Circulating tumor DNA clearance as a trial-level early efficacy signal in solid tumors: a systematic review and meta-analysis of randomized trials.

Background: Circulating tumor DNA (ctDNA) is a sensitive marker of residual disease and treatment activity, but its validity as a trial-level surrogate endpoint remains uncertain. Given scarce randomized evidence and clinical and methodological heterogeneity, we performed an exploratory, hypothesis-generating evaluation of trial-level associations between ctDNA clearance and clinical outcomes across solid tumors. Methods: Randomized controlled trials reporting ctDNA clearance and overall survival (OS), progression-free survival (PFS), or recurrence-related outcomes were identified through April 2026. Analyses were exploratory and conducted at trial level. Weighted regression, leave-one-out cross-validation, copula correlation, Bayesian hierarchical modeling, and sensitivity analyses were performed, with cross-validated R Results: Eighteen trials were included. Out-of-sample performance was limited: R Conclusions: These exploratory, hypothesis-generating findings identify an endpoint- and setting-dependent trial-level signal, with the largest observed association for PFS, but do not validate ctDNA clearance as a surrogate endpoint. Wide uncertainty intervals, few contributing trials, and limited cross-validated performance require prospective validation before use in trial qualification or individual treatment decisions.