In this case series, in heavily pre-treated melanoma patients with refractory brain metastases, triple-targeted therapy with regorafenib and BRAF/MEKi in BRAF-mutant patients and regorafenib with MEKi (+low-dose BRAFi) in NRAS-mutant patients shows a promising anti-tumor activity signal with an acceptable safety profile. The gene discussed is BRAF; the disease is neoplasm.