Background: The treatment of metastatic colorectal cancer (mCRC) pts with BRAF-mut tumors is a major challenge for physicians. They account for < 10% of mCRC, correlate with poor prognosis, and respond poorly to standard first-line regimens including chemotherapy doublets (2-CT) plus a targeted agent. Guidelines suggest treating BRAF-mut mCRC with a triplet CT regimen (3-CT; fluorouracil, irinotecan, and oxaliplatin combination) plus BEV, based on a subgroup analysis of the TRIBE study. In this analysis of 16 mCRC pts with BRAF-mut tumors, median PFS (mPFS) and OS (mOS) were 7.5 and 19 months (mo), respectively. Since the impact of 3-CT plus CET on outcomes in pts with BRAF-mut tumors is largely unexplored, we aimed to assess this subpopulation in the METHEP2 trial. Methods: This trial assessed whether 3-CT (FOLFIRINOX) compared to 2-CT (FOLFOX or FOLFIRI), combined with CET or BEV (by KRAS exon 2/RAS status), would increase R0/R1 liver resection rates in pts with initially CRLM. As an exploratory analysis, we assessed the outcome of the subset of BRAF-mut mCRC pts. Results: 256 pts were included. KRAS exon 2 and RAS (KRAS/NRAS: exon 2, exon 3, exon 4) were mutated in 91/256 pts (35.5%) and in 109/218 pts (50%), respectively. The R0/R1 liver resection rate was 57% in the 3-CT arm vs. 48% in the 2-CT arm. mPFS was 12.8 mo in the 3-CT arm vs. 11.5 mo in the 2-CT arm (HR, 1.05; 95%CI, 0.79-1.39). mOS 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). Nine out of 230 (3.9%) mCRC pts were BRAF-mut: 8/9 pts received CET and 1 (in the 2-CT arm) received BEV as the targeted agent. Efficacy results in the 2-CT (n = 4) vs. the 3-CT (n = 5) arms were as follows: objective tumor response, 0/4 vs. 4/5; R0/R1 resection, 0/4 vs. 2/5; mPFS, 1.8 vs. 6.1 mo; and mOS, 6.6 vs. 21.3 mo. Conclusions: In this small series, pts with BRAF-mut tumors treated with 3-CT plus a targeted agent had better PFS and OS than those treated with 2-CT plus a targeted agent. Moreover, intent-to-treat survival outcomes with 3-CT plus CET are in the same range than those with 3-CT plus BEV from TRIBE. Clinical trial information: NCT01442935