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Background: Non-small cell lung cancer (NSCLC) represents the 80-85% of the lung cancer. Cisplatin-based chemotherapy is the paradigm of NSCLC treatment; however, it also induces de novo DNA hyper methylation that is associated with gene expression regulation. We have previously reported that the loss of IGFBP-3 expression by promoter hypermethylation results in reduced NSCLC cells sensitivity to cisplatin. Liquid biopsy has gained increasing attention in recent years, as it is a convenient and minimally invasive alternative to interrogate tumor free DNA (ctDNA). Objective: To study the correlation between the IGFBP-3 gene promoter methylation levels in ctDNA and paired tumor tissues from NSCLC patients at advanced stages. Methods: 66 FFPE/plasma prospective paired samples from stages III-IV NSCLC patients have been collected in a prospective study at Hospital La Paz, together with the associated clinical history. ctDNA and tumor tissue DNA was isolated and bisulfite modified. Methylation levels at IGFBP3-promoter was assessed by qMSP following the next equation: Cmeth = 100/[1+2(CTCG - CTTG)]. A validation cohort of 56 retrospective samples from national biobanks was included. Results: Our first result indicate that mIGFBP-3 assessment in DNA from tumor tissue is an indicator of a worse prognosis, since 75% of patients with stages IIIC/IV present hipermethylated levels in comparison with 25% of patients in stages IIIA/IIIB, (p = 0.035). When analyzing the ctDNA, we found that 87% of patients with mIGFBP-3 progress to the disease (p=0.001), although those patients with mIGFP-3 ≤ 35.5%, present a higher Overall Survival (OS) (p=0.026). In terms of therapy response we observed that those patients with methylation levels in tissue ≤ P75 (74.7%) have a greater survival when they receive QT vs QT + RT (n = 35) (p=0.364; HR = 0.514), in fact, 80% of patients receiving only QT are still alive at 365 days versus those receiving QT + RT. Merged data including the validation cohort reached the statistical significance (p=0.042). We also found a reduced in the risk of death by 82.2% (p=0.01) and 85.9% (p=0.002) respectively, in the patients that following a specific RECITS criteria (patients who progress or have stable disease), presented mIGFBP3 levels in tissue ≤ P50 ( 12,2 %) and in ctDNA ≤ P75 (15,6%). Conclusions: Our results indicate that mIGFBP-3 is a good prognostic biomarker in patients with NSCLC at advanced stages in both, tissue and circulating tumor DNA. Furthermore, its presence in liquid biopsy may be useful as a biomarker for bad prognosis. In summary, methylation status of IGFBP3 may provide a useful clinical tool for deciding on a concomitant radiotherapy applied in both, tissue and in liquid biopsy. This tool also provides a non-invasive and novel approach for the monitoring of NSCLC patients to support the use of the RECIST criteria in order to indicate continuity in QT treatment. Citation Format: Olga Pernía, Rocío Rosas, Julia Jiménez, Itsaso Losantos, Isabel Esteban, Patricia Cruz Castellanos, Oliver Higuera, Tatiana Juste, Olga Vera Puente, Ángel Diaz Lagares, Javier de Castro, Inmaculada ibañez de Caceres. Role of mIGFBP-3 in the clinical monitoring of non-small cell lung cancer patients at advanced stages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2095.