Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma

<jats:sec> <jats:title>Objective</jats:title> <jats:p> Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Twenty-nine patients (median age: 60; range: 6–80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51–87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Median time to response was 1.87 months (range 1.64–3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1–2.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p> In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance statement</jats:title> <jats:p>NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.</jats:p> </jats:sec>