Nature cancer · 2026

Safety and activity of RO7300490, a bispecific CD40 agonist targeted to fibroblast activation protein, in patients with advanced solid tumors: a single-arm, multicenter, first-in-human, phase 1 trial

Melero I, Reis B, Rusterholz C, Epp A, Kratochwil NA, Wu C, Hettich M, Kazantzidis G, Rieder N, Schwalie PC, Badillo S, Kumpesa N, Thommen A, Vugts DJ, Moreno V, Lostes Bardaji J, Alvarez EC, de Andrea CE, Spanggaard I, Lee DH, Spicer J, Thistlethwaite F, Oh DY, Hollebecque A, Cirovic O, Symeonides SN

CD40 activation on dendritic cells (DCs) enhances tumor antigen cross-priming of tumor-specific cytotoxic T lymphocytes, strengthening anticancer immune responses. RO7300490 is a fibroblast activation protein (FAP)-targeted CD40 agonist antibody. In this phase I study, 80 patients with advanced and/or metastatic solid tumors received RO7300490 biweekly (dose range 16-1,100 mg). The primary objective was to evaluate safety and tolerability. Secondary/exploratory objectives included pharmacokinetics, antitumor activity and pharmacodynamics. Treatment-related adverse events (TRAEs) occurred in 53 patients (66.3%) and were mostly grade 1-2. Grade 3-4 TRAEs (3.8%) and TRAEs leading to discontinuation (2.5%) were uncommon. No grade 5 TRAEs were reported. RO7300490 showed target-mediated drug disposition, with sustained exposure at higher doses. No objective responses and limited clinical activity (disease control rate 42.5%) were observed despite rapid and persistent tumor uptake of radiolabeled RO7300490. Intratumoral pharmacodynamic activity was demonstrated by a significant increase in DC-LAMP+ DC density in paired tumor biopsies. An increase in B cell density was also observed, along with the formation of pretertiary lymphoid structures, co-organized in focal micro-neighborhoods with DCs. In summary, treatment with a tumor-targeted CD40 agonist antibody is feasible, clinically manageable and induces immunomodulation of the tumor microenvironment. ClinicalTrials.gov registration: NCT04857138 .