Background: The association of a chemotherapy doublet (FOLFOX/FOLFIRI) with an anti-EGFR monoclonal antibody (cetuximab or panitumumab) is an upfront option for the treatment of RAS and BRAF wt mCRC patients. Phase II studies investigating the combination of the triplet FOLFOXIRI with an anti-EGFR reported promising activity results and an acceptable safety profile when lower doses of 5FU and irinotecan were adopted. The added value of intensifying the upfront chemotherapy when combined with a targeted agent in a molecularly selected population is not established. Methods: TRIPLETE is a prospective, open label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomized to receive mFOLFOX6/pan (arm A) or mFOLFOXIRI (irinotecan 150 mg/sqm, oxaliplatin 85 mg/sqm, L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h infusion)/pan (arm B) up to 12 cycles, followed by 5FU/LV/pan until disease progression. The primary endpoint is overall response rate (ORR) according to RECIST 1.1 criteria. Secondary endpoints include safety profile, R0 resection rate, PFS and OS. Under the assumption of an ORR of 60% in arm A, to detect an increase of at least 15% in arm B, a sample size of 432 cases provided approximately 90% power to a two-sided chi square test for heterogeneity at the 0.05 significance level. Results: From September 2017 to September 2021, 435 pts were enrolled (arm A/B: 217/218) in 67 Italian sites. Main pts’ characteristics were (arm A/B): median age 59/59, ECOG PS 0 80%/84%, left-sided 88%/88%, synchronous metastases 88%/87%, prior adjuvant 2%/6%, resected primary 43%/51%, liver-only 37%/39%. Main grade > 2 adverse events were diarrhoea 7%/23%, stomatitis 7%/7%, neutropenia 20%/32%, febrile neutropenia 3%/6%, fatigue 2%/7%, skin rash 29%/19%. 160 (73%) out of 218 patients in arm B and 165 (76%) out of 217 patients in arm A achieved RECIST response (OR 0.87, 95%CI 0.56-1.34, p=0.526). No interaction effect between treatment arm and disease spread (liver-limited vs not-liver limited) was evident. No differences in early tumor shrinkage (arm A/B 58%/57%, p=0.878) and deepness of response (median arm A/B: 47%/48%, p=0.845) were reported, nor in R0 resection rate (arm A/B 29%/25%, p=0.317). At a median follow up of 26.5 mos, 305 (arm A/B: 157/148) PFS events were collected, with no significant difference between arms (median PFS: 12.7 vs 12.3 months, HR: 0.88, 95%CI 0.70-1.11, p=0.277). Conclusions: The intensification of the upfront chemotherapy backbone in combination with panitumumab in molecularly selected and mostly (88%) left-sided mCRC patients does not provide any benefit in terms of treatment activity at the price of a non-negligible increase in gastrointestinal toxicity. Clinical trial information: NCT03231722.