Larotrectinib is an FDA-approved TRK inhibitor with demonstrated efficacy in TRK fusion–positive malignancies, including primary brain tumors. NTRK fusions have been associated with favorable intracranial responses in pediatric and adult gliomas. However, data on the use of larotrectinib in gliomas with NTRK amplification, as opposed to fusions, remains lacking

A single-patient case report. The following where chart reviewed and analyzed: Clinical history, imaging, pathology, and treatment course to assess response to larotrectinib.

A 51-year-old man with multifocal, MGMT-unmethylated glioblastoma underwent resection followed by chemoradiation with temozolomide, six cycles of adjuvant temozolomide, and tumor treating fields. Four months after completing therapy, he developed progressive disease with a new left temporal lesion. He received radiation and bevacizumab, then was initiated on larotrectinib. Despite five months of therapy, disease progression continued, leading to discontinuation. Third-line lomustine and bevacizumab were subsequently initiated. Unlike reports of larotrectinib activity in NTRK fusion–positive gliomas, no clinical or radiographic response was observed in this patient with NTRK2 amplification.

In patients with glioblastoma with NTRK amplification, this case suggests limited benefit with treatment with Larotrectinib as compared to previously demonstrated significant efficacy in NTRK fusion–positive gliomas. These findings highlight the necessary requirements to distinguish between NTRK fusions and amplifications when clinically considering targeted TRK inhibition. This case reports bridges the importance of molecular profiling to guide therapy selection.