Background: The modified schedule of FOLFOXIRI (mFOLFOXIRI) in combination with an anti-EGFR agent showed a manageable safety profile and remarkable activity in RAS wild-type (wt) metastatic colorectal cancer (mCRC). The association of an active cytotoxic regimen with cetuximab (cet) may increase the exposure of tumour-associated neoantigens and induce immunogenic cell death and antibody-dependent cell-mediated cytotoxicity thus enabling the effect of immune checkpoint inhibitors. The AVETRIC study aimed at exploring the efficacy and safety of first-line mFOLFOXIRI plus cet and avelumab (ave) in RAS wt mCRC patients (pts). Methods: AVETRIC is a prospective, open label, multicenter, phase II, single arm trial in which initially unresectable and previously untreated RAS wt mCRC pts received mFOLFOXIRI (irinotecan 150 mg/sqm, oxaliplatin 85 mg/sqm, folinate 200 mg/sqm leucovorin [LV], and 5-fluorouracil [5FU] 2400 mg/sqm) plus cet (500 mg/sqm) and ave (800 mg) every 2 weeks up to 12 cycles followed by maintenance with 5FU/LV plus cet and ave until disease progression. A safety run-in phase including the first 6 enrolled pts was planned. Due to the occurrence of grade 3-4 diarrhoea in 2 (33%) pts, the protocol study was amended to reduce the irinotecan dose to 130 mg/sqm. Primary endpoint was Progression Free Survival (PFS). Fifty-eight pts were needed to detect an increase in median PFS (mPFS) from 10.0 to 19.4 months (mos), setting one-sided α and β errors at 0.05 and 0.10, respectively. The trial is registered at Clinicaltrial.gov, NCT04513951. Results: Between Jun 2020 and Dec 2021, 62 pts were enrolled in 16 Italian centres. Main pts' characteristics were: median age 56 yrs, ECOG PS 0 87%, synchronous metastases 94%, liver-only disease 42%, left-sided primary tumour 89%; all pts had BRAF wt and proficient MMR (pMMR) tumours. The primary endpoint was met. At a median follow-up of 16.0 months, 39 (63%) events were recorded and mPFS was 14.1 months (90% CI 12.0-16.7, Brookmeyer-Crowley test p < 0.001). Response rate and disease control rate were 82% and 98%, respectively, and R0 resection rate was 21% (27% in liver-only subgroup). Early tumour shrinkage was achieved in 74% pts and median deepness of response was 56%. In pts treated after study amendment (n = 56), main grade 3-4 adverse events were neutropenia (27%), diarrhoea (27%), skin rash (14%), asthenia (14%), nausea (11%), stomatitis (7%), febrile neutropenia (2%). Grade 3-4 immune-related adverse events occurred in 6% of pts. Overall survival results are still immature. Conclusions: AVETRIC study met its primary endpoint, showing that combining mFOLFOXIRI plus cet and ave achieves promising results in terms of PFS as well as response rate, in pts with pMMR RAS and BRAF wt mCRC. Translational analyses to evaluate the impact of immune-related biomarkers are ongoing. Clinical trial information: NCT04513951.