The BREAKWATER Phase III study investigated encorafenib and cetuximab plus mFOLFOX6 versus chemotherapy with or without bevacizumab for the treatment of patients with previously untreated V600E - mutant metastatic colorectal cancer. The study showed significantly improved objective response rate by blinded independent central review, and significantly longer progression-free survival by blinded independent central review and overall survival in patients treated with first-line encorafenib and cetuximab plus mFOLFOX6 compared with chemotherapy with or without bevacizumab. The safety profiles were consistent with those known for each agent. These results led to the approval of encorafenib and cetuximab plus mFOLFOX6 for the treatment of V600E-mutant metastatic colorectal cancer, including in the first line. This paradigm shift in metastatic colorectal cancer highlights the importance for early genomic testing to identify patients who would benefit from this new treatment option. We discuss the results from BREAKWATER - including progression-free survival by blinded independent central review, overall survival, objective response rate by blinded independent central review in all participants, and safety - and the meaning of these results for clinical practice as a new treatment option and the need for earlier genomic testing.: www.clinicaltrials.gov identifier is NCT04607421.