Background: Promising antitumor activity of so called rechallenge treatment with anti-epidermal growth factor receptor (EGFR) drugs in patients with RAS wild type (RAS WT) metastatic colorectal cancer (mCRC) has been recently reported. Beside the absence of resistance mutations at plasma circulating tumor DNA (ctDNA) analysis, no biomarkers of response to anti-EGFR rechallenge strategy have been identified. Methods: We conducted the single arm phase II CAVE mCRC trial to evaluate the combination of cetuximab as rechallenge plus avelumab treatment in 77 RAS WT mCRC patients, with complete (CR) or partial response (PR) to first line chemotherapy plus anti-EGFR drugs, who developed acquired resistance and received a subsequent line of therapy. A post-hoc baseline analysis of circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF and EGFR-S492R mutations was performed for 67/77 (87%) patients. The correlation of skin toxicity (ST) and other clinical variables with OS, PFS and response rate (RR) was assessed. Results: Cetuximab plus avelumab provided in the intention to treat population (ITT) median overall survival (mOS) of 11.6 months [95% Confidence Interval (CI), 8.4-14.8] and median PFS (mPFS) of 3.6 months (95% CI, 3.2-4.1) with a manageable toxicity profile. Thirty-three (42.9%) patients experienced grade 2-3 ST with mOS of 17.8 months (CI 95% 14.9-20.7), whereas 44 (57.1%) patients with grade 0-1 ST exhibited mOS of 8.2 months (CI 95% 5.6-11), (HR 0.51, CI 95% 0.29-0.89, P = 0.019). mPFS was 4.6 months (CI 95% 3.5-5.8) in patients with grade 2-3 ST, compared to 3.4 months (CI 95% 2.8-4.1) in patients with grade 0-1 ST (HR 0.49, CI 95% 0.3-0.8, P = 0.004). Grade 2-3 ST and baseline RAS/BRAF/EGFR WT ctDNA were the only variables with statistically significant effect on OS both at univariate and multivariate analyses. ST, number of metastatic sites ≤2, surgery of primary tumor and RAS/BRAF/EGFR WT ctDNA were associated with an improvement in PFS only at univariate analysis. In the 33 patients with grade 2-3 ST, 1 (3%) CR, 2 (6.1%) PR and 24 (72.7%) stable disease (SD) were observed, with disease control rate (DCR) of 81.8%. In the 44 patients with grade 0-1 ST 0 CR, 3 (6.8%) PR, 20 (45.5%) SD, with 52.3% DCR were reported. Conclusions: Cetuximab plus avelumab is effective and well tolerated as rechallenge treatment in mCRC. ST is a clinical biomarker for the identification of RAS/BRAF mCRC patients that could benefit from anti-EGFR rechallenge. Clinical trial information: NCT04561336