Background: Erlotinib (E) and gefitinib (G) are indicated as first-line therapy of EGFR-mutated NSCLC patients (pts). Many studies highlighted TKI pharmacokinetic (PK) impact on toxicities. However, data about the relationship between PK and efficacy are sparse. Recently, ctDNA has been shown to be a strong prognostic factor for metastatic NSCLC pts undergoing specific treatment. Thus, we underwent an observational study to determine plasma drug concentration and ctDNA impact on outcomes in NSCLC pts treated with E or G. Then, we explored the correlation between PK and ctDNA in order to improve management of pts treated with EGFR-TKI. Methods: We analyzed consecutive pts with EGFR-mutated NSCLC treated with TKI in Cochin and European Georges Pompidou hospitals (APHP, Paris) from April 2010 to March 2016. Plasma samples were collected 2 to 6 weeks after TKI initiation. Steady state trough concentration (Cssmin) was assessed by high performance chromatography. CtDNA was analyzed using Next-Generation Sequencing (Ampliseq ColonLungV2 panel, BPER method). Therapeutic ranges obtained from previous studies were between 1200 to 2000 ng/mL and > 200 ng/mL for E and G, respectively. Results: Out of 77 pts, 56 had Cssmin analysis, 40 ctDNA analysis and 31 both. Median age was 70 years (range: 31-90), 49 were treated with E, 24 with G. Median follow-up was 19 months. Whatever EGFR TKI, pts with Cssmin into therapeutic ranges had longer PFS than pts over or under-exposed (median: 17.5 vs 7.5 months, p = 0.002). Those with early indetectable ctDNA had significantly better PFS (median 13 vs 5.8 months, p = 0.01) and OS (median: 21.4 vs 14.3 months, p = 0.02). No correlation was found between ctDNA and Cssmin. Occurrence of toxicity > grade 2 in pts treated with E was associated with higher plasma concentration (mean 1991 vs 1184 ng/mL, p < 0.01). Conclusions: Early Cssmin and ctDNA assessment appear as markers to predict outcomes. Our observational study is the proof of concept that pts undergoing EGFR-TKI therapy could be monitored with Cssmin and ctDNA to define optimal personalized treatment strategies. A prospective study is planned to evaluate dose adaptation of TKI based on those 2 tools.