# Current Treatment Standards for Metastatic Uveal Melanoma

## TL;DR

Uveal melanoma is a rare eye cancer with poor prognosis once it spreads, but liver-directed treatments and new drugs like tebentafusp offer some hope.

## Contribution

This review highlights tebentafusp as a novel systemic therapy showing survival benefits for a subset of metastatic uveal melanoma patients.

## Key findings

- Uveal melanoma has a high metastasis rate, with up to 70% of patients developing liver metastases.
- Tebentafusp provides survival benefits for HLA-A*02:01-positive metastatic uveal melanoma patients.
- Liver-directed therapies, especially surgery, offer the best outcomes for metastatic disease.

## Abstract

Uveal melanoma is the most common primary cancer of the eye in adults, usually beginning in the choroid. It is a rare but aggressive disease with nonspecific symptoms and many cases are discovered incidentally during eye examinations. Although effective local therapies, such as radiotherapy, surgery, or enucleation, can control the primary tumor, the risk of metastases remains high, affecting up to 70% of patients. The liver is the most frequent location of distant spreading, and once metastases occur, the prognosis is poor, with survival often less than one year. Liver-directed treatments, particularly surgery, may prolong survival, but systemic therapies are generally limited in efficacy. Recently, tebentafusp, a bispecific protein, has shown a survival benefit in selected patients, representing an important step forward. This article summarizes the current knowledge of UM, including its epidemiology, genetic background, clinical features, treatment options, and perspectives for future therapy.

Background/Objectives: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, most commonly arising in the choroid. Its development is associated with phenotypic characteristics, ultraviolet radiation, and germline or somatic genetic alterations. Despite progress in diagnostics and local therapies, UM remains characterized by high metastatic risk and poor overall prognosis. This review aimed to summarize current knowledge on epidemiology, clinical features, genetic background, prognostic factors, and therapeutic approaches in metastatic UM. Methods: A structured literature review was conducted to evaluate epidemiological trends, genetic alterations, prognostic markers, clinical presentation, and therapeutic strategies. The results of different systemic treatments were analyzed, with special attention to liver-directed interventions and emerging systemic therapies. Results: The incidence of UM in Europe increases with latitude, ranging from two per million in the southern regions to more than eight per million in the North. The median age at diagnosis is 62 years, and most cases are detected incidentally during ophthalmological examinations due to nonspecific symptoms. Some genetic alterations serve as important prognostic indicators. Local treatment consists of globe-preserving procedures, including radiation therapy, surgery, laser therapy, or enucleation, with failure rates between 6.15% and 20.8%. Up to 70% of patients develop distant metastases, predominantly in the liver. Metastatic UM (mUM) carries a poor prognosis, with overall survival ranging from 3 to 30 months. Liver-directed therapies, particularly surgical resection, provide the most favorable outcomes. Systemic therapies demonstrate limited efficacy; however, tebentafusp has shown an overall survival benefit in HLA-A*02:01 (human leukocyte antigen A*02:01)-positive patients. Conclusions: UM is a rare but aggressive malignancy with limited treatment options once metastatic. Liver-directed strategies remain the mainstay of management, while novel systemic approaches, including tebentafusp, represent promising advances. Further research is required to improve survival and expand therapeutic opportunities.