Larotrectinib to Enhance RAI Avidity in Patients with Differentiated Thyroid Cancer Harboring NTRK fusions

Rákkutatás · Thyroid cancer

Larotrectinib administered before radioactive iodine therapy may improve outcomes in patients with differentiated thyroid cancer harboring NTRK fusions.

^211At, a cyclotron‑produced b1‑emitter, has attracted interest as a potential alternative to radioactive iodine (RAI) because of its superior cytotoxic properties. This first‑in‑human prospective clinical trial aimed to evaluate the safety and preliminary efficacy of [^211At]NaAt in patients with differentiated thyroid cancer (DTC). Eleven patients with metastatic RAI‑refractory DTC were enrolled. A single intravenous dose of [^211At]NaAt was administered in the setting of recombinant human thyroid‑stimulating hormone (rhTSH) stimulation and an iodine‑restricted diet. Dose escalation followed a modified 3+3 design, with doses of 1.25, 2.5, and 3.5 MBq/kg. The primary endpoint was the assessment of adverse events (AEs) and dose‑limiting toxicities (DLTs) using Common Terminology Criteria for Adverse Events version 5.0. Secondary endpoints included evaluation of pharmacokinetics, absorbed dose, and therapeutic efficacy. Dose‑limiting toxicities occurred in 3 of 6 patients who received 3.5 MBq/kg, consisting of grade 3 hematologic toxicity (lymphopenia or leukopenia) lasting more than 1 wk. Other major AEs included salivary gland swelling (predominantly grade 2), xerostomia (grades 1‑2), nausea (grade 2), decreased appetite (grade 2), and vomiting (grade 2). A reduction of >50% in rhTSH‑stimulated thyroglobulin levels was observed in 1 of 3 patients (33%) who received 2.5 MBq/kg and 2 of 5 patients (40%) who received 3.5 MBq/kg. At 6 mo, CT‑based evaluation showed stable disease (SD) in 9 patients (90%) and progressive disease in 1 patient (10%). ^131I SPECT imaging revealed SD in the only patient who received 1.25 MBq/kg. Of the 3 patients treated with 2.5 MBq/kg, a partial response was seen in 1 patient (33%) and SD in 2 patients (67%). Of the 5 patients who received 3.5 MBq/kg, complete response, partial response, and progressive disease were noted in 1 patient (20%) each, and SD was found in 2 patients (40%). Targeted b1‑therapy with [^211At]NaAt was well tolerated and showed preliminary efficacy in patients with RAI‑refractory DTC, supporting further clinical investigations.

LANTERN gives patients with advanced thyroid cancer a chance to try a new treatment that might work better than RAI therapy alone, potentially improving disease control and reducing the risk of metastatic progression.

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