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Annalice Gandini, MD, San Martino University Hospital of Genoa, Genoa, Italy, comments on the evolving therapeutic algorithm for colorectal cancer, highlighting the potential shift towards combining encorafenib and cetuximab with chemotherapy as a first-line treatment, which has shown significant survival benefits in the Phase III BREAKWATER trial (NCT04607421). The standard algorithm currently involves doublet or triplet chemotherapy plus anti-VEGF, followed by a target therapy in the second line, but this may soon change. For patients with MSI and BRAF mutations, immunotherapy is preferred as a first-line treatment, with the option to combine anti-BRAF with immunotherapy if possible. This interview took place at the European Society for Medical Oncology (ESMO) Gastrointestinal Cancer 2025 Congress in Barcelona, Spain. These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.