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.
Advances in the understanding of the biology and immune microenvironment of uveal melanoma have improved prognostication and led to promising therapeutic strategies being tested in the adjuvant and metastatic settings.
Stratification of patients by risk of metastatic disease following treatment of primary disease using anatomical, clinical and molecular features has enabled the development of individualized radiographic surveillance strategies.
Tebentafusp, a first-in-class Immune-mobilizing monoclonal T cell receptor Against Cancer (ImmTAC), is the first therapy demonstrated to improve overall survival in patients with advanced-stage uveal melanoma.
The successful development of tebentafusp highlights the clinical efficacy that can be achieved with appropriate modulation of the antitumour immune response in this disease historically considered immune-resistant.
Novel regional therapeutic strategies focused on uveal melanoma liver metastases, systemic targeted, epigenetic and immunological treatments, and combinatorial approaches are being studied, providing hope for continued progress.
Advances in the metastatic setting are driving the development of novel adjuvant therapies that might reduce the risk of metastatic spread and increase cure rates for patients with uveal melanoma.
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R.D.C. has acted as a consultant for Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics and TriSalus Life Sciences; holds stock options in Aura Biosciences, Chimeron and Rgenix; and has received research funding through his institution from Amgen, Astellis, AstraZeneca, BioMed Valley, Bolt, Bristol Myers Squibb, Corvus, Cstone, Foghorn, Ideaya, Immatics, Immunocore, InxMed, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron and Roche/Genentech. J.J.S. has acted as a consultant for Bristol Myers Squibb, Delcath, Immunocore and Merck Sharp & Dohme; has received speaker’s honoraria from Pierre-Fabre and Immunocore; and research funding through his institution from AstraZeneca, Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme and Replimune. D.J.E. has acted as a consultant for Delcath. R.O.B. has acted as a consultant for Amgen, BD/BARD, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme; has received speaker’s honoraria from Pfizer and Roche; is a shareholder of SATMEG Ventures AB; and has received research funding through his institution from Bristol Myers Squibb and SkyLineDx. J.W.H. has acted as a consultant for Castle Biosciences and Immunocore; and receives patent royalties from Washington University. S.P.P. has acted as a consultant for Advance Knowledge in Healthcare, Bristol Myers Squibb, Cardinal Health, Delcath, Immunocore, Novartis and TriSalus Life Sciences; and has received research funding through her institution from Bristol Myers Squibb, Foghorn Therapeutics, Ideaya, InxMed, Lvgen, Novartis, Provectus Biopharmaceuticals, Seagen, Syntrix Bio and TriSalus Life Sciences. A.M.J. has received research funding through his institution from Ideaya and Immunocore. M.J.J., N.D.C. and S.P.-N. declare no competing interests.
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Carvajal, R.D., Sacco, J.J., Jager, M.J. et al. Advances in the clinical management of uveal melanoma. Nat Rev Clin Oncol 20, 99–115 (2023). https://doi.org/10.1038/s41571-022-00714-1