Biom-102. Larotrectinib for NTRK Amplification in Glioblastoma: Case Report

We report a case of a 51-year-old man with left hemispheric multifocal, O6-methylguanine-DNA methyltransferase (MGMT) unmethylated glioblastoma with neurotrophic tyrosine receptor kinase 2 (NTRK2) amplification. He underwent complete resection of the dominant lesion followed by concurrent temozolomide with radiation and 6 cycles of adjuvant temozolomide as well as tumor treating fields. Four months after completion of standard treatment, he had progression of tumor (new left temporal tumor) for which he received radiation and two cycles of bevacizumab. Soon after completion of radiation he was initiated on larotrectinib (TRK inhibitor). He continued to have progressive disease despite receiving larotrectinib for 5 months. Larotrectinib was discontinued and third line treatment with lomustine and bevacizumab was initiated. Larotrectinib is a highly selective TRK inhibitor that has been approved to treat adult and pediatric patients with TRK fusion positive cancers. NTRK fusions have been reported in central nervous system tumors, particularly in pediatric high-grade gliomas, congenital glioblastomas, and some low-grade gliomas. Larotrectinib penetrates the blood-brain barrier and has demonstrated intracranial responses in patients with TRK fusion positive gliomas, including measurable tumor shrinkage and symptom improvement. However, there is no data of larotrectinib being used to treat CNS tumors with NTRK amplification. In a case report, treatment with larotrectinib in a patient with metastatic squamous cell esophageal carcinoma harboring NTRK1 gene amplification led to a partial response, evidenced by the rapid shrinkage of primary and metastatic tumors, however, subsequent disease progression was associated with the loss of NTRK1 amplification. Our patient with glioblastoma harboring NTRK2 gene amplification did not have response to larotrectinib. Larotrectinib has demonstrated efficacy in gliomas with NRTK fusions but may not have efficacy in gliomas with NRTK amplifications.