Efficacy and safety of larotrectinib in patients with TRK fusion thyroid carcinoma: An updated analysis.

6094 Background: NTRK gene fusions are oncogenic drivers in various tumor types, including thyroid carcinoma (TC). Larotrectinib (laro) is the first-in-class, highly selective, central nervous system-active TRK inhibitor, approved for tumor-agnostic use in patients (pts) with TRK fusion cancer. Here, we report updated long-term efficacy and safety data in 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 (BID) to adults; 2 pediatric pts received 100 mg/m 2 BID (maximum dose 100 mg BID). Responses were independent review committee-assessed per RECIST v1.1. Data cutoff: July 20, 2024. Results: At data cutoff, 31 pts were enrolled; 24 (77%) had differentiated TC (DTC) and 7 (23%) had anaplastic TC (ATC). Median age was 60 years (range 6–80). Median time since initial cancer diagnosis was 5 years (range 0–46). Seventeen pts (55%) were systemic treatment-naïve in the metastatic/unresectable setting, 6 (19%) received 2 or more prior therapies, and 24 (77%) received prior radioiodine. All NTRK gene fusions were identified by next-generation sequencing. Overall response rate (ORR) was 65% (95% confidence interval [CI] 45–81): 3 (10%) complete responses, 17 (55%) partial responses (PR), 5 (16%) stable disease (SD), 4 (13%) progressive disease (PD), and 2 (6%) not evaluable. For pts classified as DTC, ORR was 79% (95% CI 58–93). For pts classified as ATC, ORR was 14% (95% CI 0–58). Three (10%) pts had poorly differentiated TC, 1 classified as DTC (PR) and 2 as ATC (1 SD for >36 months and 1 PD). Median time to response for all pts was 1.9 months (range 1.6–16.2). Median duration of response, progression-free survival, and overall survival (OS) were 35 months (95% CI 19–not estimable [NE]), 39 months (95% CI 17–NE), and not reached (NR; 95% CI 28–NE), respectively, at median follow-ups of 48, 42, and 68 months. Median OS was NR (95% CI 56–NE) in DTC and 9 months (95% CI 3–NE) in ATC. The 6-year OS rate for all pts was 60% (95% CI 41–79). The 6-year OS rate was 71% (95% CI 50–91) for pts with DTC and 17% (95% CI 0–46) for pts with ATC. Median duration of treatment was 31 months (range 1–88). At data cutoff, 7 (23%) pts remained on treatment, 5 of whom had disease control. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 5 (16%) pts. There were no discontinuations due to TRAEs. Conclusions: Laro demonstrates rapid and durable responses, extended survival, and a favorable safety profile in pts with TRK fusion DTC. Limited single-agent activity is observed in pts with ATC. This supports the use of a TRK inhibitor to treat TRK fusion DTC and the importance of testing for NTRK gene fusions in patients with advanced TC needing systemic therapy. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .