Tebentafusp in first-line melanoma trials: An outperforming outlier

Uveal melanoma is distinct from other melanomas. In the advanced and metastatic stages, little to no improvement have been seen over time. Tebentafusp is a novel mechanism of action bispecific gp100 peptide-HLA-directed CD3 T-cell engager fusion protein ("-fusp"). Tebentafusp was granted full approval on January 25th 2022 in the setting of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. The approval was based on the overall survival advantage of tebentafusp over physician's choice therapy, in previously untreated uveal melanoma patients, based on the IMCgp100-202 trial. While we welcome positive results for this unmet need, three issues are raised by the trial. First, the control arm was restricted, precluding important options. Second, post-progression treatment was provided to a smaller fraction of patients than in real-life, which raises the question of whether overall survival was negatively impacted by limited care after the trial ended. Finally, the discrepancy between overall survival and progression-free survival benefit is an outlier in the context of previous melanoma trials. While it is clear that tebentafusp has an important role to play in this tumor type, the exact line is not yet well known. Confirmatory trials are needed for this compound.