New targeted alpha therapy shows promise for patients with radioiodine-resistant thyroid cancer

A new targeted alpha therapy shows promise for patients whose thyroid cancer no longer responds to radioactive iodine, the standard beta-emitting therapy. In a first-in-human study, researchers found that a single dose of the alpha-emitting radionuclide ²¹¹At (astatin) was both 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 resistant to radioactive iodine. At this point, molecularly targeted agents such as kinase inhibitors are used to treat radioiodine-resistant DTC.

Molecularly targeted 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 dermatologic toxicity. Therefore, there is a clinical need for next-generation radiopharmaceutical therapy with improved 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, University of Osaka, Japan

To address this issue, 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 adverse effects, pharmacokinetics, absorbed dose, and therapeutic efficacy of a single intravenous dose ²¹¹At-NaAt in patients with radioiodine-refractory DTC. Response was assessed by thyroglobulin measurement, CT imaging and ¹³¹Imaging SPECCT.

Researchers found that targeted alpha-therapy using ²¹¹At-NaAt 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 reductions in thyroglobulin of more than 50 percent and reduced uptake in radioiodine lesions in ¹³¹SUBJECTS.

“Our findings provide the first evidence that ²¹¹Based therapy is feasible and promising in patients who no longer respond to conventional radioactive iodine,” said Watabe. “Because ²¹¹In therapy (astatin) can achieve disease control without the need for molecularly targeted drugs, 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.”

“Furthermore,” he noted,²¹¹At can be produced using cyclotron accelerators and its availability will expand worldwide as more production facilities come online. Its successful clinical application 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.”