Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

Abstract

BACKGROUND:

Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.

METHODS:

In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

RESULTS:

A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio 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 trial treatment (2%). No treatment-related deaths were reported.

CONCLUSIONS:

Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

• Authors: Paul Nathan, Jessica C Hassel, Piotr Rutkowski, Jean-Francois Baurain, Marcus O Butler, Max Schlaak, Ryan J Sullivan, Sebastian Ochsenreither, Reinhard Dummer, John M Kirkwood, Anthony M Joshua, Joseph J Sacco, Alexander N Shoushtari, Marlana Orloff, Josep M Piulats, Mohammed Milhem, April K S Salama, Brendan Curti, Lev Demidov, Lauris Gastaud, Cornelia Mauch, Melinda Yushak, Richard D Carvajal, Omid Hamid, Shaad E Abdullah, Chris Holland, Howard Goodall, Sophie Piperno-Neumann, IMCgp100-202 Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 385 Issue 13 Pg. 1196-1206 (09 23 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 34551229 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Ipilimumab
• Recombinant Fusion Proteins
• Dacarbazine
• pembrolizumab
• tebentafusp

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents (adverse effects, therapeutic use)
• Cytokine Release Syndrome (chemically induced)
• Dacarbazine (therapeutic use)
• Exanthema (chemically induced)
• Female
• Humans
• Ipilimumab (therapeutic use)
• Male
• Melanoma (drug therapy, mortality, secondary)
• Middle Aged
• Recombinant Fusion Proteins (adverse effects, therapeutic use)
• Survival Analysis
• Uveal Neoplasms (drug therapy, mortality, pathology)