First-in-human study of the novel fibroblast activation protein-targeted 4-1BB agonist RO7122290 in patients with advanced solid tumors

ABSTRACT: This first-in-human (FIH) study evaluated RO7122290, a novel, bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein-α (FAP) binding site that effectively co-stimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced and/or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with 120mg fixed dose of the anti-PD-L1 antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 mg and 45 to 2000 mg, respectively. Three dose-limiting toxicities (DLTs) were reported, two at different RO7122290 single-agent dose levels (grade 3 febrile neutropenia, grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose (MTD) was identified. The pharmacokinetic (PK) profile of RO7122290 was typical of target-mediated drug disposition. The observed modulation of proximal and distal pharmacodynamic (PD) biomarkers is consistent with the postulated immune mode of action (MoA). Treatment-induced PD changes included an increase of proliferating and activated T cells in peripheral blood both in the single agent and combination arm. Furthermore, we observed an increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells for both treatment regimens, accompanied with the up-modulation of T cell activation genes and gene-signatures. Eleven patients experienced a complete or partial response, from which six were confirmed immune checkpoint inhibitor (CPI)-naive patients. Our results support continued evaluation of RO7122290 in combination with atezolizumab and other immuno-oncology agents.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212521 | GEO | 2022/11/16

REPOSITORIES: GEO