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- Title
Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.
- Authors
Waguespack, Steven G.; Drilon, Alexander; Lin, Jessica J.; Brose, Marcia S; McDermott, Ray; Almubarak, Mohammed; Bauman, Jessica; Casanova, Michela; Krishnamurthy, Anuradha; Kummar, Shivaani; Leyvraz, Serge; Do-Youn Oh; Park, Keunchil; Sohal, Davendra; Sherman, Eric; Norenberg, Ricarda; Silvertown, Josh D.; Brega, Nicoletta; Hong, David S.; Cabanillas, Maria E.
- Abstract
Objective: 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). Methods: 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. Results: 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. Conclusion: 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. Significance statement 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 NTRK gene fusions by next-generation sequencing.
- Subjects
MEDULLARY thyroid carcinoma; THYROID cancer; PATIENT safety; ADVERSE health care events; GENE fusion; PROGRESSION-free survival; PAPILLARY carcinoma
- Publication
European Journal of Endocrinology, 2022, Vol 186, Issue 6, p631
- ISSN
0804-4643
- Publication type
Article
- DOI
10.1530/eje-21-1259