Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors.

PURPOSE: The prognosis of metastatic uveal melanoma (mUM) remains poor, and immune checkpoint inhibitors (ICIs) show limited efficacy, with response rates typically below 5%. Tebentafusp, an immune therapy targeting the gp100 protein, is the first drug to improve overall survival (OS) in mUM. Somatic MBD4 deficiency induces a hypermutated phenotype in a fraction of UM cases and may predict benefit from ICIs. METHODS: We retrospectively analyzed patients with mUM carrying somatic or germline MBD4 alterations and treated with ICIs at Institut Curie (Paris, France). Clinical characteristics, treatments, and outcomes were collected. RESULTS: Twelve patients received ICIs (nine pembrolizumab, two ipilimumab + nivolumab, one pembrolizumab + lenvatinib). Most (83%) had M1a liver-only disease. The overall response rate was 50% (two complete, four partial) with a disease control rate of 83%. The median follow-up was 22 months (range, 9.9-116.8), and within this time frame median progression-free survival and OS were not reached. At 12 months, 73% of patients were progression free, and the estimated 2-year OS was 86%. CONCLUSIONS: We observed that, in patients with MBD4-mutated mUM, ICIs achieved a 50% response rate and prolonged survival, demonstrating strong and sustained clinical activity in this distinct molecular subgroup and exceeding outcomes reported with ICIs or tebentafusp. TRANSLATIONAL RELEVANCE: Our findings support further evaluation of MBD4 mutation as a predictive biomarker and suggest that ICIs should be considered as a preferred first-line option in MBD4-mutated mUM.