ESMO 2025 - Metastatic uveal melanoma: a promising new treatment combination

With 500 new cases diagnosed each year in France¹, uveal melanoma is a rare cancer affecting the uvea, the pigmented membrane inside the eye that includes the choroid (tissue covering the retina), iris and ciliary body. This is the most common malignant eye tumor in adults, for which metastases (often in the liver) are frequent. Institut Curie is a national expert center for the management of patients with uveal melanoma.

The standard treatment for metastatic uveal melanoma is immunotherapy with tebentafusp, a bispecific antibody (capable of redirecting the patient's CD3+ T lymphocytes against the gp100 glycoprotein expressed by skin cells and melanoma tumor cells). But Tebentafusp can only be used in about 45% of patients (those with a specific form of HLA (HLA serotype*02:01)²), necessary to trigger this anti-melanoma immunity). Other immunotherapies such as anti-PD-1 have a lower efficacy, illustrating the need to identify new treatment strategies for patients with metastatic uveal melanomas.

Phase 2 PLUME clinical trial aims to evaluate the efficacy and tolerability of the combination of immunotherapy using an anti-PD-1 antibody (pembrolizumab) with targeted treatment (lenvatinib - tyrosine kinase inhibitor). "There are pre-clinical and clinical data that show that this combination of lenvatinib with pembrolizumab is more effective than monotherapy, especially in endometrial and kidney cancers," specifies Dr Manuel Rodrigues, principal investigator of the PLUME clinical trial, medical oncologist and researcher at Institut Curie.

The positive results presented at the ESMO show that in the 51 patients included in the study, the combination of immunotherapy with targeted therapy reached the main evaluation criterion (namely fewer relapses at 6 months than expected with pembrolizumab alone). 

"The treatment was particularly effective in patients who had previously been treated with tebentafusp. Our hypothesis is that tebentafusp triggers an immune reaction, which is reactivated or amplified by the combination of pembrolizumab and lenvatinib. Currently, we are continuing our work in order to understand if the addition of lenvatinib is essential in this situation, and we are also exploring biomarkers that would allow us to better understand the success of this treatment in some people and not in others, " concludes Dr. Manuel Rodrigues.

PLUME : a single-arm phase II trial of pembrolizumab (pembro) plus lenvatinib (lenva) in patients (pts) with metastatic uveal melanoma (mUM) – Session mini-oral : october 18, 2025 – Dr Manuel Rodrigues

[1] Source National Cancer Institute

[2] The HLA gene, for Human Leukocyte Antigen, codes for a protein expressed on the surface of immune cells. A sort of “cellular passport,” this protein serves to recognize the body’s cells among themselves.