INNV-49. Efficacy of TRK inhibitors in NTRK2 fusion-positive high-grade glioma: clinical and molecular insights from two cases

Abstract Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare in high-grade gliomas. The FDA approved the use of selective TRK inhibitors in 2018 for TRK fusion-positive cancers. However, clinical evidence in gliomas remain limited due to the rarity of these mutations. We present the clinical course of two adult patients with high grade glioma who were successfully treated with TRK inhibitors. Both patients presented with seizures and were found to have high grade glioma of the temporal lobe. NTRK2 fusion was detected via next-generation sequencing (NGS) testing. They underwent standard of care treatment including surgical resection and concurrent chemoradiation. TRK inhibitor therapy was added to conventional adjuvant chemotherapy in the adjuvant setting. Patients were evaluated monthly for clinical response and side effect profile, and magnetic resonance imaging of the brain was obtained every other month to ensure response. At the time of disease progression, these patients underwent surgical resection with NGS testing repeated on recurrent disease. Follow up NGS showed loss of NTRK2 fusion, suggesting successful treatment of the targeted NTRK fusion. This case series shows potential benefit of integrating TRK inhibitors with standard chemotherapy in NTRK fusion-positive high-grade gliomas. The evolution in NGS findings highlight the heterogeneous and evolving nature of tumor microenvironment and support obtaining serial molecular testing, when possible, to guide treatment planning. Further prospective studies are needed to validate these findings, evaluate long-term outcomes, and better understand the resistance mechanism in this patient population.