Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

TY - JOUR

T1 - Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

AU - Nathan, Paul

AU - Hassel, Jessica C

AU - Rutkowski, Piotr

AU - Baurain, Jean-Francois

AU - Butler, Marcus O

AU - Schlaak, Max

AU - Sullivan, Ryan J

AU - Ochsenreither, Sebastian

AU - Dummer, Reinhard

AU - Kirkwood, John M

AU - Joshua, Anthony M

AU - Sacco, Joseph J

AU - Shoushtari, Alexander N

AU - Orloff, Marlana

AU - Piulats, Josep M

AU - Milhem, Mohammed

AU - Salama, April K S

AU - Curti, Brendan

AU - Demidov, Lev

AU - Gastaud, Lauris

AU - Mauch, Cornelia

AU - Yushak, Melinda

AU - Carvajal, Richard D

AU - Hamid, Omid

AU - Abdullah, Shaad E

AU - Holland, Chris

AU - Goodall, Howard

AU - Piperno-Neumann, Sophie

AU - IMCgp100-202 Investigators

AU - Gebhardt, Christoffer

N1 - Copyright © 2021 Massachusetts Medical Society.

PY - 2021/9/23

Y1 - 2021/9/23

N2 - 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.).

AB - 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.).

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Humanized/therapeutic use

KW - Antineoplastic Agents/adverse effects

KW - Cytokine Release Syndrome/chemically induced

KW - Dacarbazine/therapeutic use

KW - Exanthema/chemically induced

KW - Female

KW - Humans

KW - Ipilimumab/therapeutic use

KW - Male

KW - Melanoma/drug therapy

KW - Middle Aged

KW - Recombinant Fusion Proteins/adverse effects

KW - Survival Analysis

KW - Uveal Neoplasms/drug therapy

U2 - 10.1056/NEJMoa2103485

DO - 10.1056/NEJMoa2103485

M3 - SCORING: Journal article

C2 - 34551229

VL - 385

SP - 1196

EP - 1206

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 13

ER -