Tilsotolimod with ipilimumab drives tumor responses in anti-PD-1 refractory melanoma.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase 1/2 trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1-resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase 2 dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in non-injected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local interferon-alpha gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase 3 clinical trial with this combination (NCT03445533) is ongoing.