Next-Generation Targeted Alpha Therapy using Astatine Shows Promise in Thyroid Cancer Resistant to Conventional Treatment

Reston, VA (December 4, 2025)--A new targeted alpha therapy is showing promise for patients whose thyroid cancer no longer responds to radioactive iodine, the standard beta-emitting treatment. In a first-in-human study, investigators found that a single dose of the alpha-emitting radionuclide ²¹¹At (astatine) 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 refractory to radioactive iodine. At that point, molecular-targeted agents, such as kinase inhibitors, are used to treat radioactive iodine-resistant DTC.

"Molecular-targeted agents can be challenging 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,"  said Tadashi Watabe, MD, PhD, FANMB, nuclear medicine physician at the Graduate School of Medicine at the University of Osaka in Japan. "Therefore, there is a clinical need for next-generation radiopharmaceutical therapy with improved tolerability and efficacy that can be used to treat radioactive iodine-refractory patients."

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

The researchers found that targeted alpha-therapy using ²¹¹At-NaAt can be safely administered to patients with DTC. Although dose-limiting toxicities were observed with the 3.5 MBq/kg dose, toxicities remained within a tolerable range. Preliminary evidence of efficacy was observed in some patients treated with either 2.5 or 3.5 MBq/kg, including thyroglobulin reductions of 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 both feasible and therapeutically promising in patients who no longer respond to conventional radioactive iodine,"  stated Watabe. "Because ²¹¹At (astatine) therapy may achieve disease control without requiring molecular targeted drugs, it has the potential to reduce treatment burden, limit adverse effects associated with systemic therapies, and broaden 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."

Figure: (Upper) Graphical abstract illustrating the concept of targeted alpha therapy using [²¹¹At]NaAt in patients with radioactive iodine--refractory differentiated thyroid cancer (DTC). (Lower) Representative ¹³¹I planar and SPECT/CT images in patient with follicular thyroid cancer with multiple bone metastases after administration of [²¹¹At]NaAt (3.5 MBq/kg). ¹³¹I accumulation in lumbar spine and sacral metastases almost disappeared over time.

The authors of "First-in-Human Study of [²¹¹At]NaAt as Targeted α-Therapy in Patients with Radioiodine-Refractory Thyroid Cancer (Alpha-T1 Trial)" include Tadashi Watabe and Noriyuki Tomiyama, Department of Radiology, Graduate School of Medicine, University of Osaka, Osaka, Japan, and Institute for Radiation Sciences, University of Osaka, Osaka, Japan; Kosuke Mukai, Tomoaki Hayakawa, Atsunori Fukuhara, Toru Takano, and Iichiro Shimomura, Department of Metabolic Medicine, Graduate School of Medicine, University of Osaka, Osaka, Japan; Sadahiro Naka, Department of Pharmacy, University of Osaka Hospital, Osaka, Japan; Hidetaka Sasaki and Takashi Kamiya, Department of Medical Technology, University of Osaka Hospital, Osaka, Japan; Yoshifumi Shirakami, Kazuhiro Ooe, and Atsushi Toyoshima, Institute for Radiation Sciences, University of Osaka, Osaka, Japan; Satoshi Shigeno, Department of Gastroenterology and Hepatology, Graduate School of Medicine, University of Osaka, Osaka, Japan, and Medical Innovation Center, University of Osaka Hospital, Osaka, Japan; Satomi Okamura and Kazuho Masumura, Medical Innovation Center, University of Osaka Hospital, Osaka, Japan; Eisuke Hida, Department of Biostatistics and Data Science, Graduate School of Medicine, University of Osaka, Osaka, Japan; Hiromitsu Haba, RIKEN Nishina Center for Accelerator-Based Science, Wako, Japan; and Kayako Isohashi, Department of Radiology, Graduate School of Medicine, University of Osaka, Osaka, Japan.

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