[ ²²⁵ Ac]Ac-AKY-1189, a Nectin-4 targeted radiopharmaceutical, in patients with previously treated locally advanced or metastatic solid tumors: Phase 1b Nectinium-2 study.

TPS902 Background: Nectin-4 is a clinically validated target in metastatic urothelial cancer and is over-expressed in multiple additional solid tumor types suggesting a broad therapeutic potential. AKY-1189 is a high affinity and selective Nectin-4 targeted miniprotein which is rapidly cleared from plasma and shows a favorable normal tissue biodistribution in humans when conjugated to 68 Ga (Sathekge et al, 2024). [ 225 Ac]Ac-AKY-1189 is under development for the treatment of patients with locally advanced or metastatic solid tumors. [ 225 Ac]Ac-AKY1189 has been shown to induce regression and stasis in preclinical models of urothelial carcinoma after a single administration. Target-dependent efficacy of the radiopharmaceutical is observed at well-tolerated dosages. Available data support investigating the efficacy and safety of [ 225 Ac]Ac-AKY-1189 in a clinical study. Methods: The NECTINIUM-2 (NCT07020117) study is a first in human, phase 1b, 2-part (dose escalation and dose expansion), multi-center, open-label study of [ 225 Ac]Ac-AKY-1189. Key inclusion criteria are age ≥18 years; histologically or cytologically confirmed locally advanced or metastatic solid tumors; ≥1 measurable lesion per RECIST v1.1; ECOG of 0 or 1; adequate end-organ function; documented progression on prior lines of chemotherapy in the metastatic setting; and tumor uptake on a [ 64 Cu]Cu-AKY-1189 PET/CT scan. Key exclusion criteria are prior radiopharmaceutical therapy; investigational treatment in the past 4 weeks; and anticancer therapy or external beam radiotherapy in the past 3 weeks. The Part 1 dose escalation will investigate ascending doses of [ 225 Ac]Ac-AKY-1189 (up to 6 cycles) in ~30 patients with locally advanced or metastatic urothelial cancer. The aim of Part 1 is to determine the maximum tolerated dose (MTD) or maximum administrated dose (MAD) and the recommended Part 2 dose (RP2D) of [ 225 Ac]Ac-AKY-1189. Once RP2D is established, part 2 will evaluate the clinical activity of [ 225 Ac]Ac-AKY-1189 in 3 cohorts of patients with Nectin-4 positive solid tumors. NECTINIUM-2 has started enrolling subjects in the United States. Clinical trial information: NCT07020117 .