State-of-the-art in Metastatic Uveal Melanoma Treatment: A 2025 Update : How to treat Metastatic Uveal Melanoma in 2025

Abstract

Purpose of review: Uveal melanoma (UM) is the most common intraocular malignancy in adults, representing a rare but aggressive melanoma subtype with a distinct molecular landscape, unique metastatic behavior and limited therapeutic options in the metastatic setting. This review provides an in-depth analysis of the latest evidence on the evolving treatment landscape of metastatic UM.

Recent findings: For liver-only metastatic disease, locoregional therapies provide significant benefit compared to systemic therapies. The recent approval of tebentafusp-tebn, a bispecific gp100 peptide-HLA-directed CD3 T-cell engager, marks a pivotal advancement for HLA-A*02:01-positive patients with unresectable/metastatic UM, demonstrating a clinically significant survival benefit. Several clinical studies are currently active, examining emerging locoregional and systemic treatments for metastatic UM, with promising early data. Despite effective local disease control through radiotherapy and enucleation, approximately 50% of patients develop metastatic disease, predominantly in the liver, with a median survival of less than one year. The approval of tebentafusp represents a landmark achievement in UM treatment, while promising experimental combinations have demonstrated clinical utility in late phase clinical trials, offering hope for further improvement in patient survival.

Keywords: Immune checkpoint inhibitors; Immunotherapy resistance; Targeted therapies; Tebentafusp; Uveal melanoma.

Fig. 1

Mechanism of action of systemic treatment modalities for metastatic uveal melanoma. TIL: tumor infiltrating lymphocytes; ImmTAC: Immune-mobilizing monoclonal T cell receptors Against Cancer; ADC: antibody–drug conjugate