MGEC is associated with poor overall survival (OS) of approximately 4–10 months. CtDNA is emerging as a promising prognostic biomarker with high potential for early relapse detection. However, until now, there was little knowledge on serial ctDNA detection and its impact on early treatment evaluation and prognosis in mGEC. Methods: ctDNA detection (ddPCR) was carried out serially in 37 matched tissue (NGS) patients with mGEC prior to systemic treatment initiation and every two weeks thereafter until restaging (n = 173 samples). The results have been correlated with response to treatment (restaging CT), overall survival (OS), and progression-free survival (PFS). Results: The pretherapeutic detection rate was 77.8%. Response to treatment assessment was correct in 54.2% (pretherapeutically pos./neg.) and 85.7% (dynamics at week 4). Moreover, a decline in ctDNA (MAF in %) below 57.1% of the pretherapeutic value after 2 weeks of systemic treatment was accompanied by a sensitivity of 57.1% and a specificity of 90% (AUC = 0.73) for correct restaging assessment (response evaluation by CT after 3 months) evaluating 76.5% of patients correctly after only 2 weeks. In contrast to mere pretherapeutic ctDNA positivity (p = 0.445), a decline in ctDNA dynamics to under 57.1% of its initial value was significantly associated with OS (4.1 (95% Cl 2.1–6.1) vs. 13.6 (95% CI 10.4–16.6) months, p < 0.001) and PFS (3.2 (1.9–4.5) vs. 9.5 (95% CI 5.5–13.5) months, p = 0.001) after two weeks of treatment. Additionally, the change in detectability from positive pretherapeutic levels to negative during treatment was associated with similar survival as for patients who were always regarded as ctDNA-negative (9.5 (95%Cl 0.4–18.5) vs. 9.6 (95%Cl 1.3–17.9)). The absence of becoming undetectable was associated with worse survival (4.7 months). Conclusions: ctDNA is a promising additional biomarker allowing for early evaluation of response to treatment and saving unevaluated treatment time for patients with mGEC, and could allow for an early change in treatment with anticipated prognostic benefit in the future.