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

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.

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.

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%.

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.

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.