Abstract： Objective:To investigate the significance of plasma circulating tumor DNA (ctDNA) T790M mutation and total metabolic tumor volume (TMTV) in the prognosis of patients with advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs).Methods:96 patients with advanced EGFR mutant NSCLC were included consecutively from January 2018 to February 2021. The significance of TMTV and ctDNA T790M mutations was analyzed by 18F-FDG positron emission tomography/X-ray computed tomography (FDG-PET/CT) and plasma ctDNA T790M mutations by droplet digital polymerase chain reaction (TBT) to analyze the prognostic significance of TMTV and ctDNA T790M.Results:Throughout the follow-up period, there were 48 (50.0%) patients with disease progression and 29 (30.21%) deaths, with a median progression-free survival (PFS) of 11 months and a median overall survival (OS) of 17 months. After treatment with EGFR TKIs, 52 patients (54.17%) developed ctDNA T790M mutations, and the proportions of TMTV, death and disease progression in the ctDNA T790M mutation group were significantly lower than those in the ctDNA T790M wild-type group(P<0.05). TMTV was significantly higher in the disease progression group or death group (P<0.001). The receiver operating characteristic curve showed that the best cut-off values of TMTV for predicting disease progression and mortality were 26.10 cm3 and 59.20 cm3(P<0.001). The PFS[Log-Rank (Mantel-Cox)=22.732] and OS[Log-Rank (Mantel-Cox)=26.663] in patients with ctDNA T790M mutation were significantly higher than those in patients with ctDNA T790M mutation; the PFS[Log-Rank (Mantel-Cox)=23.199] was significantly lower in patients with TMTV≥26.10 cm3 than in patients with TMTV<26.10 cm3; the OS[Log-Rank (Mantel-Cox)=34.201] in patients with TMTV≥59.20 cm3 was significantly lower than that in patients with TMTV<59.20 cm3; the PFS[Log-Rank (Mantel-Cox)=33.604] in patients with ctDNA T790M negative and TMTV≥26.10 cm3 was the shortest; the OS[Log-Rank (Mantel-Cox)=57.078] in ctDNA T790M negative and TMTV≥59.20 cm3 was the shortest; all P<0.001. The COX multivariate model showed that TMTV and ctDNA T790M mutation status were independently associated with PFS or OS (P<0.05).Conclusion:It is feasible to detect plasma ctDNA T790M and baseline TMTV in patients treated with EGFR TKI for predicting the prognosis of NSCLC patients. After treatment, ctDNA T790M and baseline TMTV were independent prognostic factors for PFS and OS in NSCLC patients.