Long-Term Efficacy and Safety of Larotrectinib in Patients with Advanced TRK Fusion-Positive Thyroid Carcinoma

• Tropomyosin receptor kinase (TRK) fusions are rare but recurrent oncogenic drivers.
  • TRK expression is primarily limited to the nervous system
  • Three structurally related TRK receptors are encoded by three distinct genes
    • TRKA, TRKB and TRKC are encoded by NTRK1, NTRK2 and NTRK3, respectively
    • NTRK gene fusions encode TRK fusion proteins with highly active kinase activity that drive tumorigenesis
  • NTRK gene fusions have been identified across diverse pediatric and adult cancers
  • Occur in up to 1% of all solid tumors andin 5–25% of thyroid cancers
  • Larotrectinib is a first-in-class, highly selective, and CNS-active TRK inhibitor
• Methods
  • 29 patients, both adult and pediatric, with measurable metastatic or locally advanced TRK fusion thyroid cancer
    • The primary endpoint for this study isobjective response rate and the secondary endpoints were duration of response, progression free survival, overall survival, and safety.
    • Adult patients received larotrectinib 100mg twice daily and pediatric patients received 100mg/m2 twice daily.
• Results
  • Among 28 evaluable patients, ORR was 71% (95% confidence interval [CI] 51-87): 2 (7%) complete responses, 18 (64%) partial responses, 4 (14%) stable disease, 3 (11%) progressive disease, and 1 (4%) not determined.
  • ORR was 86% (95% CI 64-97) among patients with differentiated TC (DTC) and 29% (95% CI 4-71) among those with ATC.
    • Median time to response was 1.87 months (range: 1.64–3.68 months)
    • At the data cut-off, 6 patients (21%) had progressed with 4 (14%) continuing treatment post-progression
    • Patients with ATC were more likely to discontinue due to progressive disease than patients with DTC
    • Treatment was ongoing in 19 patients (66%) at data cut-off
    • Safety:
      • TEAEs were mainly Grade 1–2
      • Grade 3 TRAEs occurred in 2 (7%) patients: Anemia and lymphocyte count decreased
      • 2 (7%) patients had a Grade 5 TEAE - metastatic papillary thyroid cancer, tracheal hemorrhage in an anaplastic patient, both unrelated to larotrectinib
      • No patients discontinued treatment due to TEAEs; 2 patients with dose reductions
• Conclusions
  • NTRK gene fusions are identified in various thyroid carcinoma histologies and across the age spectrum
  • Larotrectinib demonstrated a high ORR (71%) and rapid and durable disease control in patients with TRK fusion thyroid carcinoma, especially those with differentiated thyroid carcinoma
  • Larotrectinib demonstrated a favorable safety profile and was
    well-tolerated
  • Testing for NTRK gene fusions in advanced thyroid carcinoma patients requiring systemic therapy should be considered

1. Waguespack SG, Drilon A, Lin JJ, et al. Long-Term Efficacy and Safety of Larotrectinib in Patients with Advanced TRK Fusion-Positive Thyroid Carcinomapresented at: 2021 American Thyroid Association, September 30-October 1, 2021; Abstract 15.