Uveal melanoma (UM) is a malignancy that occurs in the uvea — the choroid, ciliary body, and pigmented tissue in the iris of the eye. Most UMs (90%) affect the choroid, while 6% are found in the ciliary body and 4% in the iris.1 Despite being the most common malignant primary intraocular tumor in adults, UM is a rare disease with a variable regional incidence ranging from 0.3 per million population per year in Africa to 9.8 million population per year in Australia.1,2 The age-adjusted incidence of UM in the United States is 5.2 per million population.3 Figure 1 shows race and cancer history in UM cases, age-adjusted incidence of primary UM in the US, and other risk factors for UM.1-3
Like other melanoma subtypes, including the more prevalent cutaneous melanoma, UM probably derives from melanocytes. However, UM differs greatly from other melanoma subtypes, including in its epidemiology, genetic drivers of malignancy (and therefore the potential usefulness of various therapeutic options), and patterns of metastasis. Unlike cutaneous and conjunctival melanomas, UM is usually not associated with ultraviolet light exposure or a high mutational burden.4 Risk factors for UM include fair skin, light eye color (ie, blue or gray), melanocytoma, congenital ocular melanocytosis, family history of cutaneous melanoma or UM, and germline mutations in BAP1, MLH1, PALB2, and SMARCE1.1 UM is also associated with occupational exposures to welding and cooking.5
Clinical Manifestations and Disease Course
Patients with UM are typically diagnosed between the ages of 50 and 70 years, and UM is rarely diagnosed in children and adolescents.1 The majority of patients (up to 87%) present with changes in vision or other ocular symptoms, including blurred or altered vision, visual field loss, and photopsia.1,6 However, a study reported that approximately 30% of patients with UM do not experience symptoms.7
In contrast to many other cancer types, UM is often diagnosed based on clinical examinations without histological assessment.6 Ophthalmologists and ophthalmic oncologists use various techniques to diagnose UM and to differentiate UM from other ocular lesions, such as benign choroidal nevi, fundus lesions, or other types of tumors. Differential diagnosis, particularly of small UMs, can be challenging, and techniques employed include eye slit lamp biomicroscopy, indirect ophthalmoscopy, gonioscopy, transillumination, fluorescein angiography, ultrasonography, and optical coherence tomography.1
Treatment for primary UM depends on several factors, including the location and size of the tumor and related features such as retinal detachment, vitreous hemorrhage, and retinal invasion; roughly 90% of patients achieve local disease control with radiotherapy, enucleation, or other treatment modalities.1,6 The 5-year and 15-year UM-related mortality was 31% (95% CI, 26-37) and 45% (95% CI, 40-51), respectively, in a study with long-term follow-up.8
While fewer than 3% of patients with UM have detectable metastases at diagnosis, 40% to 50% of patients eventually experience metastasis.6 In a study of 8033 patients with UM, the 10-year rates of metastasis among patients with iris, ciliary body, and choroidal melanoma were 7%, 33%, and 25%, respectively.9 The majority of patients with metastatic UM (mUM) have liver metastases, but other patterns of metastasis are also observed.6 In metastatic choroidal UM, metastases were most frequently detected in the liver (93%), lungs (24%), and bone (16%).10
Historically, immune checkpoint inhibitors have shown limited efficacy for treating mUM.1 However, in January 2022, a novel immune therapy, tebentafusp-tebn, was approved by the US Food and Drug Administration (FDA) for the treatment of a subset of patients with mUM.11 In a phase 3 trial that included patients with mUM who were positive for HLA-A*02:01, overall survival (OS) at 1 year was 73% in the tebentafusp-tebn group compared with 59% in the control group (treated with investigator’s choice of single-agent pembrolizumab, ipilimumab, or dacarbazine; hazard ratio for death, 0.51; 95% CI, 0.37-0.71; P <.001).12
Prognostic Evaluation in UM
The prognosis of patients with UM is commonly evaluated using the American Joint Committee on Cancer (AJCC) classification system, which is based on clinical features such as tumor size, ciliary body involvement, and extraocular extension. Studies have demonstrated that prognostication can be improved with analysis of biopsy tissue samples, and tissue biopsy is recommended by the National Comprehensive Cancer Network (NCCN) guidelines for UM for patients who are not treated with enucleation.6
