Abstract 575: 225Ac-SSO110 as next-generation SSTR2 targeting radiopharmaceutical for small cell lung cancer

SSO110 (DOTA-JR11) is a somatostatin receptor 2 (SSTR2) antagonist currently under clinical development in small cell lung cancer (SCLC). SSO110 targets a higher number of SSTR2 binding sites and shows longer tumor retention than the SSTR2 agonist DOTATATE translating into higher anti-tumor efficacy of 177Lu-SSO110 compared to 177Lu-DOTATATE. The aim of this study was to identify the most potent radioisotope (225Ac, 212Pb, 161Tb, 177Lu) for SSO110 in comparison to DOTATATE to guide further clinical development. Balb/c or Swiss nude mice were engrafted with SSTR2-positive xenografts NCI-H69 (SCLC model) or AR42J (pancreatic cancer model). The therapeutic efficacy of 225Ac, 161Tb-, 212Pb-, and 177Lu-labelled SSO110 was compared to 225Ac- and 161Tb-labelled DOTATATE after single-dose intravenous injection. In the NCI-H69 SCLC model, 20 MBq 177Lu-SSO110 and 21 kBq 225Ac-SSO110 demonstrated significantly better anti-tumor efficacy than 42 kBq 225Ac-DOTATATE, 20 MBq 161Tb-DOTATATE, or 20 MBq 161Tb-SSO110. Most remarkably, a single dose of only 30 kBq 225Ac-SSO110 (human equivalent dose: 7.3 MBq) induced complete tumor remissions and long-term survival. Various doses of 212Pb-SSO110 were less or equally effective than 177Lu-SSO110. In contrast to treatment with 225Ac-SSO110, no complete remissions were induced with 212Pb-SSO110. In the AR42J model, 37 kBq 225Ac-SSO110 induced tumor growth inhibition immediately after treatment and tumor volume remained low and constant leading to 100% survival of all animals. Histopathological assessment of the tumors showed a lower mitotic index, higher necrosis and a regressing phenotype of neoplastic cells in comparison to tumors from the vehicle group (median survival of 11 days). 37 kBq 225Ac-DOTATATE could not control tumor growth and median survival was reached after 33 days. 20 MBq 161Tb-SSO110 induced a slightly stronger tumor growth delay than 20 MBq 177Lu-SSO110 (median survival 36 vs 30.5 days). All treatments were well-tolerated. The preclinical in vivo comparison demonstrates superior efficacy of SSO110 over DOTATATE across all isotopes tested (Lu-177, Ac-225, Tb-161). Our results highlight the exceptionally strong anti-tumor efficacy of 225Ac-SSO110 in vivo even at low, single doses. Interestingly, 212Pb-SSO110 was not superior to 177Lu-SSO110 and 225Ac-SSO110, most likely due to the long tumor half-life of SSO110 (>7 days) that matches better with the long-lived isotopes Ac-225 and Lu-177. 161Tb-SSO110 demonstrated modestly better efficacy than 177Lu-SSO110, but only in the AR42J model with high and homogenous target expression. Based on promising emerging clinical data from the LuSato1 study with 177Lu-SSO110 and the outstanding preclinical activity of 225Ac-SSO110, a global phase I/II clinical study with 225Ac-SSO110 in patients with ES-SCLC or Merkel Cell Carcinoma on Immune-Checkpoint Inhibitor monotherapy is being initiated. Citation Format: Anika Jaekel, Prachi Desai, Manuel Sturzbecher-Hoehne, Dennis Mewis, Germo Gericke, Manfred Ruediger. 225Ac-SSO110 as next-generation SSTR2 targeting radiopharmaceutical for small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 575.