Redifferentiating Effect of Larotrectinib in NTRK-Rearranged Advanced Radioactive-Iodine Refractory Thyroid Cancer

Metastatic thyroid cancers may dedifferentiate and become radioactive-iodine (RAI) resistant. A redifferentiating effect can be observed with inhibitors of the mitogen-activated protein kinase pathway in thyroid cancers with point mutation in oncogenes. This effect allows RAI reuptake that may lead to a therapeutic effect different from the antitumoral effect of the inhibitor. The potential redifferentiating effect of inhibitors targeting oncogenic fusion-genes was suggested by one adult and one pediatric patient using larotrectinib in NTRK-rearranged tumors. We report on three consecutive adult patients with metastatic RAI-resistant NTRK-rearranged thyroid cancer who received larotrectinib for disease progression and for whom the redifferentiating effect was examined. Larotrectinib-induced RAI reuptake in all or part of the metastatic disease for two patients and no reuptake was noted for the other patient. We demonstrate that redifferentiation of NTRK-rearranged RAI-resistant thyroid cancer with larotrectinib may exist but does not occur in all patients.