Uveal Melanoma: Changing Paradigms of Treatment.

Background: Despite effective management of the primary tumor, up to 50% of patients with uveal melanoma develop metastases, with poor outcomes. Summary: In 2022, tebentafusp became the first approved systemic therapy to improve overall survival in metastatic UM. Tebentafusp is an immune-modulating bispecific fusion protein restricted to HLA A02:01, using a T-cell receptor targeting glycoprotein 100, a melanocyte lineage-specific antigen expressed on UM cells, capable of recruiting and activating polyclonal CD3 T cells. Reduction in circulating tumor DNA is associated with improved survival across all response categories and may serve as a surrogate biomarker to guide treatment decisions. Tebentafusp's mechanism of action and safety profile support combination trials with regional or systemic therapies and its evaluation in the ATOM adjuvant study for high-risk UM patients. As half of the patients are HLA A02:01 negative, alternative strategies are under investigation, including the protein kinase C inhibitor darovasertib in the NADOM neoadjuvant/adjuvant trial and in combination with crizotinib in metastatic UM. DYP688, a first-in-class PMEL17-targeting antibody-drug conjugate that inhibits GNAQ/11 signaling, has shown promise in metastatic UM and other GNAQ/11-mutant melanomas. Key Message: The landscape of UM treatment is rapidly evolving following the identification of new targets and pathways such as PKC or PRAME. Combination of liver-directed therapies with personalized systemic immunotherapies or targeted agents in the metastatic disease, as well as the early use of systemic therapies in the primary tumor setting will refine treatment strategies in UM and suggest improved outcomes in the near future.