Teaching pack: Uveal melanoma

Uveal melanoma arises from melanocytes of the choroid, ciliary body or iris and is driven by GNAQ/GNA11 (or CYSLTR2/PLCB4) mutations activating Gαq signalling, with metastatic risk set by BAP1 loss and monosomy 3 (gene-expression class 2, PRAME expression) versus SF3B1 and EIF1AX mutations (lower risk). The primary tumour is controlled by plaque brachytherapy or proton beam in most cases (COMS showed equivalence to enucleation), but about half of patients relapse, typically in the liver, with a median survival historically under a year.

Unlike cutaneous melanoma, the tumour mutational burden is low and checkpoint inhibitors give response rates around 5%. Tebentafusp, a gp100×CD3 ImmTAC restricted to HLA-A*02:01, was the first therapy to improve overall survival in metastatic uveal melanoma (IMCgp100-202, 2021; approved 2022). Liver-directed therapy (percutaneous hepatic perfusion with melphalan, approved 2023 as Hepzato; radioembolisation; resection) controls hepatic disease. Darovasertib (PKC inhibitor) with crizotinib is in phase 2/3 in metastatic and neoadjuvant settings.

• Tebentafusp is the first TCR-based bispecific approved in any cancer and the first drug to improve survival in metastatic uveal melanoma.
• Liver-directed therapy has a randomised trial (FOCUS) behind percutaneous hepatic perfusion.
• Gene-expression profiling reliably separates patients who will and will not metastasise, but there is still no adjuvant therapy that helps them.
• Gαq-pathway inhibition (darovasertib ± crizotinib) is the leading targeted strategy.

1. 2001COMS: brachytherapy equals enucleation for medium tumours
2. 2004Gene-expression classes 1 and 2 predict metastasis (Onken, Harbour)
3. 2009GNAQ mutations discovered (Van Raamsdonk); GNA11 in 2010
4. 2010BAP1 loss drives metastasis (Harbour, Science)
5. 2021Tebentafusp improves overall survival (NEJM)
6. 2022Tebentafusp approved
7. 2023Percutaneous hepatic perfusion (Hepzato) approved

• Tebentafusp (product)
• Percutaneous hepatic perfusion (chemosaturation) (technology)
• Brenetafusp (product)

• Half of patients metastasise with no adjuvant therapy despite accurate prediction.
• Tebentafusp only for HLA-A*02:01 (about 45% of white patients, fewer elsewhere) and gives few objective responses despite OS benefit.
• Liver-tropic metastasis biology poorly understood.
• Vision-preserving local therapy still causes radiation retinopathy.

1. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
2. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.
3. What is brachytherapy and where is it essential?
   Answer

   Placing a radioactive source directly inside or next to the tumour; essential in cervical cancer, used in prostate (seeds or HDR), breast, skin, and eye melanoma.
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.

• NCCN Guidelines: Uveal Melanoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488
• Tebentafusp IMCgp100-202 (NEJM 2021): https://doi.org/10.1056/NEJMoa2103485
• Ocular Melanoma Foundation: https://ocularmelanoma.org/
• Wikipedia: https://en.wikipedia.org/wiki/Uveal_melanoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488