were lower in these patients compared to those with classical EGFR L858R. Notably, patients with EGFR L833 and H835 mutations achieved a median progression‐free survival (PFS) of 16.4 months, similar to patients with classical EGFR mutations. PFS was comparable across mutation subtypes and different generations of EGFR‐TKIs received. Conclusions This study highlights the unique molecular characteristics of NSCLC patients with EGFR L833 and H835 mutations and confirms their sensitivity to all generations of EGFR‐TKIs, with PFS comparable to L858R, providing real‐world evidence for clinical decision‐making.