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. Summary: 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.

Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.