Tebentafusp Yields Favorable 5-Year OS Data in HLA-A*02:01+ Uveal Melanoma

The 5-year survival rate was favorable with tebentafusp-tebn (Kimmtrak) compared with investigator’s choice of therapy (ICT) for patients with HLA-A*02:01-positive uveal melanoma, according to results from the phase 3 IMCgp100-202 study (NCT03070392) presented at the 2026 American Association for Cancer Research Annual Meeting.¹

The median overall survival (OS) at 5 years was 21.6 months (95% CI, 19.0-24.3) in the tebentafusp group vs 16.9 months (95% CI, 12.9-19.5) in the ICT arm (HR, 0.67; 95% CI, 0.54-0.85). Of note, a 16% five-year OS rate was observed in the tebentafusp arm compared with 8% for the ICT arm. The OS benefit of tebentafusp was maintained when effect from subsequent therapy was removed (HR, 0.52; 95% CI, 0.31-0.83).

A benefit or trend of benefit was observed in favor of tebentafusp across most subgroups. Additionally, there was an OS benefit regardless of disease location or burden at baseline.

After day 100, the median OS was 15.1 months (95% CI, 11.5-17.4) in the tebentafusp arm vs 10.1 months (95% CI, 5.4-13.6) in the ICT arm (HR, 0.61; 95% CI, 0.43-0.88). In the tebentafusp arm, the disease control rate (DCR) was 46%, the stable disease (SD) rate was 35%, the progressive disease (PD) rate was 52%, and 11% of patients had a complete response (CR)/partial response (PR).

In the ICT arm, the DCR was 27%, the SD rate was 22%, the PD rate was 65%, and the PR rate was 5%.

“What we can see is a continued, maintained separation of the survival curves with these 5-year landmark data. The hazard ratio for overall survival is 0.67. Importantly, at the 5-year landmark, twice as many patients were alive who were randomized to tebentafusp as those who were randomized to the comparator investigator choice arm. The absolute numbers [were] 16% vs 8%; we’ve proved that there are patients who have long-term, durable benefit from this agent,” Paul Nathan, MBBS, PhD, MCRP, professor and Consultant Medical Oncologist at HCA UK at University College Hospital, and lead author of this study, said to CancerNetwork® in an exclusive interview.

A total of 378 patients were randomly assigned 2:1 and stratified by lactate dehydrogenase (LDH) level to either the tebentafusp arm (n = 252) or the ICT arm (n = 126). In the ICT arm, patients were given either pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. The primary end point was OS, with secondary end points being overall response rate, progression-free survival, DCR, DOR, and safety. Patients with uveal melanoma who were HLA-A*02:01 positive with no prior systemic therapy in the advanced setting, no prior liver-directed therapy except for surgery, and any LDH were included in the trial.

Circulating tumor DNA (ctDNA) response was assessed in the overall group (n = 123) with a molecular response rate (MRR) of 81%. For those with a PR, the MRR was 93%; for those with SD, the MRR was 86%; and for those with PD, the MRR was 75%.

Based on ctDNA levels, the OS was assessed. For baseline, the median OS was 27.3 months (95% CI, 24.1-34.3) for those with undetectable ctDNA compared with 18.4 months (95% CI, 14.8-22.5) for those with detected (HR, 0.5; 95% CI, 0.36-0.68). The on-treatment change in ctDNA levels by week 9 was also assessed. The median OS for those who were cleared was 29.6 months (95% CI, 23.0-37.0) vs 10.2 months (95% CI, 8.3-13.2) in those who were not cleared (HR, 0.32; 95% CI, 0.21-0.49). The median OS for those with a 50% or more reduction was 19.8 months (95% CI, 14.1-23.9) vs 9.1 months (95% CI, 5.6-14.5) for those with less than 50% reduction (HR, 0.41; 95% CI, 0.26-0.67).

In the tebentafusp arm, 71% of patients had no detectable ctDNA at baseline for those who survived 5 years or more, while 29% achieved clearance on treatment by week 9.

Treatment was assessed beyond radiographic progression based on longitudinal tumor kinetics. In the tebentafusp arm, the post PD reduction was 27% compared with 4% in the ICT arm. Beyond radiographic progression, 57% of patients in the tebentafusp arm vs 25% in the ICT arm continued treatment. Additionally, there was approximately a 7-fold higher rate of tumor reduction with treatment beyond radiographic progression in the tebentafusp arm vs the ICT arm.

A stepwise Cox model was used to determine that continued treatment with tebentafusp was associated with a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.44-0.83).

In 2021, the 3-year results were presented. The OS rate at 1 year was 73% in the tebentafusp arm vs 59% in the ICT arm (HR, 0.51; 95% CI, 0.37-0.71; P <.001).² At 6 months, the progression-free survival rate was 31% in the tebentafusp arm vs 19% in the ICT arm (HR, 0.73; 95% CI, 0.58-0.94; P = .01).

Dr Nathan has disclosed that he is a consultant/advisory board member for: Agenus, BMS, Eisai, Ideya, Immunocore, Ionctura, Ipsen, Medicenna, Monta, MSD, Merck, Novartis, Pfizer, ReBio, Regeneron, and Sun Pharma. He is part of the Speaker’s Bureau for BMS, Immunocore, and iOnctura. He has received Grant/Research support from Immunocore and Novartis.

References

1. Nathan P, Piperno-Neumann S, Hassel JC, et al. Five-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial. Presented at the 2026 American Association for Cancer Research Annual Meeting; San Diego, CA; April 17-22, 2026. Abstract CT029.
2. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485