Response to a novel type II RAF inhibitor in diffuse leptomeningeal glioneuronal tumor with BRAF fusion.

backgroundDiffuse leptomeningeal glioneuronal tumor (DL-GNT) is a rare disease which is more often diagnosed in children and adolescents than adults. Activation of the MAPK/ERK pathway is implicated in the majority of cases, and BRAF fusions are the most common genetic alteration. BRAF fusions result in dimerization and constitutive downstream MAPK/ERK activity, against which type I RAF inhibitors have limited efficacy. Type II RAF inhibitors stabilize RAF in an inactive conformation and inhibit both dimer protomers, thus inhibiting downstream MAPK/ERK activity in the setting of BRAF fusions. CASE PRESENTATION: A previously-healthy 33 year old man was diagnosed with DL-GNT, which harbored a pathogenic BRAF:KIAA1549 gene fusion. He was initially treated with a MEK inhibitor but developed drug-related cardiotoxicity. Without treatment, he developed significant functional limitations due to leptomeningeal disease. A compassionate use indication was pursued for an investigational CNS-penetrant type II BRAF inhibitor, tovorafenib. Within 3 months of initiating the medication, the patient experienced notable gains in functional status and with over 12 months of treatment has been able to rejoin recreational activities.

conclusionsThis case highlights the importance of tumor molecular characterization, particularly in rare tumors, whereby identification of the BRAF:KIAA1594 gene fusion led to an appropriate selection of a type II BRAF inhibitor.