The Role of De Novo T790M Mutation in The Origin of T790M Resistance Clone and in The Clinical Outcomes For Advanced EGFR-Mutant NSCLC Patients Receiving EGFR-TKIs

Abstract

Background: Increasing evidence suggests that de novo T790M mutation occurs at a low frequency in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the effects of this mutation on the formation of T790M resistant clones and efficacy of EGFR tyrosine kinase inhibitors (TKIs) remain unclear. Methods: Fifty-nine treatment-naïve in-patients with advanced EGFR-mutant NSCLC were enrolled in this study between 2017 and 2018. We dynamically monitored T790M mutation in ctDNA of patients before and during treatment with first-generation EGFR-TKIs, which were administered every 2 to 3 months until disease progression. Results: Among the patients, 28.81% (17/59) had a low-frequency de novo T790M mutation, 66.67% (10/15) of them retained T790M mutation and resistance in this group was defined as “selection” resistance. T790M mutation was detected after treatment in 42.3% (11/26) of patients without de novo T790M mutation who experienced disease progression and resistance in this group was defined as “acquisition” resistance. After treatment with third-generation EGFR-TKI, patients with the “selection” T790M resistance mutation had significantly better objective response rate (ORR) and longer progression-free survival (PFS) than those with the “acquisition” T790M resistance mutation. Conclusion: Our study provides evidence that low-frequency de novo T790M mutation is not rare in patients with advanced EGFR-mutant NSCLC. T790M resistance mutations can have two origins: the selection of low-frequency de novo T790M clones or the acquisition of the mutation in initially T790M-negative cells clinically. Since the origin of T790M resistance mutations can affect the efficacy of third-generation EGFR-TKIs, these EGFR-TKIs may be more effective for the treatment of NSCLC patients with “selection” T790M resistance mutations.