Multinational phase 1 trial of mRNA-2752 with or without durvalumab in patients with advanced solid tumors

mRNA-2752 is a lipid nanoparticle-encapsulated, mRNA-based therapeutic encoding OX40L, IL-36γ, and IL-23, which has demonstrated modulation to the tumor microenvironment (TME) and antitumor efficacy in combination with immune checkpoint inhibitors (CPI) in CPI-resistant models. A multinational phase 1 trial evaluated intratumoral mRNA-2752 monotherpay (arm A) or mRNA-2752 plus durvalumab in advanced solid tumors. Primary objectives were safety, tolerability, determination of the maximum tolerated dose (MTD), and objective response rate (ORR) in CPI-resistant melanoma (arm B only). Among 134 patients (19 in arm A and 115 in arm B), the MTD was not reached; a recommended dose for expansion of ≤ 8 mg was selected. Dose-limiting toxicities included two grade 2 cytokine-release syndrome events in arm B. Treatment-related adverse events were mostly grade 1 or 2; grade 3 mRNA-2752-related AEs occurred in 1 patient (5.3%) in arm A and in 29 patients (25.2%) in arm B. In the CPI-resistant melanoma cohort (n=28), the confirmed ORR was 17.9% (95% CI 6.1-36.9) and the disease control rate was 42.9% (24.5-62.8). Increased peripheral cytokine levels and sustained inflammatory responses in the TME were observed, particularly in patients with an objective response. The authors conclude that mRNA-2752 monotherapy or in combination with durvalumab demonstrated antitumor efficacy with manageable safety in patients with pretreated, relapsed, or resistant solid tumors. Biomarker analyses demonstrated a sustained inflammatory response within the TME. These findings support the investigation of mRNA-based therapeutics for patients with advanced cancer.