Peptide Receptor Radionuclide Therapy (PRRT) Using Actinium-225- and Ac-225/Lutetium-177-Labeled (TANDEM) Somatostatin Receptor Antagonist DOTA-LM3 in Patients with Neuroendocrine Neoplasm: A Retrospective Study Concerning Safety and Survival.

Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective study aimed to assess [225Ac]Ac-DOTA-LM3 safety in advanced NEN patients (as monotherapy and with Lutetium-177 as TANDEM), survival, and follow-up duration. Thirty-five patients received a total of 57 [225Ac]Ac-DOTA-LM3 cycles (March 2022-September 2024): 24 monotherapies and 33 TANDEM therapies. The pancreas was the most common primary site (n = 19). PRRT-related toxicity was assessed, focusing on hematological, renal, and hepatic toxicity (Common Terminology Criteria for Adverse Events-CTCAE v5.0). Therapy was generally well tolerated, with mostly mild acute adverse events (primarily nausea, n = 8). Some new grade 3/4 long-term adverse events were reported after treatment: anemia grade 3 (n = 2), leukocytopenia grade 4 (n = 1), absolute neutrophil count reduction grade 3 (n = 1), thrombocytopenia grade 3 (n = 7), acute myeloid leukemia (n = 1), nephrotoxicity grade 3 (n = 2), and hepatotoxicity grade 3 (n = 2). During follow-up, 13 patients died (survival range 5-30 months); 22 patients were alive (follow-up range 1-18 months). Our retrospective analysis shows that [225Ac]Ac-DOTA-LM3 PRRT is relatively safe concerning acute and long-term toxicity and bears promising survival outcomes in patients progressing after [177Lu]Lu-DOTATATE or [177Lu]Lu-DOTATOC PRRT.