Overview

Most common primary intraocular malignancy in adults. Distinct from cutaneous melanoma - lacks BRAF mutations but harbors GNAQ/GNA11 (85%) or BAP1 alterations. Primary tumor treated with radiation (brachytherapy or proton beam) or enucleation. 50% develop liver metastases. Tebentafusp (gp100-targeted bispecific) improves survival in HLA-A*02:01 patients with metastatic disease. Liver-directed therapies (embolization, isolated hepatic perfusion) for liver-dominant disease.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

Uveal melanoma is the most common primary intraocular malignancy in adults, with approximately 2,000 new cases annually in the United States. Despite successful local control of the primary tumor (with plaque brachytherapy or enucleation), approximately 50% of patients develop metastatic disease, predominantly to the liver (in over 90% of cases). The median time from diagnosis to metastasis is 2-3 years, and once metastatic, median survival is approximately 12-15 months. Uveal melanoma affects predominantly fair-skinned individuals with light iris color. Unlike cutaneous melanoma, UV radiation is not a significant risk factor, and the molecular biology is fundamentally different.

Molecular Biology & Biomarkers

Uveal melanoma is molecularly distinct from cutaneous melanoma. Rather than BRAF or NRAS mutations, uveal melanoma is driven by activating mutations in GNAQ (approximately 50%) or GNA11 (approximately 45%), which encode G-protein alpha subunits activating the MAPK and YAP pathways. These mutations are mutually exclusive and present in virtually all uveal melanomas. Prognostic classification relies on gene expression profiling (Class 1 versus Class 2) and cytogenetic features, with monosomy 3 and BAP1 loss strongly predicting metastatic risk. Class 2 tumors with BAP1 loss have approximately 70% metastatic rate, while Class 1A tumors have less than 5% risk.

Evolving Treatment Landscape

The treatment of metastatic uveal melanoma was transformed by tebentafusp (Kimmtrak), a first-in-class bispecific gp100-directed CD3 T-cell engager approved in 2022 based on the IMCgp100-202 trial showing improved overall survival versus investigator's choice. Tebentafusp is restricted to HLA-A*02:01-positive patients (approximately 50% of the population). Unlike cutaneous melanoma, uveal melanoma responds poorly to checkpoint immunotherapy (response rates under 10% with anti-PD-1 monotherapy), likely due to its low mutational burden and liver-dominant metastatic pattern. Hepatic-directed therapies (transarterial chemoembolization, immunoembolization, percutaneous hepatic perfusion with melphalan) are important given the liver tropism. Combination approaches and novel bispecific molecules targeting different antigens are under active investigation.

Approved Uveal Melanoma Therapies

Kimmtrak
tebentafusp-tebn
FDA Approved 2022 HLA-A*02:01-positive
Approved Indications (US/FDA)
Treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. This is the first and only FDA-approved treatment specifically for metastatic uveal melanoma.
Dosing Schedule
20 mcg IV Day 1, 30 mcg IV Day 8, 68 mcg IV Day 15, then 68 mcg IV weekly
Drug Class
Bispecific gp100×CD3 T-cell Engager
Manufacturer
Immunocore
Approval Year
2022
Pivotal Trial
NCT03070392 ↗
Key Publication
Nathan et al. NEJM 2021 (IMCgp100-202) ↗