What is it about?

Metastatic uveal melanoma is known for liver-dominant spread and poor responses to standard immunotherapy. Our open-access review explains how tebentafusp, a T-cell receptor-CD3 bispecific, directs the immune system to gp100 presented by HLA-A*02:01. We summarise the phase III evidence showing a clear survival advantage with tebentafusp despite modest scan responses: 1-year overall survival 73% vs 59%, hazard ratio 0.51, median 21.6 vs 16.9 months. We outline who can receive it, how step-up dosing works, what side-effects to expect early on, and how to monitor patients. The article also introduces practical biomarkers, including circulating tumour DNA, to help clinicians judge benefit.

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Why is it important?

This is the first systemic therapy to improve survival in metastatic uveal melanoma, a disease historically lacking effective drugs. The review translates complex trial data into everyday practice: test for HLA-A*02:01, start step-up dosing safely, anticipate and manage early cytokine-driven fever and rash, and track benefit beyond radiographic shrinkage. It provides clinicians and patients with clear, quantitative expectations and a service-ready pathway, while highlighting research priorities such as combinations, liver-directed strategies, and biomarker-guided care. In short, it sets a new benchmark and a pragmatic playbook for real-world adoption.

Perspectives

ebentafusp (IMCgp100) is a novel bispecific immunotherapy that contains a specifically engineered soluble T-cell receptor (TCR) capable of recognising the gp100 epitope on the surface of tumour cells presented by human leukocyte antigen-A*02:01 (HLA- A*02:01 (HLA-A2) is a specific allele within the HLA-A2 group). The HLA-A2 is then fused to the single-chain variable fragment of anti-CD3, which binds to T-cells and destroys them. Tebentafusp has been shown to cause a significant increase in pro-inflammatory cytokine levels that are detrimental to the tumour. The preliminary results of tebentafusp in solid tumours are encouraging, particularly in advanced/metastatic uveal melanoma (UM). In a randomised phase III study (IMCgp100-202; n = 378), patients with untreated HLA*02:01 positive metastatic UM (mUM), tebentafusp significantly improved overall survival (OS) with a hazard ratio (HR) of 0.51 compared to the investigator’s choice, mainly pembrolizumab (82%). The one-year OS rate for tebentafusp was 73% compared to 59% for pembrolizumab. For comparison, the single-arm GEM1402 study (n = 52) reported a one-year OS rate of 52% for the combination of nivolumab and Ipilimumab in metastatic UM. The most common adverse reactions related to tebentafusp include cytokine release syndrome (CRS) and dermatological reactions such as rash. It is the first drug with OS benefit in advanced/metastatic UM patients. However, further research is needed to optimise its use, improve patient selection, develop combination therapies and identify predictive and prognostic biomarkers.

Piotr Remiszewski
Maria Sklodowska- Curie National Research Institute of Oncology

Read the Original

This page is a summary of: Tebentafusp (IMCgp100) in the treatment of uveal melanoma — from preclinical evidence to clinical practice, Nowotwory Journal of Oncology, April 2025, VM Media SP. zo.o VM Group SK,
DOI: 10.5603/njo.104457.
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