For a study, researchers sought to investigate the utility of Liquid Biopsy cfDNA-based epidermal growth factor receptor (EGFR) mutation testing in patients with non-small cell lung cancer (NSCLC) as a monitoring tool. The study included patients with NSCLC who had EGFR mutations and received first-line therapy according to institutional protocol. Plasma samples were taken at baseline and started to evaluate EGFR mutation status after treatment. Patients with an EGFR mutation were designated circulating tumor DNA (ctDNA)-positive if the mutation was discovered or remained after treatment began. The primary endpoints were progression-free survival (PFS) and overall survival (OS) for ctDNA-positive and negative patients after treatment initiation; the secondary endpoints were baseline EGFR status concordance between tissue and plasma and the proportion of patients who were ctDNA-positive after treatment initiation. Investigators enrolled 158 patients, with 76 receiving gefitinib and 82 receiving gefitinib combined with chemotherapy. The average follow-up period was 42 months. After therapy, about 25% of patients tested positive for ctDNA. The median PFS for ctDNA-negative patients was 14 months (95% CI, 12.0–17.0), while the median PFS for ctDNA-positive patients was 8 months (95% CI, 6.0–10.0). The median OS for ctDNA-negative patients was 27 months (95% CI: 24.0–32.0), while the median OS for ctDNA-positive patients was 15 months (95% CI: 11.0–19.0). At baseline, 75.4% of tissue and plasma samples were in agreement. Patients with EGFR-mutant NSCLC receiving first-line treatment could use plasma-based EGFR mutation testing after treatment commencement as a prognostic marker for the outcome.