Background: Liquid biopsy (LB) analysis using circulating-tumour DNA (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in non-small cell lung cancer (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and therefore outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. Methods: We searched Embase, MEDLINE, PubMed and Cochrane Database, between 01/01/2000 and 01/08/2022. The primary outcome was progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), sensitivity and specificity of the test. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). Results: Twenty-seven studies reporting 2424 patients were included. Eleven studies (n = 1359) reported an association of baseline ctDNA levels, while 16 studies (n = 1649) reported an association of dynamic ctDNA changes to treatment, with clinical outcomes of PFS and/or OS. Baseline ctDNA-negative patients had higher PFS (pooled hazard ratio [pHR] = 2.97; (95%CI: 1.92-4.85; I²= 97.4%), and OS (pHR = 3.49; (95%CI: 1.73-6.95; I²= 84.2%), than ctDNA-positive patients. Egger’s test suggested publication bias (p < 0.001). Early reduction/clearance of ctDNA levels after treatment improved PFS (pHR = 3.78; 95%CI: 1.91-7.38; I²= 98.4%) and OS (pHR = 2.20; 95%CI: 1.49-3.28; I²= 90.6%), compared to those with no reduction/persistence of ctDNA levels. The PFS was comparable for patients stratified by age (age ≤60 years [pHR = 2.92; 95%CI: 1.43-5.93; I²= 98.3 %] vs. age > 60 years [pHR = 3.94; 95%CI: 1.54-10.07; I²= 83.6 %]). The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good quality studies (pHR = 3.67; 95%CI: 1.79-7.54; I²= 91.6 %), but not for poor or fair quality studies. Conclusions:This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels, and early reduction in ctDNA following treatment are strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management. Systematic review registration: PROSPERO registration No. CRD42022347791 Keywords: non-small cell lung cancer; NSCLC; liquid biopsy; circulating tumour DNA; ctDNA; progression-free survival; targeted therapies.