Recently, the phase 3 clinical trial results of T cell receptor (TCR) therapy, tebentafusp, have been released. The results showed that it reached the primary endpoint in the treatment of metastatic uveal melanoma (mUM): compared with the therapy selected by the researchers, tebentafusp significantly prolonged the overall survival (OS). It is worth mentioning that this is the first positive phase 3 clinical trial of TCR therapy and bispecific therapy in solid tumors. The prognosis of patients with mUM is very poor, and the situation has not changed significantly in the past few decades. If approved, tebentafusp will be the first new treatment in 40 years to improve the OS of patients with mUM.

Tebentafusp is a novel bispecific protein, which is formed by the fusion of soluble TCR and anti-CD3 immune effector domain. It targets gp100, a pedigree antigen expressed in melanocytes and melanoma, which aims to redirect and activate T cells to recognize and kill tumor cells. FDA has granted tebentafusp orphan drug designation (ODD) and fast track designation (FTD) in the treatment of uveal melanoma (UM).

The study was conducted among previously untreated mUM patients. A total of 378 patients were randomly assigned to tebentafusp or therapies selected by researchers at 2:1. In this study, the therapies selected by researchers included dacarbazine, Yervoy (ipilimumab, anti-CTLA4 therapy), Keytruda (pembrolizumab, anti-PD-1 therapy). The primary endpoint of the study was the OS.

The results showed that in the first pre-planned mid-term analysis, the study reached a predefined threshold in terms of the main endpoints of the OS. The OS Hazard Ratio (HR) in the intent-to-treat population favored tebentafusp, HR=0.51 (95% CI: 0.36, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 12% ipilimumab; 6% dacarbazine), equivalent to a 49% reduction in the risk of death. Although not yet mature, the Kaplan-Meier estimates suggest a 1-year OS rate of approximately 73% vs 58%, respectively (tebentafusp group vs. control group). Tebentafusp’s positive results represent a potentially innovative treatment for mUM.