Biopsy analyses may include DNA analysis, RNA analysis, and/or histopathology, and results can be used to stratify patients into molecular subtypes based on genomic alterations, gene expression patterns, and/or inflammatory cell infiltration (Table 1).1,6 For example, the DecisionDX-UM test can be used to evaluate the prognosis of patients with UM based on the expression of 15 genes in biopsy samples, and it reliably predicts the risk of metastasis. Analysis of The Cancer Genome Atlas (TCGA) data has shown that particular cytogenetic, mutation, and expression patterns with prognostic significance tend to cluster with the gene expression profile classes identified by DecisionDX-UM.6
Importance of Human Leukocyte Antigen Analysis in mUM
Human leukocyte antigen (HLA) analysis can provide both prognostic information and can be used to guide patient selection for the targeted therapy tebentafusp-tebn.13,14 Studies have found that unlike in other cancers, low HLA class I expression is associated with patient survival and good outcomes in UM. This is hypothesized to be related to the ability of natural killer cells to eliminate tumor cells with low HLA class I expression levels, thus preventing the establishment of liver metastases.1
A key role of HLA molecules is to present peptide antigens on the cell surface that can be recognized by T-cell receptors on T cells.15 Cancer-specific antigens can be displayed by HLA molecules on cancer cells and theoretically can be recognized and eliminated by the immune system, but tumors often use immunosuppressive mechanisms to prevent an effective immune response.16 While UM tends to have few mutations and thus low levels of cancer-specific antigens, UMs do express pigment-related antigens that can be recognized by T cells, such as gp100.1
Several types of immunotherapies aim to increase T-cell cytotoxicity against cancer cells, including tebentafusp-tebn, an immune-mobilizing monoclonal T-cell receptor against cancer (ImmTAC).15 ImmTACs recognize tumor cells by binding to a specific HLA-antigen complex, and then they recruit and activate T cells, leading to tumor cell killing.17 Tebentafusp-tebn specifically binds to gp100 complexed with a particular HLA-A*02 allele, HLA-A*02:01, thus recruiting T cells that have cytotoxic activity against UM cells to the UM tumor microenvironment.14,16
Cells that express other HLA-A*02 alleles are not effectively targeted by tebentafusp-tebn, meaning that only patients with the HLA-A*02:01 allele can benefit from treatment with tebentafusp-tebn. Thus, to determine whether a patient with mUM may benefit from treatment with tebentafusp-tebn, the HLA genotype of the patient must first be determined. Due to the high level of sequence similarity between different HLA-A*02 alleles, high-resolution HLA-A genotyping must be performed to identify patients with the HLA-A*02:01 allele.14
Several options exist for high-resolution HLA-A typing, and next-generation sequencing-based methods are often employed.14 Due to potentially false-negative HLA results occurring from tumor heterogeneity, it is recommended that high-resolution HLA testing be performed on a whole-blood specimen rather than a tumor biopsy sample.18 Because the turnaround time for high-resolution HLA typing results can be lengthy, some researchers have proposed performing HLA genotyping for all patients with mUM at diagnosis.14
Summary
Patients with mUM have historically had poor outcomes, with a median OS of around 1 year. The ImmTAC tebentafusp-tebn has been shown to improve outcomes in patients with mUM who are HLA-A*02:01-positive, and it was approved for patients with mUM in January 2022. Patients with mUM should undergo HLA genotyping to determine if they are candidates for treatment with tebentafusp-tebn.
References
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10. Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol. 2001;119(5):670-676. doi:10.1001/archopht.119.5.670
11. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. News release. US Food and Drug Administration. January 26, 2022. Accessed April 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tebentafusp-tebn-unresectable-or-metastatic-uveal-melanoma
12. Nathan P, Hassel JC, Rutkowski P, et al; IMCgp100-202 Investigators. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485
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15. Middleton MR, McAlpine C, Woodcock VK, et al. Tebentafusp, a TCR/anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res. 2020;26(22):5869-5878. doi:10.1158/1078-0432.CCR-20-1247
16. Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. Immunology. 2017;152(3):425-438. doi:10.1111/imm.12779
17. Oates J, Hassan NJ, Jakobsen BK. ImmTACs for targeted cancer therapy: why, what, how, and which. Mol Immunol. 2015;67(2 pt A):67-74. doi:10.1016/j.molimm.2015.01.024
18. Kimmtrak® HLA testing. Immunocore Ltd. February 2023. Accessed April 4, 2023. https://www.kimmtrakhcp.com/KIMMTRAK-HLA-testing.pdf
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Reviewed April 2023
