In the randomised, phase III study, treatment with tebentafusp, a soluble T-cell receptor and CD3-directed bispecific fusion protein, was associated with longer overall survival (OS) than the investigator’s choice of therapy in HLA-A*02:01–positive patients with metastatic uveal melanoma. The results are published on 23 September 2021 in The New England Journal of Medicine by Dr. Paul Nathan of the Mount Vernon Cancer Centre in Northwood, United Kingdom and the IMCgp100-202 study investigators.
Uveal melanoma is the most common intraocular cancer in adults. It represents approximately 3-5% of all melanomas. Although it arises from melanocytes, uveal melanoma is distinct from cutaneous melanoma, with different molecular drivers and metastatic patterns, different tumour-immune microenvironment, and low tumour mutational burden. A clinical response to systemic treatment, including immune checkpoint inhibitors is poor. During the course of disease, almost half patients with uveal melanoma develop metastases, predominantly in the liver with median OS in these patients of approximately 1 year.
The authors explained in the background that molecules termed immune-mobilising monoclonal T-cell receptors against cancer (ImmTAC) are a new class of T-cell–redirecting bispecific fusion proteins. Tebentafusp (formerly IMCgp100) consists of a soluble affinity-enhanced HLA-A*02:01–restricted T-cell receptor that is specific for the glycoprotein 100 (gp100) peptide YLEPGPVTA and is fused to an anti-CD3 single-chain variable fragment. Once ImmTAC molecules are bound to their specific peptide–HLA complexes on the target-cell surface, they recruit and activate polyclonal T-cells, through CD3, to release cytokines and cytolytic mediators against target cells.
In a single-group, phase II study involving 127 patients with previously treated metastatic uveal melanoma, tebentafusp monotherapy showed more promising OS than historical controls. Responses defined according to RECIST v1.1 were observed, but this surrogate endpoint did not sufficiently predict long-term survival benefit. Clinical benefit included indolent tumour growth and slow tumour shrinkage.
In this open-label, phase III study, the researchers randomly assigned previously untreated HLA-A*02:01–positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine, and stratified according to the lactate dehydrogenase level. The primary endpoint was OS.
In total, 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group of the investigator’s choice of therapy (126 patients). In the intention-to-treat population, the OS at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio [HR] for death 0.51; 95% confidence interval [CI] 0.37 to 0.71; p < 0.001).
Progression-free survival was also significantly higher in the tebentafusp group than in the control group, 31% versus 19% at 6 months (HR for disease progression or death 0.73; 95% CI 0.58 to 0.94; p = 0.01).
The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events due to T-cell activation and skin-related events due to glycoprotein 100–positive melanocytes, including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the treatment (2%). No treatment-related deaths were reported.
Anti-tebentafusp antibodies developed in some patients, with minimal effect on the tebentafusp concentration and no apparent effect on either OS or the risk of hypersensitivity reactions. Whether the antibodies neutralise the effect of tebentafusp has not yet been determined.
The authors concluded that in this randomised, controlled, phase III study in patients with previously untreated metastatic uveal melanoma, treatment with tebentafusp resulted in significantly longer OS than the investigator’s choice of treatment with pembrolizumab, ipilimumab, or dacarbazine.
Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med 2021;385(13):1196-1206.