In conclusion, we demonstrated that a novel BRAF and CDK 4/6 inhibitor combination therapy exhibits significant anti-angiogenic and anti-proliferative effects in experimental human melanomas in mice and that the according alterations in tumor pathophysiology can be monitored non-invasively and in vivo by 18F–FDG-PET/CT and DW-MRI. This evidence concerns the gene BRAF and melanoma.