Dosimetry Results from the Phase 1b/3 ACTION-1 Trial of [<sup>225</sup>Ac]Ac-DOTATATE (RYZ101) in Patients with Somatostatin Receptor-Expressing, Well-Differentiated GEP-NETs.

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are biologically and clinically heterogeneous tumors, most of which overexpress somatostatin receptors (SSTRs). The presence of SSTRs enables staging and allows patient selection for treatment with radiolabeled somatostatin analogs (SSAs), such as DOTATATE. [225Ac]Ac-DOTATATE is an α-emitting radiopharmaceutical in development for the treatment of patients with SSTR2-expressing solid tumors. α particles have a shorter path length and higher linear energy transfer than do β particles, leading to largely irreparable double-strand DNA breaks and cytotoxicity. ACTION-1 (NCT05477576) is a 2-part, randomized, controlled, open-label, phase 1b/3 trial of [225Ac]Ac-DOTATATE in patients with SSTR-expressing GEP-NETs whose disease progressed after 177Lu-labeled SSA therapy. ACTION-1 included a dosimetry substudy to determine the feasibility of obtaining imaging data with 225Ac. The objectives of the substudy were to estimate radiation absorbed doses of [225Ac]Ac-DOTATATE in critical organs and tumors. Methods: [225Ac]Ac-DOTATATE was administered intravenously every 8 wk for 1-4 cycles to adults with grade 1 or 2, well-differentiated, inoperable SSTR2-expressing GEP-NETs that progressed after 2-4 cycles of 177Lu-lableled SSA. Dosimetry was assessed after cycles 1 and 4 of [225Ac]Ac-DOTATATE via SPECT/CT of 221Fr (4.8-min half-life), the first daughter and surrogate for 225Ac and 213Bi (46.6-min half-life, surrogate for later daughters). Absorbed doses and absorbed dose coefficients adjusted for a relative biological effectiveness factor of 5 (ADCRBE=5) to target tissues and tumors were calculated; tumor doses were estimated by MIRD S-value methodology. Results: Dosimetry data were obtained from 9 of 17 patients in phase 1b, each completing 4 cycles. 213Bi mostly remained with DOTATATE in the tumors; a minor fraction went to the kidneys. The estimated absorbed doses to kidneys and red bone marrow were 22.3 and 1.1 Gy, respectively. The ADCRBE=5 to selected tumors ranged from 488 to 8775 mGy/MBq across both treatment cycles. The ADCRBE=5 for most tumors was lower in cycle 4 than in cycle 1; many tumors defined in cycle 1 were unidentifiable in cycle 4. Conclusion: Dosimetry data from ACTION-1 demonstrated the feasibility of image-based dosimetry of 225Ac through SPECT/CT imaging of 221Fr and 213Bi. The 213Bi daughter mostly remained with DOTATATE in tumors, decaying at the same location as 221Fr. The favorable tumor-to-normal tissue absorbed dose ratio of [225Ac]Ac-DOTATATE supports its use in patients with SSTR-expressing GEP-NETs.