Background: pts with unresectable CRLM who respond to induction CT allowing curative-intent liver surgery have longer overall survival (OS) than pts who do not. Triplet (3-) or doublets (2-) CT, combined with CET or BEV, are often used in this setting. However, the best CT regimen remains to be determined. Methods: METHEP2 assessed whether 3-CT (FOLFIRINOX) compared to 2-CT (FOLFOX or FOLFIRI), combined with CET or BEV (by KRAS/RAS status), would increase R0/R1 liver-resection rate in pts with initially unresectable CRLM. Randomization was stratified by KRAS (amended to RAS) status, meta- vs. synchronous CRLM, and reason for non-resectability (technical vs. oncological). It was designed to demonstrate a 20% increase in the R0/R1 liver-resection rate (2-CT arm, 50% vs. 3-CT arm, 70%; bilateralα-test, 5%; β, 10%). Results: 256 pts were included, 126 in the 2-CT arm (FOLFIRI, 56; FOLFOX4, 70) and 130 in the 3-CT arm. KRAS and RAS were mutated in 91 pts (35.5%) and in 109 pts (42.6%), respectively. After a median follow-up of 45.6 months (mo), R0/R1 liver resection was achieved in 74/130 pts (56.9%; 95%CI, 48-66) in the 3-CT arm vs. 61/126 pts (48.4%; 95%CI, 39-57) in the 2-CT arm (p = 0.17). The odds for R0/R1 resection were higher in the 3-CT than in the 2-CT arm (OR, 1.8; 95%CI, 1.1-2.7; p < 0.02) when using a logistic regression model adjusted on stratification factors. Median OS was 42.9 mo in the 3-CT arm vs. 37.6 mo in the 2-CT arm (HR = 0.80; 95%CI, 0.56-1.16). Efficacy by targeted agent was as follows: R0/R1 resection 86/153 (56.2%; 95%CI, 48-64) and 49/103 (47.6%; 95%CI, 38-58), objective response: 120/153 (78.4%; 95%CI, 71-85) and 58/103 (56.3%; 95CI, 46-66), mPFS: 12.8 mo (95%CI, 11.6-13.1) and 10.7 mo (95%CI, 9.7-13.1), OS: 43.6 mo (95%CI, 40.0-51.8) and 34.2 mo (95%CI, 27.8-40.4), for CET- and BEV-treated pts, respectively. Conclusions: Despite not reaching our primary objective, FOLFIRINOX tends to be superior to FOLFIRI/FOLFOX, combined with CET or BEV, in terms of R0/R1 liver-resection rate in pts with initially unresectable CRLM. Clinical trial information: NCT01442935