Change is on the horizon in the management of uveal melanoma

Uveal melanoma is a relatively rare condition, accounting for only ~5% of melanomas and ranging in incidence from <1 case per million-person years in Asia to >10 cases per million-person years in Northern Europe (Exp Ther Med. 2021;22:1428; Invest Ophthalmol Vis Sci. 2023;64:45). Approximately 50% of patients eventually develop metastatic disease (most commonly in the liver) and have a median overall survival (OS) <1 year. Treatment options are limited; currently, tebentafusp is the only approved systemic therapy, but its use is restricted to patients with HLA-A*02:01-positive disease and it has limited efficacy (Eur J Cancer. 2025;214:115161; Cancer Treat Rev. 2023;119:102599). There is a major unmet need for more effective, broadly applicable and durable therapies.

After a lengthy period of inertia, the development of novel treatment strategies for uveal melanoma has recently been attracting much interest, likely due to several factors: the identification of novel targets and pathways such as PRAME, which is expressed in almost all patients with this malignancy; development of PRAME-directed T-cell receptor (TCR) therapies (Nat Med. 2025;31:2365–2374; Cancers (Basel). 2022;14:1215) and protein kinase C (PKC) inhibitors (Front Pharmacol. 2023;14:1232787); optimism around improved disease outcomes with immunotherapy and immunotherapy combinations (Front Cell Dev Biol. 2025;13:1619150); and encouraging data with systemic strategies in primary tumours to preserve vision and quality of life. These developments, and the challenge of how to sequence the various therapies in different stages of the disease, makes for an interesting field of research.

This is reflected in several presentations at the ESMO Congress 2025 (Berlin, 17–21 October) reporting positive, potentially practice-changing data with novel treatment strategies for uveal melanoma in both metastatic and primary disease. In today’s Presidential Symposium, the first convincing evidence was presented of a PRAME-directed TCR therapy, IMA203, achieving substantial tumour shrinkage. Treatment demonstrated a remarkably high confirmed objective response rate (ORR; 67%), with durable responses, median progression-free survival (PFS) of 8.5 months (range 1.4–32.9), median overall survival (OS) not reached (range >4.3–>34.2) at median follow up of 14.3 months, and favourable tolerability in 16 heavily pre-treated patients with advanced or metastatic uveal melanoma (Abstract 1600O). A further study in a larger cohort is now planned.

The importance of immunotherapy combinations in the future treatment of this uncommon cancer is highlighted in a further, potentially practice-changing study. In the phase II CHOPIN trial, significant clinical benefits were demonstrated with dual checkpoint blockade (ipilimumab plus nivolumab) combined with percutaneous hepatic perfusion compared with perfusion alone in 76 patients with liver-only or liver-dominant metastatic uveal melanoma (LBA59). The primary endpoint was met, with 1-year PFS of 54.7% in the combination arm versus 15.8% in the perfusion arm. Median PFS was 12.8 months versus 8.3 months, respectively (hazard ratio [HR] 0.34; 95% confidence interval [CI] 0.19–0.60; p<0.001), median OS was 23.1 months versus 19.6 months (HR 0.39; 95% CI 0.20–0.77; p=0.006), and best ORR was 76.3% versus 39.5% (p<0.001). Toxicity was higher in the combination arm (grade ≥3 adverse events: 81.6% versus 40.5%), but was described as manageable. These data represent an important step forward for integrated systemic and locoregional therapy in liver-dominant metastatic uveal melanoma. A phase III trial, SCANDIUM-III (NCT06519266), is currently testing the same combination but with ipilimumab and/or nivolumab as comparator and should provide further insights.

The potential clinical benefits of an immunotherapy (pembrolizumab) and targeted therapy (lenvatinib) combination have also been demonstrated in 51 patients with metastatic disease in the phase II PLUME study (LBA58). In contrast to the limited activity previously reported with immune checkpoint inhibitors alone in this setting (Eur J Cancer. 2025;214:115161), the combination met a predefined statistical threshold for success; activity was observed in both tebentafusp-naïve and tebentafusp-pre-treated cohorts, although especially strong activity was observed in pre-treated patients (27-week PFS 31.8% versus 60.7%, respectively). While not curative, unlike tebentafusp the regimen offers a promising systemic option for patients with either HLA-positive or HLA-negative disease, and may be particularly beneficial in the second line, although additional data are needed.

A further area of growing interest is the development of novel treatment strategies for non-metastatic uveal melanoma. At the ESMO Congress, neoadjuvant therapy with the selective PKC inhibitor, darovasertib, was associated with tumour shrinkage in a phase II trial of 94 efficacy evaluable patients; ≥20% tumour shrinkage was observed in 50.0% and 60.5% of patients requiring enucleation or plaque brachytherapy, respectively. This enabled enucleation prevention, radiation dose reduction and preservation of vision in a significant proportion of patients, thus providing proof of concept of the benefits of systemic therapy in the primary setting (Abstract 1602O). This groundbreaking research positions darovasertib as potentially the first systemic agent to impact primary uveal melanoma management, and while confirmatory trials are needed, it will likely drive the field forward in early-stage disease.

Collectively, these studies signal that positive change is on the near horizon for the management of uveal melanoma. Diversification of therapy with the inclusion of multiple mechanisms, and combinations of systemic immunotherapies with targeted agents or liver-directed modalities, will become increasingly integrated into the current treatment paradigm. Personalised treatment options will be dependent on a variety of factors such as HLA status, PRAME expression, tumour genetics and disease distribution (liver-dominant versus extrahepatic), and there will likely be a shift towards greater use of systemic therapy in the primary disease space, resulting in a reduced need for vision-sacrificing interventions and the potential for reduced recurrences. While none of these approaches is likely to provide a cure for this rare cancer type in the metastatic setting, early data are extremely positive and suggest that these advances hold the promise of extended patient survival, with some subsets potentially achieving durable disease control.