RYZ101 (Ac-225 DOTATATE) Opportunity Beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small Cell Lung Cancer.

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). SCLC accounts for approximately 13%-15% of lung cancer and lacks effective therapeutic options. Immunohistochemical analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analog, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analog. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki=0.057nM) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 uCi (0.111 MBq) or 4 uCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The anti-tumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.