A first-in-human study of the fibroblast activation protein–targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors.

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti–programmed death-ligand 1 (anti–PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8⁺ and Ki67⁺CD8⁺ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors. Costimulating T cells to treat tumors: Most patients with cancer do not respond to immune checkpoint inhibitors (ICIs). Co-stimulatory agents targeted to tumors could lead to enhanced immune system response and increased antitumor immunity in these patients. Here, Melero and colleagues studied the safety, mechanism of action, and activity of RO7122290, a fibroblast activation protein-α-targeted 4-1BB agonist designed to co-stimulate activated CD8⁺ T cells and natural killer cells, either as a single agent or when given with the ICI atezolizumab in patients with advanced solid tumors. Treatment resulted in increased proliferating and activated T cells in the peripheral blood and increased infiltration of intratumoral CD8⁺ cells. Eleven patients experienced complete or partial response. These results support further clinical evaluation of RO7122290 in combination with ICIs. —MN [ABSTRACT FROM AUTHOR]