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

gene fusions encode TRK fusion proteins with highly active kinase activity that drive tumorigenesis

 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

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.

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

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

 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

 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.

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Dr. Waguespack reviews efficacy and safety data for larotrectinib in patients with TRK fusion-positive thyroid carcinoma. 

Steven Waguespack, MD

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