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

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.