We report a rare NRF1-BRAF fusion with novel breakpoints, identified by next-generation sequencing–based assay, from a 69-year-old man with metastatic urothelial carcinoma (UC) of the renal pelvis and his initial clinical response to a second-generation MEK inhibitor, trametinib...Based on the genomic findings, the patient opted to begin a trial of trametinib (Mekinist), a second-generation mitogen-activated protein kinase kinases (MEK) inhibitor. After two and a half months of treatment, a MRI scan demonstrated an overall 48.4% decrease in size of the liver lesions: from 6.3 cm to 2.4 cm in segment 8; from 6.6 cm to 3.6 cm in segment 5; and from 2.8 cm to 1.6 cm in segment 2