Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.