Abstract 5357: Mutational landscape and tyrosine kinase inhibitor sensitivity in <i>EGFR</i> L833 and H835 mutated non-small cell lung cancer

Abstract Background: EGFR L833 and H835 mutations account for 0.5% of EGFR-mutated non-small cell lung cancer (NSCLC) cases and are not classified as sensitive mutations to EGFR tyrosine kinase inhibitors (TKIs) according to NCCN guidelines, while chemotherapy remains the standard of care for patients with these mutations. Previous case reports have shown favorable EGFR-TKIs efficacy in patients with EGFR L833 and H835 mutations, this has yet to be validated in larger cohorts. Methods: DNA sequencing data from 240 NSCLC patients with EGFR L833 and H835 mutations were analyzed, including 57 with documented EGFR-TKI treatment records. Additionally, an external cohort of 346 NSCLC patients with EGFR L858R mutations and wild-type EGFR L833 and H835 was evaluated for comparative analyses of molecular landscapes. Kaplan-Meier survival curves were generated, and the log-rank test was employed to compare survival times between subtypes. Results: In the study cohort, 98.3% (235/239) of patients with EGFR L833 mutations and 100% (82/82) with EGFR H835 mutations had concurrent EGFR mutations. Interestingly, 97.5% (78/80) of patients with EGFR H835L mutations had concurrent L833V mutations, while the most frequent co-mutations of EGFR L833V being L858R (44.1%, 93/211) and H835L (37.0%, 78/211). Compared to EGFR L858R patients in the external cohort, those with EGFR L833V+H835L and L833V+L858R mutations had lower frequencies of LRP1B, RB1, TP53 mutations, as well as CD4K amplifications and mutations in the RTK-RAS and cell cycle signaling pathways. Tumor mutational burden (TMB), chromosomal stability, whole-genome duplication rates, and age-related and APOBEC-associated mutational signatures were also lower in patients with EGFR L833V+H835L and L833V+L858R mutations compared to those with EGFR L858R, with significant differences in TMB (P = 0.110 and P = 0.001), chromosomal instability (P = 0.036 and P = 0.042), whole-genome duplication rates (P = 0.008 and P = 0.028), age-related signatures (P = 0.006 and P = 0.027), and APOBEC-associated signatures (both P &amp;lt; 0.001). Notably, EGFR-TKI efficacy data revealed that patients with EGFR L833 and H835 mutations can benefit from EGFR-TKI treatment, with a median progression-free survival (PFS) of 16.4 months. PFS was comparable across mutation subtypes (L833V+H835L vs. L833V+L858R vs. others, P = 0.096) and across different generations of EGFR-TKIs received (P = 0.533). Conclusion: This study demonstrates that patients with EGFR L833 and H835 mutations can benefit from EGFR-TKIs, with comparable median PFS to those with classical EGFR L858R mutations in previous literatures. Additionally, patients with L833 and H835 mutations displayed distinct molecular features compared to L858R, characterized by lower TP53 mutation frequencies, lower TMB values, and lower chromosomal instability. Citation Format: Nong Yang, Long Huang, Dou Ren, Fanxu Zeng, Chengchuan Jiang, Weiwei Zhang, Weifeng He, Wei Yin, Peng Huang, Hanlin Chen, Xiaoying Wu, Jiaohui Pang, Haimeng Tang, Xue Wu, Qiuxiang Ou. Mutational landscape and tyrosine kinase inhibitor sensitivity in EGFR L833 and H835 mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5357.