Background: Platinum based regimens are used in the first line setting for advanced Thymic Epithelial Tumors (TETs). Angiogenesis plays an important role in TETs: VEGF is overexpressed in TETs, and associated with aggressiveness and advanced stage. Etoposide inhibits angiogenesis in vitro and in vivo by decreasing VEGF production and microvessel density. The aim of this study is to assess the activity of metronomic oral etoposide, with identification of circulating predictive and pharmacodynamics biomarkers. Methods: Patients with advanced platinum pretreated TET referred from 2014 to 2019 at Rare Tumors Reference Center of Naples, were prospectively enrolled in this study. Oral etoposide 50 mg daily for 3 weeks on and 1 week off every 28 days, has been delivered until progression of disease, complete response or unacceptable toxicity. Response rate (RR), progression free survival (PFS), toxicity and ratio between time to etoposide progression (TTPe) and time to previous best treatment progression (TTPp) were evaluated. Serum samples were prospectively obtained from ten patients with simultaneously radiological assessment. cfDNA quantification was assessed using Qubit Fluorometric Quantitation. Results: 21 patients were enrolled: median age 59 years range (41 - 88); 70% male, 60% T (4 B1, 3 B2, 4 B3, 1 B1-B2); 40% had TC. A median of 5 (range 1-9) prior therapy regimens had been administered. Median follow-up since etoposide was 5 years (range 0.5-5). Obtaining an overall response rate of 85%, 3 patients achieved complete response and 15 partial response. Median PFS was 16 months [95%CI 3-60] with respectively a median PFS of 12 for T (95%CI 3-38) and 19 for TC (95%CI 6-60). No grade 3-4 related events occurred, G1-2 myelotoxicity has been registered in 20% of patients. Therapy is still ongoing for 15 patients and all are still alive. Median TTPe was 16 months, TTPp was 9 months and TTPe / TTPp ratio equal to 1.7. The median cfDNA of 8 responder patients, before starting therapy, was 2.2 ng/μl (0.178-5.24), dropping dramatically at radiological response to 0.5 ng/μl (0.323-2.56). 2 out of 3 non-responder patients had a median baseline value of 2.49 ng/μl, increasing to 4.6 ng/μl at progression. Variation of circulating VEGF correlates with radiological response. Conclusions: Taking into account that other antiangiogenic drugs, showing some activity in second and further lines treatment, are very expensive and associated with several side effects, we suggest that low dose oral etoposide might become the preferred treatment option in heavily pretreated TETs.