Compared with available therapies, treatment with tebentafusp significantly improved overall survival in patients with previously untreated metastatic uveal melanoma in a phase-3 study. Uveal melanoma is a rare and aggressive form of melanoma that affects the eye. Metastatic uveal melanoma has a poor prognosis and, until now, no systemic therapy has shown a survival benefit. "Tebentafusp has the potential to be practice-changing in uveal melanoma," Dr. Jessica Hassel of the National Center for Tumor Diseases of University Hospital Heidelberg, in Germany, said at a press briefing at the American Association for Cancer Research (AACR) virtual annual meeting, where the findings were presented. Tebentafusp is a novel investigational bispecific fusion protein being developed by Immunocore, which funded the study. The protein consists of a soluble T-cell receptor (TCR) that detects HLA-A*02:01 present in the gp100 protein expressed in melanoma cells and an anti-CD3 chain that binds and activates T cells. "Tebentafusp builds a bridge between the tumor and the immune cells, enabling the immune cells to attack the tumor," Dr. Hassel explained in an AACR news release. Tebentafusp was compared with investigator's choice as first-line therapy in 378 previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma; 252 patients received tebentafusp, 103 received the checkpoint-inhibitor pembrolizumab, 16 received ipilimumab (another checkpoint inhibitor) and seven received dacarbazine. Overall survival (OS) was the primary endpoint. Median OS was significantly longer with tebentafusp than investigator's choice (21.7 months vs. 16.0 months), with a one-year OS of 73.2% in the tebentafusp group compared with 58.5% in the investigator's choice group. After a median follow-up of 14.1 months, compared with the other treatments, tebentafusp halved the risk of death (hazard ratio: 0.51; P<0.0001). The overall survival benefit was seen in all subgroups and even in patients without objective response, based on Response Evaluation Criteria in Solid Tumors (RECIST), Dr. Hassel reported. She noted that tebentafusp had a "predictable and manageable" adverse-event profile consisting mainly of cytokine-mediated and skin-related adverse events in line with the mechanism of action of tebentafusp. Most adverse events occurred in the first few weeks of treatment and decreased in frequency and severity. The rate of discontinuation was low and there were no treatment-related deaths. AACR president and briefing moderator Dr. Antoni Ribas noted that this is the "first-ever study that has shown an improvement in overall survival in patients with uveal melanoma." "Patients with metastatic uveal melanoma have no effective treatment. In over 50 to 60 years of research, there has never been a treatment that has shown improvement in overall survival. This one being the first," he told the briefing. "Tebentafusp is the first TCR therapeutic that has been successfully developed and the first therapeutic targeting melanoma antigens that has shown improvement in a randomized trial. This is a practice-changing study and we hope to be able to use this agent in the clinic," Dr. Ribas added. Tebentafusp has been granted breakthrough therapy and fast-track designations from the U.S. Food and Drug Administration. —Megan Brooks Source
