Melanomas arising in the uveal tract of the eye are a rare form of the disease with a biology and clinical phenotype distinct from their more common cutaneous counterparts. Treatment of primary uveal melanoma with radiotherapy, enucleation or other modalities achieves local control in more than 90% of patients, although 40% or more ultimately develop distant metastases, most commonly in the liver. Until January 2022, no systemic therapy had received regulatory approval for patients with metastatic uveal melanoma, and these patients have historically had a dismal prognosis owing to the limited efficacy of the available treatments. A series of seminal studies over the past two decades have identified highly prevalent early, tumour-initiating oncogenic genomic aberrations, later recurring prognostic alterations and immunological features that characterize uveal melanoma. These advances have driven the development of a number of novel emerging treatments, including tebentafusp, the first systemic therapy to achieve regulatory approval for this disease. In this Review, our multidisciplinary and international group of authors summarize the biology of uveal melanoma, management of primary disease and surveillance strategies to detect recurrent disease, and then focus on the current standard and emerging regional and systemic treatment approaches for metastatic uveal melanoma.
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