Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–PD-1 Refractory Melanoma
Cara Haymaker, Daniel H. Johnson, Ravi Murthy, Salah-Eddine Bentebibel, Marc Uemura, Courtney W. Hudgens, Houssein Safa, Marihella James, Robert H.I. Andtbacka, Douglas B. Johnson, Montaser Shaheen, Michael A. Davies, Shah Rahimian, Srinivas K. Chunduru, Denái R. Milton, Michael T. Tetzlaff, Willem W. Overwijk, Patrick Hwu, Nashat Gabrail, Sudhir Agrawal, Gary C. Doolittle, Igor Puzanov, Joseph Markowitz, Chantale Bernatchez, Adi Diab
Abstract
Abstract Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II 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 II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. Significance: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861