NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer

Purpose Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC).

The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials.

In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC).

Methods A total of 184 TC patients with testing for NTRK gene fusions were included.

Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan–Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy.

Results 8/184 (4%) patients harbored NTRK gene fusions.

Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 ( n  = 4) and NTRK3 ( n  = 2) gene fusions were treated with larotrectinib.

Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy.

All patients had morphologically progressive disease before treatment initiation.

Objective response rate was 83%, including two complete remissions.

Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0–57.4) and median OS was not reached (NR) (95% CI, NR).

Adverse events were of grade 1–3.

Conclusion The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients.

Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.