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The BRAFV600E mutation, present in approximately 10% of metastatic colorectal cancers (mCRC), is associated with an aggressive phenotype and a historically poor prognosis. BRAF inhibition alone has proven ineffective in mCRC due to adaptive resistance mechanisms involving EGFR reactivation, leading to the development of combination strategies. The combination of encorafenib and cetuximab has thus become the standard second-line treatment following the BEACON study. The phase III BREAKWATER study, the results of which have been presented in recent months, demonstrates that in first-line treatment, the addition of encorafenib and cetuximab to mFOLFOX6 chemotherapy in patients with BRAFV600E-mutated pMMR/MSS mCRC significantly improves response rate, progression-free survival, and overall survival compared to standard chemotherapy, with an acceptable safety profile. This strategy corrects the prognostic disadvantage of this subgroup and establishes the combination of encorafenib + cetuximab + mFOLFOX6 as the new first-line treatment standard for pMMR/MSS BRAFV600E-mutated mCRC.