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Alpha radioligand therapy in neuroendocrine neoplasms: current landscape and spotlight on RYZ101

Udhayvir S Grewal1,2, Olumide B Gbolahan3,4, Amol M Takalkar4,5

  • 1Division of Hematology, Oncology and Bone and Marrow Transplantation, University of Iowa Health Care, Iowa City, IA, USA.

Future Oncology (London, England)
|March 31, 2025
PubMed

Insights

Alpha radioligand therapy (RLT) agents like RYZ101 show promise for neuroendocrine tumors (NETs). This advanced RLT offers potential advantages over beta RLT, with ongoing trials evaluating its efficacy and safety.

Area of Science:

  • Oncology
  • Nuclear Medicine
  • Radiopharmaceutical Therapy

Background:

  • The treatment of neuroendocrine tumors (NETs) has expanded significantly with options like somatostatin analogs (SSAs), targeted therapies, chemotherapy, and radioligand therapy (RLT).
  • Beta-emitting RLT (e.g., 177Lu-DOTATATE) is approved for NETs, but its full therapeutic potential remains to be realized.
  • Alpha RLT agents present a novel approach with potential for greater efficacy and reduced side effects compared to beta RLT.

Purpose of the Study:

  • To review the current landscape of RLT for NETs and highlight the potential of alpha RLT agents, specifically RYZ101.
  • To discuss the mechanism of action, preclinical and clinical data, and ongoing trials investigating RYZ101 in NET patients.
  • To explore the future prospects of alpha RLT in enhancing NET treatment strategies.

Main Methods:

  • Review of existing preclinical and clinical data on alpha RLT agents, focusing on RYZ101 (225Ac-DOTATATE).
  • Analysis of the ongoing ACTION-1 phase 1b/3 trial comparing RYZ101 with standard care in advanced gastroenteropancreatic NETs.
  • Discussion of the comparative advantages of alpha RLT (e.g., DNA damage, targeted cytotoxicity) over beta RLT.

Main Results:

  • Preclinical and clinical data suggest favorable safety and efficacy profiles for RYZ101 in NET patients.
  • RYZ101 demonstrates potential for inducing more complex DNA breaks and targeted cytotoxicity.
  • The ACTION-1 trial is actively evaluating RYZ101 in patients with advanced NETs post-177Lu-SSA therapy.

Conclusions:

  • Alpha RLT agents, exemplified by RYZ101, represent a promising advancement in NET therapy.
  • RYZ101 offers a potential therapeutic advantage due to its mechanism of targeted cytotoxicity and DNA-damaging capabilities.
  • Further investigation and long-term data from ongoing trials are crucial to fully establish the role of alpha RLT in NET management.
Keywords:
225Ac-DOTATATENeuroendocrine neoplasmsalpha radioligand therapypeptide receptor radionuclide therapysomatostatin receptor targetingtargeted alpha therapy

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