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Purpose  Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.    Methods  From 2016 to 2019, 81 NSCLC patients with  EGFR  T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.    Results  In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97  vs . 6.10 months; HR 0.2109;  P  < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1  vs . 4.4 months; HR 0.2192;  P  < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085;  P  < 0.001) and longer OS (HR 0.499;  P  = 0.034). The most common resistant mutations of the third-generation TKIs were  EGFR  C797S (24%).  CDK6  CNV,  GRIN2A ,  BRCA2, EGFR  D761N,  EGFR  Q791H,  EGFR  V843I, and  ERBB4  mutation genes may possibly be new resistant mechanisms.    Conclusions  Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs