mRNA-4359 (PD-L1/IDO1 mRNA immunotherapy) + pembrolizumab drives 83% ORR in 1L metastatic melanoma (Phase 1/2)

mRNA-4359 is an intramuscular mRNA cancer antigen therapy encoding PD-L1 and IDO1 epitopes, designed to induce antigen-specific T cells against tumor and immunosuppressive cells, and was combined with pembrolizumab (anti–PD-1) in the Phase 1/2 mRNA-4359-P101 dose-expansion Arm 2a (NCT05533697) for previously untreated locally advanced/metastatic melanoma (n=12; data cutoff December 1, 2025). At median follow-up 54.2 weeks, ORR was 83% (2 CR, 8 PR; DCR 92%), median DOR and median PFS were not reached, and responses were seen across PD-L1 TPS subgroups (TPS ≥1%: ORR 88% [2 CR/5 PR]; TPS <1%: ORR 67% [2 PR]). Safety looked mostly additive to pembrolizumab: mRNA-4359-related TEAEs were 92% and all grade 1/2 (injection-site pain 67%), while pembrolizumab-related grade 3/4 TEAEs were 33% (no regimen-specific novel signal described); as a benchmark, pembrolizumab monotherapy in advanced melanoma has historically delivered ORR ~34–40% and median PFS ~8–9 months with grade 3/4 TRAEs ~13–17% in KEYNOTE-006-era datasets—so the efficacy signal here is far above SOC expectations, but in a very small, early-phase cohort.