Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

N Engl J Med. 2021 Sep 23;385(13):1196-1206. doi: 10.1056/NEJMoa2103485.

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.).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Ipilimumab
  • Dacarbazine
  • pembrolizumab

Associated data

  • ClinicalTrials.gov/NCT03070392
  • EudraCT/2015-003153-18