Background
Open-label phase 3 trial (IMCgp100-202) randomizing 378 previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma 2:1. Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T-cell engager (soluble TCR fused to anti-CD3).
Interventions and follow up
Arm A: IV tebentafusp 20 μg day 1, 30 μg day 8, then 68 μg weekly
Arm B: Investigator choice of pembrolizumab 2 mg/kg (max 200 mg) q21d, or ipilimumab 3 mg/kg q21d x4, or dacarbazine 1000 mg/m2 q21d
Primary endpoint: Overall survival
Secondary endpoints: PFS, ORR, safety
mFollow up: 14.1 mo
Arm B: Investigator choice of pembrolizumab 2 mg/kg (max 200 mg) q21d, or ipilimumab 3 mg/kg q21d x4, or dacarbazine 1000 mg/m2 q21d
Primary endpoint: Overall survival
Secondary endpoints: PFS, ORR, safety
mFollow up: 14.1 mo
Results
mOS: 21.7 mo vs 16.0 mo; HR 0.51, 95%CI 0.37-0.71, P<.001
1-yr OS: 73% vs 59%
1-yr PFS: 31% vs 19%; HR 0.73, 95%CI 0.58-0.94, P=.01
ORR: 9% vs 5%
1-yr OS: 73% vs 59%
1-yr PFS: 31% vs 19%; HR 0.73, 95%CI 0.58-0.94, P=.01
ORR: 9% vs 5%
Adverse events
Overall grade ≥3: 44% vs 17% (tebentafusp vs control)
Cytokine-mediated: cytokine release syndrome 89% vs 3%, pyrexia 76% vs 3%, fatigue 41% vs 26%, nausea 43% vs 19%
Skin (any grade): rash 83% vs 24%, pruritus 69% vs 21%; events mostly grade 1-2 and decreased after early cycles
Cytokine-mediated: cytokine release syndrome 89% vs 3%, pyrexia 76% vs 3%, fatigue 41% vs 26%, nausea 43% vs 19%
Skin (any grade): rash 83% vs 24%, pruritus 69% vs 21%; events mostly grade 1-2 and decreased after early cycles
Conclusions
Tebentafusp significantly prolonged overall survival versus investigator's choice in previously untreated HLA-A*02:01-positive metastatic uveal melanoma, despite low objective response rates, with a distinctive cytokine-mediated and cutaneous toxicity profile.
Key Limitations
Restricted to HLA-A*02:01-positive patients (~50% of population), limiting applicability. OS benefit dissociated from radiographic response, complicating on-treatment assessment. Open-label design.
Clinical Context
Supported FDA approval (Jan 2022) of tebentafusp-tebn (Kimmtrak) for HLA-A*02:01-positive unresectable/metastatic uveal melanoma, the first TCR-based therapeutic and first agent approved for this disease; ESMO recommends it as preferred first-line therapy in eligible patients.