LAUSR

TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion cancers (Drilon et al., NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors. Patients with primary CNS tumors harboring a TRK fusion treated with larotrectinib on two clinical trials (NCT02637687 and NCT02576431) were identified by local molecular testing. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019. 18 patients with various histological types of glial tumors (11 high-grade, 4 low-grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n=13), NTRK1 (n=2) and NTRK3 (n=2); one was not determined. Median age was 10 years (range 1–79); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR, 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. One patient (3.7 years old) with glioblastoma progressed after 5.5 months on larotrectinib. Sequencing revealed a solvent front mutation and the patient was subsequently enrolled in compassionate use protocol for BAY2731954 (formerly known as LOXO-195). Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Confirmed responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors.