Oncology

Gastroenteropancreatic Neuroendocrine Tumors

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Updates on Alpha-Particle–Emitting Somatostatin Analogues

conference reporter by Jennifer R. Eads, MD
Overview

Given the efficacy of beta-particle–emitting SSAs for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the development of alpha-particle–emitting SSAs has also become a major area of interest. At the North American Neuroendocrine Tumor Society (NANETS) 2024 Multidisciplinary NET Medical Symposium, researchers discussed the available data on and the potential clinical relevance of these therapies for GEP-NETs.

 

Following these presentations, featured expert Jennifer R. Eads, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Eads are presented here.

“The hope with alpha-emitting therapy is that it may be a higher-impact therapy than beta-emitting therapy but also more refined in the sense that the particles are not as widely disseminated, so you get a really large focal hit.”
— Jennifer R. Eads, MD

There is a lot of interest in alpha-emitting somatostatin therapy, particularly in agents using lead and actinium, but the reality of the situation is that we have very little information about it as of yet because studies are still ongoing. The hope with alpha-emitting therapy is that it may be a higher-impact therapy than beta-emitting therapy but also more refined in the sense that the particles are not as widely disseminated, so you get a really large focal hit. I think that this, theoretically, sounds promising, and, anecdotally, one of my patients was treated with an alpha therapy overseas and had an amazing response. However, I am concerned about the potential for toxicities associated with alpha-emitting therapy, both short- and long-term. The combination of using radioligand therapy and having patients who are living longer because of more effective therapies means that they may be more apt to develop long-term toxicities. The risk of cytopenias and the potential development of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are particularly concerning to me, and the risk of MDS and AML was a topic of discussion in a presentation from Yusuf Menda, MD, during a symposium on advancements and challenges of radiopharmaceutical therapy for NETs at the NANETS 2024 Multidisciplinary NET Medical Symposium.

 

I think it is great that there are a lot of different alpha-emitting agents that are being considered and a lot of ongoing studies that are evaluating them. The field seems kind of crowded, though. If they all work, will US Food and Drug Administration (FDA) approval be based on which one is easiest to manufacture or obtain? There is an alpha-emitting therapy study being conducted at Penn, and, for a period, it was essentially paused because we could not get the actinium. So, if it is that hard to generate or find the alpha-emitting agent, what does that mean long-term? Especially since there are many other diseases beyond NETs where radioligand therapies are starting to be used. If many people are using these agents, will there be a limit as to how much is going to be available? This was discussed in a talk by Cathy Cutler, PhD, during the same symposium at NANETS 2024.

 

Also at the NANETS 2024 Multidisciplinary NET Medical Symposium, Jonathan R. Strosberg, MD, presented phase 2 data on 212Pb-DOTAMTATE from the ALPHAMEDIX 02 trial in patients with advanced SSTR-positive GEP-NETs (abstract 28402). We have not had any other agent with an overall response rate like the approximately 54% reported for PRRT-naive patients in this abstract. I think that we need a larger randomized study to confirm this. In his presentation, Dr Strosberg mentioned that dysphagia was reported with some patients in the study. As far as I know, there is nothing that is targeting the esophagus with this therapy. It is not like how it is with esophageal cancer, where you give the patient radiation therapy to the esophagus and they can develop dysphagia, which makes sense. This is a systemic therapy, and, as far as we are aware, it does not target the esophagus specifically, so it is unclear why it would cause dysphagia. I am not sure what to make of that, but this is another reason larger studies and more information are needed.

References

Bhimaniya S, Shah H, Jacene HA. Alpha-emitter peptide receptor radionuclide therapy in neuroendocrine tumors. PET Clin. 2024;19(3):341-349. doi:10.1016/j.cpet.2024.03.005

 

Cutler C. Sourcing and availability: issues with alpha emitters and post-Azedra therapy options [NANETS/Society of Nuclear Medicine and Molecular Imaging Joint Symposium: Radiopharmaceutical therapy for NETs: advancements and challenges]. Symposium presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Menda Y. Demystifying alpha emitters: therapy expectations, dosimetry, and active clinical trials [NANETS/Society of Nuclear Medicine and Molecular Imaging Joint Symposium: Radiopharmaceutical therapy for NETs: advancements and challenges]. Symposium presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Rubira L, Deshayes E, Santoro L, Kotzki PO, Fersing C. 225Ac-labeled somatostatin analogs in the management of neuroendocrine tumors: from radiochemistry to clinic. Pharmaceutics. 2023;15(4):1051. doi:10.3390/pharmaceutics15041051

 

Strosberg JR, Naqvi S, Cohn AL, et al. Targeted alpha therapy with 212Pb-DOTAMTATE in subjects with advanced somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors [abstract 28402]. Abstract presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Strosberg JR. Targeted alpha therapy with 212Pb-DOTAMTATE in subjects with advanced somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors [Featured abstracts 1: advances in PRRT]. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

 

 

This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the North American Neuroendocrine Tumor Society.

Jennifer R. Eads, MD

Professor of Medicine
Physician Lead, GI Clinical Research
Director, National Clinical Trials Network
Director, Penn Neuroendocrine Tumor Program
Division of Hematology and Oncology
University of Pennsylvania, Abramson Cancer Center
Perelman Center for Advanced Medicine
Philadelphia, PA

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