Research Funding: MD Anderson Cancer Center, Houston, TXGuardant Health Inc., Redwood City, CA...Background: Identifying non-responders to expensive salvage therapies with modest benefits and substantial treatment related adverse events (TRAEs) (e.g. regorafenib [Reg] or TAS102 [Tas] in mCRC) is key to precision care... In the first prospective study of clinical utility of monitoring ctDNA in mCRC, baseline ctDNA was strongly prognostic for clinical benefit from salvage therapies in mCRC. Adjusted for this prognostic impact, ΔctDNA between C1D1 and C1D15 was predictive of clinical outcomes. Efforts are needed to establish novel signatures, optimal cutoffs/intervals for assessing ctDNA response in mCRC, tailored to pts and their therapy.