Abstract 5042: Anti-tumor activity of RYZ101 (Ac-225 DOTATATE) in somatostatin receptor-expressing preclinical models of small-cell lung cancer
Authors: Han Guangzhou , Hwang Eunmi , Lin Fanching , Clift Renee , Kim Daniel , Bischoff Eric , Moran Susan , Li Gary 
Published: April 2023

Abstract
Introduction: Overexpression of somatostatin receptors (SSTRs), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and subsets of other solid tumors such as small-cell lung cancer (SCLC). β-emitting radiopharmaceutical therapy Lu-177 DOTATATE has been approved for SSTR-expressing (SSTR+) GEP-NETs, but the relatively low objective response rate and frequent post-treatment progression represent an unmet medical need. Based on preliminary clinical anti-tumor efficacy, RYZ101 (Ac-225 DOTATATE) is being developed for inoperable SSTR+ well-differentiated GEP-NETs with disease progression following Lu-177-somatostatin analogue (SSA) therapy (ACTION-1, NCT05477576). SCLC accounts for approx. 13% of lung cancer and lacks effective therapeutic options. Immunohistochemistry analysis indicates that ~50% of SCLC tumors are SSTR2+, with a substantial subset showing high and homogenous expression. The goal of this study was to provide preclinical support for RYZ101, as a single-agent or in combination with carboplatin and etoposide, for SSTR+ SCLC.
Methods: RYZ101 is comprised of the α-emitting radioisotope actinium-225, chemical chelator DOTA, and SSA octreotate (TATE). Binding affinity to human SSTR1-5 was determined using a competitive radioligand binding assay in engineered cell lines expressing individual SSTR. Internalization was measured by PathHunter SSTR2 Activated GPCR Internalization Assay. The preclinical biodistribution of RYZ101 was carried out in non-tumor-bearing BALB/c mice of both sexes. The efficacy studies were performed in cell line-derived and patient-derived xenograft (PDX) models of SCLC.
Results: In preclinical studies where Lanthanum (La3+) was used as a surrogate for Ac-225, RAYZ-10001-La (La-DOTATATE) had high binding affinity (Ki=0.057nM) to human SSTR2 (&gt;600-fold more potent than other SSTR subtypes) and exhibited efficient internalization. In a preclinical biodistribution study, RYZ101 performed similarly to Lu-177 DOTATATE. In multiple SCLC xenograft models, RYZ101 significantly inhibited tumor growth and prolonged survival, with deeper responses, including sustained regression, observed in the models with higher SSTR2 level. The anti-tumor effect was further enhanced when combining RYZ101 with carboplatin and etoposide at clinically relevant doses.
Conclusions: In summary, RYZ101 is a first-in-class, highly potent, α-emitting radiopharmaceutical therapy being developed for the treatment of SSTR+ solid tumors. Preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR+ SCLC.
Citation Format: Guangzhou Han, Eunmi Hwang, Fanching Lin, Renee Clift, Daniel Kim, Eric Bischoff, Susan Moran, Gary Li. Anti-tumor activity of RYZ101 (Ac-225 DOTATATE) in somatostatin receptor-expressing preclinical models of small-cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5042.