Background: Currently there is an intense debate concerning therapeutic strategies in EGFR positive NSCLC patients with advance disease. Osimertinib is superior to standard EGFR Tyrosine Kinase Inhibitors (TKIs) as first line treatment. However, it is yet unclear whether this option is superior to sequential treatment of a 1^st or 2^nd generation TKI followed by osimertinib. In order to clarify this issue it is important to identify which patients are at high risk of progression disease. Methods: This is a prospective, multicentre, cross-sectional study promoted by Spanish Lung Cancer Group. 698 plasma samples from 196 advanced NSCLC patients with tumors harboring an EGFR activating mutation and treated with a first line TKI (afatinib, gefitinib, erlotinib or osimertinib) were analyzed. Plasma samples were prospectively collected before treatment (T0), after 3 months of treatment (T3), after 6 months of treatment (T6) and at first disease progression. EGFR mutations were analyzed by dPCR. Multivariate Cox proportional hazards analysis was used to determine the significance of ctDNA in the prediction of prognosis. Results: The median follow up was 19.8 months. At baseline patients with plasma EGFR sensitizing mutations at allele frequency (AF) ≥ 10% had worse OS and PFS than patients in which the opposite occurred (HR = 1.86; 95 %CI: 1.09-3.17, and HR = 1.65; 95 %CI: 1.07-2.58, respectively). Noteworthy, median OS and PFS time were 18.6 and 8.8 months respectively, in patients with plasma AF≥10% before treatment initiation compared to 37.9 and 12.4 months for patients with plasma AF < 10%. Similar results were obtained when a cutoff of AF≥ 5% was used (HR = 1.73; 95%CI: 1.02-2.94 for OS, and HR = 1.72; 95%CI: 1.13-2.61 for PFS). Patients who remained ctDNA-positive after 3 months of treatment exhibited also poorer outcomes (HR = 3.24; 95%CI: 1.77-5.94 for OS, and HR = 3.1; 95%CI: 1.91-5.03 for PFS). In the same way, detectable levels of ctDNA after 6 months of treatment predicted shorter OS and PFS (HR = 3.3; 95%CI: 1.53-7.13 and HR = 2.62; 95%CI: 1.62-4.25, respectively). Conclusions: ctDNA levels significantly predict survival. Moreover, ctDNA levels before treatment initiation can be useful to assess patient’s progression risk which is not possible to assess otherwise facilitating treatment decision making.