Background: Utilization of ctDNA has been rapidly adopted as a predictive diagnostic in advanced Non-Small Cell Lung Cancer and indications in GI cancers may be emerging. We aimed to evaluate ctDNA as an early biomarker of efficacy of new therapies for mCRC. Methods: mCRC patients (pts) who consented to a genomic matching protocol and had started a new line treatment with regorafenib or TAS-102 were eligible. Droplet digital PCR (ddPCR) assays were performed using 3 mL of plasma samples from pts with tumors harboring RAS mutations (BioRad). Serial plasma samples also underwent retrotransposable element (RE) based multiplexed qPCR assay using 300 µL of plasma; a DNA Integrity Index (DII) was calculated using a ratio of long to short DNA fragment size concentrations (Innogenomics). Progressive disease (PD) by ctDNA, defined as any increase in allele frequency (AF) by ddPCR and any decrease in DII by RE-qPCR, was compared to RECIST at first restaging. Results: 40 mCRC pts were included. 16 pts were treated with regorafenib and 31 with TAS-102 (7 pts received both drugs). Therefore, 47 treatment regimens were included in this study with serial monitoring completed in 22 treatments with ≥ 2 serial plasma samples. At baseline, the median AF by ddPCR was 18.1% and the median DII was 0.112. A moderate correlation was seen between baselines CEA and AF by ddPCR (r = 0.43; p = 0.056). The sensitivity and specificity of ddPCR in detecting PD by RECIST was 61.5% (95%CI: 32% - 86%) and 100%, respectively. RE-qPCR had a sensitivity of 47.4% (95%CI: 24% - 71%) and specificity of 100%. Unlike ddPCR which was limited to monitoring patients with common mutations in KRAS and NRAS, the DII was successfully obtained in all patients. There was no false-positive in either assays. Serial change in CEA was more sensitive (77.8%), but less specific (16.8%). Conclusions: Our findings suggest that pts with ctDNA predicted PD may be safely switched to another treatment before radiologic restaging. ctDNA by both ddPCR and RE-qPCR can predict later radiological progression with high specificity, with RE-qPCR providing benefits of a universal assay and limited sample requirements.