The Phase 3 trial (CT029) randomized 378 unresectable or metastatic uveal melanoma patients with HLA-A*02:01 positivity in a 2:1 ratio to receive tebentafusp-tebn or investigator’s choice therapy, primarily pembrolizumab (82% of control arm). Inclusion criteria encompassed patients with varying tumor burdens, LDH levels, and extrahepatic disease.

At five years, overall survival in the tebentafusp arm reached 16% versus 8% in the control group, corresponding to a hazard ratio of 0.67 (95% CI: 0.54-0.85). This represents the longest follow-up for any T cell engager in a solid tumor and marks a first-in-class long-term survival benefit.

Median overall survival on tebentafusp was 21.6 months compared to 16.9 months for investigator’s choice, with Kaplan–Meier curves separating early and maintaining separation. Survival advantages were consistent across high tumor burden (≥10cm), elevated LDH, extrahepatic disease and even in patients whose best radiographic response was progressive disease.

Patients continuing tebentafusp beyond progression experienced a 27% tumor reduction rate versus 4% for controls and longer post-progression survival. Notably, 71% of five-year survivors had undetectable baseline ctDNA and ctDNA reductions ≥50% by week 9, underscoring early molecular response as a prognostic marker.