HGG-15. SUCCESSFUL TREATMENT OF AN NTRK-FUSION POSITIVE INFANTILE GLIOBLASTOMA WITH LAROTRECTINIB, A TARGETED TRK INHIBITOR

Abstract

PURPOSE: Targeted inhibition of NTRK-fusion proteins has shown promise in treatment of infantile fibrosarcoma in a phase 1 open-label study. Herein we report successful treatment of an NTRK-driven infantile glioblastoma with larotrectinib, a small molecule TRK inhibitor. RESULTS: A 2-month-old term female presented with hydrocephalus due to 10-cm right frontal lobe mass plus leptomeningeal (LM) dissemination to the posterior fossa and spinal cord. She underwent a sub-total resection of the supratentorial tumor, which harbored an in-frame TPM3-NTRK1 activating fusion as the solitary pathogenic alteration, absent alterations involving IDH1, IDH2, H3F3A, HIST1H3B, ATRX, TERT, TP53, SETD2, PPM1D, ACVR1, MET, EGFR, PTEN, NF1, BCOR, BCORL1, BRAF, RAF1, FGFR1, CIC, or INI1. She received 1 cycle of oral etoposide without response and then started larotrectinib (LOXO-101) 100 mg/m² BID (NCT03025360). Due to neutropenia, dose reductions were required to 25 mg/m²BID. Tumor responses noted were an initial decrease in the intensity of LM Gadolinium enhancement followed by measurable decrease in the frontal lobe tumor bulk after 6 cycles. At age 17 months, larotrectinib was held for a procedure (shunt revision) unrelated to the therapy during which time there was evidence of tumor growth. Upon restarting larotrectinib, decrease in the size of intracranial enhancing lesions and stabilization of LM disease was noted again. She is currently 22 months old with resolved neutropenia and is tolerating full dose (100mg/m²BID) larotrectinib. CONCLUSION: Our experience with targeted treatment for NTRK-driven infantile glioblastoma demonstrates favorable early results even in the setting of disseminated disease. However, long-term outcomes for TRK inhibitor therapy have not been established. Treatment with small molecule inhibitors targeting the kinase gene fusions that are frequent in infantile glioblastomas may allow for delaying radiation therapy during this critical developmental period. Genomic testing should be considered an essential screening study for this tumor population.