Prevalence and therapeutic response of EGFR T790I mutation in NSCLC patients with acquired resistance to EGFR-TKIs: a retrospective cohort study

The EGFR T790I mutation is a potential resistance mechanism against EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, its prevalence and clinical significance remain unexplored. We aim to delineate the mutational spectrum of EGFR T790I in NSCLC patients and investigate its association with clinical outcomes and resistance to EGFR-targeted therapies. We retrospectively reviewed the clinico-genomic databases of Chinese NSCLC patients who underwent next-generation sequencing (NGS) at Geneseeq from January 2017 to June 2024. The clinicopathological features and treatment histories of patients harboring the EGFR T790I mutation were analyzed. The EGFR T790I mutation was exclusively observed in patients previously treated with EGFR-TKIs. Among those who developed resistance to first- or second-generation TKIs, six (0.054%) patients had the T790I mutation. All six cases exhibited concurrent EGFR L858R mutations and no other sensitizing mutations were detected. Notably, the T790I mutation was identified in various sample types, including tissue, plasma and pleura effusion samples, collected post-progression on EGFR-TKIs. In matched pre- and post-treatment samples from two patients, T790I was newly acquired post resistance to first-generation EGFR-TKI therapies. Two patients benefited from osimertinib, suggesting its activity against T790I-induced resistance. These findings underscore the importance of continuous genetic monitoring and personalized therapeutic strategies. While the T790I mutation is rare, its significant implications for disease progression and treatment resistance warrant further exploration and targeted intervention of third-generation inhibitors like osimertinib. retrospectively registered.