Intratumoral CD40 agonist sotigalimab in combination with pembrolizumab induces rapid activation of antigen presenting cells and drives anti-tumor responses in non-injected tumors in metastatic melanoma: Results of a phase 1/2 study

Checkpoint inhibitors (CPIs) benefit metastatic melanoma (MM) patients, but resistance remains a challenge. This phase 1/2 (NCT02706353) study evaluated intratumoral sotigalimab (an anti-CD40 agonistic antibody) with pembrolizumab in 32 CPI-naïve MM patients. Primary endpoints included determining safety and tolerability, the recommended phase 2 dose (RP2D) of sotigalimab, and the objective response rate (ORR). The most common adverse events (AEs) related to sotigalimab were injection-site reactions, pruritus, and fatigue. The ORR was 47% and the disease control rate (DCR) was 91% for all patients, and 50% and 92% at the RP2D, respectively. Multiomic biomarker analyses of tumor and blood samples collected before and during treatment demonstrated that sotigalimab effectively engaged the CD40 pathway, boosting the infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells (DCs) and macrophages. The combination therapy activated both innate and adaptive immunity, in both injected and non-injected tumors. TCR sequencing analysis showed increased T-cell clonality with expanded new clones shared between injected and non-injected tumors. Clinical responses correlated with these immunologic changes, but not with baseline immunological features associated with response to anti-PD1 monotherapy. In the B16 melanoma mouse model, single- cell RNA sequencing analysis showed that the combination therapy enhanced antitumor immunity and reduced the immunosuppressive tumor environment. These findings suggest that intratumoral sotigalimab may enhance anti-PD1 therapy, supporting the need for further randomized phase 2 trials to better evaluate its therapeutic potential in the 'in situ' immunization approach.