323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC

<b>Background</b><br/>Despite major advancements with immune checkpoint inhibitors (CPIs), many patients’ disease does not respond or ultimately relapses, underscoring the need for novel approaches. mRNA-4359 is an intramuscular mRNA-based cancer antigen therapy that encodes programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1 (PD-L1/IDO1) peptides to stimulate antigen-specific T cells. These T cells are intended to target cancer and immunosuppressive cells to promote an immune-permissive tumor microenvironment. mRNA-4359 is being evaluated in combination with CPIs to potentially enhance anti-tumor activity.<br/><b><br/>Trial Design</b><br/>mRNA-4359-P101 (NCT05533697) is an ongoing, phase I/II, open-label, first-in-human, non-randomized study evaluating mRNA-4359 alone or in combination with CPIs. Following completion of dose-escalation and dose-optimization, Protocol Amendment 3.0 (published 28 July 2025) added and/or expanded upon cohorts in melanoma and non-small cell lung cancer (NSCLC). Primary and secondary objectives include safety, tolerability, anti-tumor activity, and T cell profile changes. Expansion cohorts are: (Arm 2b) first-line advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and EGFR/ALK-negative (n=50); (Arm 2c) first-line advanced melanoma treated with ipilimumab/nivolumab (n=45); (Arms 1b and 2d) ≥ second-line CPI-resistant/refractory (CPI-R/R) melanoma with PD-L1 TPS ≥1% (combined planned n=97). Patients receive intramuscular mRNA-4359 with intravenous pembrolizumab in Arms 1b, 2b, and 2d, and with ipilimumab/nivolumab in Arm 2c. Enrollment is now ongoing in these expansion cohorts.<br/><b><br/>Clinical trial identification</b><br/>NCT05533697.