First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer
Ryan J. Sullivan, Oladapo Yeku, Deanna Teoh, Shilpa Gupta, Daniela Matei, Andressa S. Laino, Jing Sun, Lili Zhu, Linh Van, Stéphanie Pascarella, Sima J. Zacharek, T. Khanh, Antonio Jimeno
Abstract
BACKGROUND: mRNA-2416 is a novel lipid nanoparticle-encapsulated messenger RNA (mRNA) encoding human OX40 ligand (OX40L) for intratumoral (Itu) injection. OX40L plus immune checkpoint inhibitor (ICI) increased preclinical antitumor activity, thus mRNA-2416 plus ICI may potentiate antitumor activity. METHODS: This first-in-human, phase I/II, open-label, multicenter study examined the safety, tolerability, and efficacy of mRNA-2416 alone (arm A) or with durvalumab (arm B) in patients with advanced solid tumors or lymphoma (NCT03323398). Phase I primary objectives included assessment of safety/tolerability and maximum tolerated dose (MTD)/recommended dose for expansion; phase II arm B dose expansion assessed objective response rate in ovarian cancers. Secondary objectives included pharmacokinetics, disease control rate, duration of response, and progression-free survival (PFS). Assessments of immunologic response to treatment were exploratory. RESULTS: From August 2017 to August 2021, 79 patients were enrolled; 61 received treatment (arm A: 39, arm B: 22), including 16 in the expansion cohort. MTD was not reached. Treatment-related emergent adverse events were primarily grade 1/2, with 8 grade 3 and no grade 4/5 events. On-treatment tumor biopsies demonstrated increased OX40L protein expression, elevated PD-L1, and proinflammatory responses. Tumor shrinkage occurred in injected and surrounding non-injected tumors. Median (95% CI) PFS was 60.0 (50.0 to 108.0) and 50.0 (38.0 to 55.0) days for arms A and B, respectively. CONCLUSIONS: mRNA-2416 alone or with durvalumab was well tolerated. Pharmacodynamic analyses support Itu mRNA proof-of-concept. Predefined primary efficacy endpoints were not met in an exploratory cohort of ovarian cancer. Additional research is warranted to further inform this therapeutic approach.