A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors
Ignacio Melero 1 2 , Tamara Tanos 3 , Mariana Bustamante 3 , Miguel F Sanmamed 1 2 4 , Emiliano Calvo 5 , Irene Moreno 5 , Victor Moreno 6 , Tatiana Hernandez 6 , Maria Martinez Garcia 7 , Alejo Rodriguez-Vida 7 , Josep Tabernero 2 8 , Analia Azaro 8 , Mariano Ponz-Sarvisé 2 4 , Iben Spanggaard 9 , Kristoffer Rohrberg 9 , Ernesto Guarin 3 , Eveline Nüesch 3 , Iakov I Davydov 3 , Chiahuey Ooi 3 , José Duarte 3 , Evelyne Chesne 3 , Christine McIntyre 10 , Maurizio Ceppi 3 , Marta Cañamero 11 , Oliver Krieter 11
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.
CITATION Sci Transl Med. 2023 May 10;15(695):eabp9229. doi: 10.1126/scitranslmed.abp9229