Long-term efficacy and safety of larotrectinib (laro) in patients (pts) with TRK fusion thyroid carcinoma (TC).
Authors: Cabanillas Maria E. , Lin Jessica Jiyeong , Brose Marcia S. , McDermott Raymond S. , Almubarak Mohammed , Bauman Jessica R , Casanova Michela , Kummar Shivaani , Lee Se-Hoon , Leyvraz Serge , Oh Do-Youn , Shen Lin , Neu Natascha , Bernard-Gauthier Vadim , Mussi Chiara E. , Hong David S. , Drilon Alexander E. , Waguespack Steven G. 
Published: August 2024

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Background: NTRK gene fusions are oncogenic drivers in TC. Laro is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on overall response rate (ORR) in pts with various tumor types. Here, we report long-term efficacy and safety in a subset of pts with TRK fusion TC treated with laro. Methods: Pts with TRK fusion TC enrolled in 3 laro clinical trials (NCT02576431, NCT02122913, NCT02637687) were included. Laro was administered at 100 mg twice daily to most pts; 2 pediatric pts received 100 mg/m2. Responses were assessed per independent review committee (IRC) using RECIST v1.1. Results: As of July 20, 2023, 31 pts were enrolled and eligible for efficacy assessment by IRC. Of the 4 pts with known CNS metastases at baseline, 3 received prior cranial radiotherapy (2, 12 and 15 months prior to laro initiation, respectively). Median age was 60 years (range 6-80) and median time since initial cancer diagnosis was 5 years (range 0-46). All NTRK gene fusions were identified by next-generation sequencing (NGS). 17 pts (55%) received no prior systemic therapies, 6 (19%) received 2 or more; 22 (71%) received prior radioiodine. ORR was 65% (95% CI 45-81): 3 (10%) complete responses, 17 (55%) partial responses (PR), 5 (16%) stable disease (SD) (4 for >30 months), 4 (13%) progressive disease (PD), and 2 (6%) not evaluable. For pts classified as differentiated TC (DTC; n=24 [77%]), ORR was 79% (95% CI 58-93). For pts classified as anaplastic TC (ATC; n=7 [23%]), ORR was 14% (95% CI 0-58). There were 3 pts with poorly differentiated TC, 1 (3%) classified as DTC (PR) and 2 (6%) as ATC (1 SD for >39 months and 1 PD). Median time to response was 1.9 months (range 1.6-16.2) for all pts. Median duration of response was 40.5 months (95% CI 19.4-not estimable [NE]) at a median follow-up of 39.8 months. Median progression-free survival was 44.0 months (95% CI 16.6-NE) at a median follow-up of 38.7 months. Median overall survival (OS) was not reached (NR; 95% CI 48.7-NE) at a median follow-up of 58.0 months; the 48-month OS rate was 72% (95% CI 56-89). Median OS was NR (95% CI 56.3-NE) in DTC and 8.8 months (95% CI 2.6-NE) in ATC. Treatment duration ranged from 1 to 76+ months. At data cutoff, 11 pts had progressed, with 7 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 3 (10%) pts. There were no treatment discontinuations due to TRAEs. Conclusions: Laro continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in pts with TRK fusion DTC. Limited single-agent activity was observed in ATC. These results support the wider adoption of NGS panels, which include NTRK gene fusions in pts with advanced TC, to identify those who may benefit from targeted treatment. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .