Uncommon de novo EGFR^T790M-Mutant NSCLC characterized with unique genetic Features: Clinical response and acquired resistance to the third-generation EGFR-TKIs treatment

Introduction: The literature on de novo EGFR(T790M)-mutant patients diagnosed with lung cancer is limited, and there is currently no consensus concerning the most effective treatment protocols. This study aimed to investigate the genomic characteristics of de novo EGFR(T790M)-mutant non-small cell lung cancer (NSCLC) and provide insights into its clinical response and resistance mechanism to third-generation EGFR-TKIs. Methods: Next-generation sequencing was utilized to screen a substantial cohort of 4,228 treatment-naive patients from the Mygene genomic database to identify the de novo EGFR-T790M mutation. Meanwhile, we recruited 83 individuals diagnosed with lung cancer who harbored de novo EGFR(T790M) mutation in the real world. In addition, 166 patients who acquired EGFR-T790M mutation after becoming resistant to first- or secondgeneration EGFR-TKIs were included as a comparison cohort. Results: De novo EGFR(T790M) mutation identified by next-generation sequencing is rare (similar to 1.3 %) in Chinese lung cancer patients. The relative variant allele frequency (VAF) of de novo EGFR(T790M) mutation was either comparable to or significantly lower than those of EGFR-activating mutations. Patients with de novo-T790M mutations exhibited less favorable clinical outcomes when administered third-generation EGFR-TKIs as first-line therapy than those with 19del mutations due to a high overlap rate in EGFR p.L858R mutation. In patients with a de novo EGFR(T790M) mutation, no correlation was observed between T790M clonality and treatment outcomes with thirdgeneration EGFR-TKIs. In contrast, the sub-clonality of the T790M mutation detrimentally affected the thirdgeneration EGFR-TKI treatment efficacy in patients with acquired T790M mutation. Potential resistance mechanisms of third-generation EGFR TKIs in NSCLC patients with de novo or acquired EGFR(T790M) mutations included EGFR p.C797S in cis or EGFR p.E709X mutation, as well as activation of bypass pathways. Conclusions: The present study characterized the uncommon but unique de novo EGFR(T790M)-mutant NSCLC and laid a foundation for designing future clinical trials in the setting of uncommon EGFR mutation.