Moderna & Merck: 5‑Year Data — Intismeran plus KEYTRUDA Reduces Recurrence in High‑Risk Resected Stage III/IV Melanoma

Study and design

KEYNOTE-942/mRNA-4157-P201 is a randomized Phase 2b (n=157) in resected high-risk Stage III/IV melanoma, randomized 2:1 to individualized mRNA neoantigen therapy intismeran autogene (mRNA-4157/V940) plus pembrolizumab versus pembrolizumab alone; dosing: intismeran 1 mg every 3 weeks for nine doses and pembrolizumab 200 mg every 3 weeks up to 18 cycles (~1 year).

Five-year efficacy

At median 60.3 months follow-up the combination reduced risk of recurrence or death by 49% (RFS HR 0.51, 95% CI 0.294–0.887) and risk of distant metastasis or death by 59% (DMFS HR 0.411, 95% CI 0.200–0.843); an exploratory overall survival analysis showed a favorable trend (HR 0.471, 95% CI 0.165–1.345; n=14).

Safety

Safety was consistent with prior analyses: most common adverse events attributed to the combination were fatigue (59.6%), injection-site pain (59.6%) and chills (51.0%); most events were Grade 1–2 (31.7% Grade 1; 51.9% Grade 2), fatigue was the most common Grade 3 event (4.8%), no Grade 4–5 events attributed to intismeran, and immune-related AEs occurred at similar rates in both arms (~45%).

Translational and subgroup findings

RFS benefit was observed across subgroups (age, sex, stage, PD-L1, BRAF, TMB, ctDNA); combination therapy doubled the proportion and magnitude of novel expanded T-cell clonotypes versus pembrolizumab alone (median summed frequency 0.030 vs 0.016), with higher novel-clone expansion associated with remaining recurrence-free and linked to intismeran-encoded neoantigens.

Ongoing development

Nine Phase 2 and Phase 3 trials are underway across multiple tumor types, including fully enrolled adjuvant melanoma INTerpath-001 (NCT05933577) and ongoing NSCLC and bladder and RCC studies (trial identifiers cited in source).