Background
Final 5-year overall survival analysis of the international, open-label, randomized phase 3 trial (IMCgp100-202; NCT03070392) of tebentafusp, a gp100×CD3 bispecific T-cell engager (ImmTAC), versus investigator's choice in previously untreated HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma (mUM). The trial randomized patients 2:1, stratified by LDH; tebentafusp is the established first-line standard of care for this population.
Results
Interventions and follow up: Arm A: tebentafusp (gp100-directed bispecific T-cell engager), weekly IV
Arm B: investigator's choice of pembrolizumab, ipilimumab, or dacarbazine
Primary endpoint: overall survival (ctDNA reduction was an exploratory endpoint)
mFollow up: minimum 5 years
Results: OS (median): 21.6mo vs 16.9mo (tebentafusp vs control); stratified HR 0.67, 95%CI 0.54-0.85
5-yr OS: 16% vs 8%
Poor-prognosis subgroups: OS benefit retained in baseline tumors ≥10cm and in patients whose best RECISTv1.1 response was progressive disease
Treatment beyond progression (post hoc): longer OS than discontinuation after covariate adjustment
ctDNA (exploratory): undetectable baseline or ≥50% reduction by week 9 associated with longer OS
Arm B: investigator's choice of pembrolizumab, ipilimumab, or dacarbazine
Primary endpoint: overall survival (ctDNA reduction was an exploratory endpoint)
mFollow up: minimum 5 years
Results: OS (median): 21.6mo vs 16.9mo (tebentafusp vs control); stratified HR 0.67, 95%CI 0.54-0.85
5-yr OS: 16% vs 8%
Poor-prognosis subgroups: OS benefit retained in baseline tumors ≥10cm and in patients whose best RECISTv1.1 response was progressive disease
Treatment beyond progression (post hoc): longer OS than discontinuation after covariate adjustment
ctDNA (exploratory): undetectable baseline or ≥50% reduction by week 9 associated with longer OS
Adverse events
Cytokine-mediated: cytokine release syndrome common, predominantly low grade and confined to early cycles (per prior reports)
Skin: rash and pruritus common, early-onset
Grade ≥3 / discontinuation rates: NR in this 5-year update
Skin: rash and pruritus common, early-onset
Grade ≥3 / discontinuation rates: NR in this 5-year update
Conclusions
With a minimum of 5 years of follow-up, tebentafusp continued to deliver a clinically meaningful overall survival benefit (5-yr OS 16% vs 8%; HR 0.67) in first-line HLA-A*02:01-positive metastatic uveal melanoma — the longest survival follow-up of any randomized trial in this disease. Benefit persisted even among patients with radiographic progression, and the analysis reinforces tebentafusp's role as first-line standard of care.
Key Limitations
Mature OS update of a previously reported phase 3 rather than a new primary readout; treatment-beyond-progression benefit and covariate-adjusted survival are post hoc, and ctDNA analyses exploratory; eligibility restricted to HLA-A*02:01-positive patients (roughly half of the mUM population), limiting applicability; open-label design with a heterogeneous control arm (pembrolizumab/ipilimumab/dacarbazine).
Clinical Context
Tebentafusp (Kimmtrak) received FDA approval in January 2022 and EMA approval in 2022 for HLA-A*02:01-positive unresectable/metastatic uveal melanoma — the first therapy to demonstrate an OS benefit in this historically treatment-resistant disease. NCCN and ESMO recommend tebentafusp as preferred first-line therapy for HLA-A*02:01-positive mUM. This 5-year analysis reinforces its established positioning.
References
Piperno-Neumann S et al, Ann Oncol 2026 (tebentafusp 5-year; IMCgp100-202); PMID 42162665 | Nathan P et al, N Engl J Med 2021; PMID 34597430