Long-term survival benefits with tebentafusp persist in previously untreated HLA-A∗02:01-positive patients with unresectable or metastatic uveal melanoma (mUM), as shown in the longest survival follow-up of a phase III trial.
“[T]he long-term survival benefit of tebentafusp is maintained at 5 years and best captured by a combination of survival outcomes and sensitive molecular biomarkers rather than traditional radiographic endpoints,” the researchers said.
Overall, 378 eligible patients were randomized 2:1 to receive either tebentafusp (n=252) or an investigator’s choice of single-agent pembrolizumab, ipilimumab, or dacarbazine (n=126; control group), stratified by lactate dehydrogenase level.
Tebentafusp was administered intravenously weekly (68 μg) after step-up disease of 20 μg (day 1) and 30 μg (day 8). Pembrolizumab (2 mg/kg, max 200 mg), ipilimumab (3 mg/kg, up to four doses) and dacarbazine (1,000 mg/m2) were also given intravenously on day 1 of 21-day cycles. Baseline characteristics were similar between treatment groups.
The median overall survival (OS) after a minimum 5-year follow-up was 21.6 months in the tebentafusp group and 16.9 months in the control group (stratified hazard ratio, 0.67, 95 percent confidence interval, 0.54‒0.85). OS at 5 years was 16 percent vs 8 percent, respectively. [Ann Oncol 2026;37:1266-1277]
Even patients with poor prognoses had improved survival with tebentafusp, particularly those with baseline tumours ≥10 cm or those whose best RECISTv1.1 response was progressive disease, including patients whose target tumour growth exceeded 20 percent.
In a post hoc analysis, patients on tebentafusp who were beyond radiographic progression enjoyed longer OS than those who discontinued treatment. Longer OS also correlated with undetectable circulating tumour (ct) DNA at baseline or ctDNA reductions ≥50 percent by week 9. Deep ctDNA reductions occurred regardless of baseline tumour burden or radiographic response.
“Prospective validation of ctDNA-guided monitoring and deeper investigation of tebentafusp-induced immune and microenvironmental changes will help improve early assessments and guide treatment beyond progression,” the researchers said. [Nat Commun 2025;16:2374; Cell Rep Med 2025;6:102076]
Mechanism of action
Tebentafusp works by redirecting polyclonal T cells to destroy tumour cells in a “TCR-agnostic manner,” inducing antitumour activity via repeated redirected cytotoxicity.
“This process may both support and be enhanced by subsequent tumour microenvironment changes, alterations in antigen presentation, and subsequent epitope spread, as evidenced by the induction of de novo cancer-specific T and B cell responses after five to eight doses of tebentafusp in a subset of patients with advanced melanoma,” the researchers said. [J Immunother Cancer 2022;10:A650]
“However, the persistence and functional contribution of these responses alongside ongoing weekly T cell redirection remain to be established,” they added.
Prior to tebentafusp, specifically approved therapies for mUM were lacking. “Even with the progress reported in this study, a high unmet need remains,” according to the researchers. “Although benefit was evident across subgroups, its extent requires further characterization in patients with rapid disease progression and in subgroups with limited patient numbers (eg, extrahepatic only disease).”
Additionally, HLA-A∗02:01-negative patients remain without an established standard of care. They comprised 49 percent of individuals prescreened, consistent with the rate in another study. [Cell Rep Med 2025;6:101994]
Current treatment options for these patients include immune checkpoint inhibitors and participation in clinical trials, the researchers said.