Response to a novel type II RAF inhibitor in diffuse leptomeningeal glioneuronal tumor with BRAF fusion.
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BACKGROUND: Diffuse 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. CONCLUSIONS: This 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.