This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 patients with ICB-naïve MM. Primary endpoints were safety and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase II dose, the ORR was 50%, and the disease control rate was 92%, with ORRs of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed that sotigalimab effectively engaged the CD40 pathway, boosting infiltration and activation of myeloid cells, including CD11c+ DC-LAMP+ dendritic cells and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. T-cell receptor sequencing showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes but not with baseline features associated with response to anti–PD-1 monotherapy.
