New targeted alpha therapy shows promise for patients with thyroid cancer refractory to radioactive iodine

A new targeted alpha therapy shows promise for patients whose thyroid cancer no longer responds to radioactive iodine, the standard beta-emitting treatment. In a first-in-human study, researchers found that a single dose of the alpha-emitting radionuclide 211At (astatin) was well tolerated and effective, achieving disease control without molecularly targeted drugs. The findings were published in the December issue of The Journal of Nuclear Medicine.

Beta-emitting radioactive iodine is the standard treatment for patients with recurrent or metastatic differentiated thyroid cancer (DTC) after total thyroidectomy. However, despite repeated administration, some patients experience disease progression and are classified as refractory to radioactive iodine. At that time, molecularly targeted agents, such as kinase inhibitors, are used to treat radioactive iodine-resistant DTC.

Molecular agents can be difficult for patients to take as they require daily oral administration and are associated with a high rate of adverse effects, including proteinuria and dermatological toxicity. “Therefore, there is a clinical need for a next-generation radiopharmaceutical therapy with increased tolerability and efficacy that can be used to treat patients refractory to radioactive iodine.”

Tadashi Watabe, MD, PhD, FANMB, nuclear medicine physician, Graduate School of Medicine, Osaka University, Japan

To address this problem, Watabe and colleagues developed a targeted alpha therapy using the radionuclide 211At-NaAt. In a phase I clinical trial, they used a dose escalation model (1.25, 2.5, and 3.5 MBq/kg) to evaluate the adverse events, pharmacokinetics, absorbed dose, and therapeutic efficacy of a single intravenous dose of 211At-NaAt in patients with radioactive iodine-resistant DTC. Response was assessed by thyroglobulin measurement, CT imaging, and 131I SPECT imaging.

Researchers found that 211At-NaAt-targeted alphatherapy can be safely administered to patients with DTC. Although dose-limiting toxicities were observed at the 3.5 MBq/kg dose, toxicities remained within a tolerable range. Preliminary evidence of efficacy was seen in some patients treated with 2.5 or 3.5 MBq/kg, including thyroglobulin reductions greater than 50 percent and decreased uptake in radioactive iodine-avid lesions on 131I SPECT.

“Our findings provide the first evidence that 211At-based therapy is feasible and therapeutically promising in patients who no longer respond to conventional radioactive iodine,” Watabe said. “Because 211At (astatin) therapy can achieve disease control without requiring molecularly targeted medications, it has the potential to reduce treatment burden, limit adverse effects associated with systemic therapies, and expand access to effective care for patients with refractory disease.”

“In addition,” he noted, “211At can be produced using accelerator cyclotrons, and its availability will expand globally as more production facilities come online. The successful clinical application of 211At in this study marks an important milestone for the field, opening the door to widespread adoption of cyclotron-based alpha therapy and accelerating future innovations in molecular imaging and targeted radionuclide therapy.”