Tebentafusp Sustains Survival Benefit at 5 Years in Metastatic Uveal Melanoma

Tebentafusp-tebn (Kimmtrak) continued to confer an overall survival (OS) benefit over investigator’s choice of therapy after a minimum of 5 years of follow-up among previously untreated patients with HLA-A*02:01–positive unresectable or metastatic uveal melanoma, according to the final analysis of the phase 3 IMCgp100-202 trial (NCT03070392) published in Annals of Oncology.¹

At the 5-year landmark, the OS rate was 16% (95% CI, 11%-21%) in the tebentafusp group vs 8% (95% CI, 4%-14%) in the control group. The median OS was 21.6 months (95% CI, 19.0-24.3) vs 16.9 months (95% CI, 12.9-19.5), respectively (HR, 0.67; 95% CI, 0.54-0.85). The 5-year data were previously presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting in April.²

“What we can see is a continued, maintained separation of the survival curves with these 5-year landmark data. The HR for [OS] 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,” said study lead Paul Nathan, MBBS, PhD, FRCP, professor and consultant medical oncologist at HCA UK at University College Hospital, in a presentation of the data at the AACR meeting, as previously reported by CancerNetwork®.² “We’ve proved that there are patients who have long-term, durable benefit from this agent.”

“In the longest survival follow-up of a randomized trial in [metastatic uveal melanoma], tebentafusp continues to provide long-term survival benefit in previously untreated HLA-A*02:01-positive patients,” wrote first authors Sophie Piperno-Neumann, MD, of the Department of Medical Oncology at Institut Curie in Paris, France, and colleagues, in the study.¹

What were the efficacy results from the IMCgp100-202 trial?

Because most deaths were related to disease progression (91%), melanoma-specific survival closely mirrored the overall population, with an HR of 0.69 (95% CI, 0.54-0.88). Among patients who survived at least 5 years, 44% (n = 11/25) in the tebentafusp group reportedly received only tebentafusp, whereas 6 of 7 long-term survivors in the control group had received subsequent tebentafusp.

The survival benefit persisted across prespecified subgroups and in exploratory analyses regardless of metastasis location or baseline tumor burden. Having a largest metastatic lesion of 3 cm or smaller emerged as the strongest baseline predictor of benefit with tebentafusp (HR, 0.39), which the investigators said underscores the importance of early patient identification and intervention.

More patients in the tebentafusp group than the control group continued treatment beyond radiographic progression (57% vs 25%). After adjusting for covariates, continued tebentafusp was associated with improved post-progression survival (HR, 0.61; 95% CI, 0.44-0.83), and 27% of patients treated beyond progression had subsequent tumor reduction vs 4% in the control group. The investigators noted that these patients generally had more favorable prognostic features, suggesting a clinically selected subgroup.

Consistent with prior reports, tebentafusp produced a modest radiologic response rate compared with control (11% vs 5%), along with a longer median duration of response (11.1 vs 9.7 months) and greater tumor reduction (40% vs 24%). Stable disease was more frequent with tebentafusp (35% vs 22%), yielding a disease control rate of 46% vs 27%. In a landmark analysis after day 100, the median OS was 15.1 months (95% CI, 11.5-17.4) with tebentafusp vs 10.1 months (95% CI, 5.4-13.6) with investigator’s choice (HR, 0.61; 95% CI, 0.43-0.88). A survival benefit was also observed in patients with tumor growth greater than 20% (HR, 0.63; 95% CI, 0.42-0.94).

Were post-hoc and exploratory analyses conducted with tebentafusp?

To determine whether subsequent therapy influenced results, the investigators conducted a post hoc analysis that censored patients at the time of first subsequent therapy and reweighted them using inverse probability of censoring weighting. The analysis produced an HR of 0.52 (95% CI, 0.31-0.83), suggesting that the benefit of tebentafusp remained when the effect of later treatment was removed. Overall, 60% and 61% of patients in the tebentafusp and control groups received at least 1 subsequent line of systemic therapy, respectively; 22% of the control group received subsequent tebentafusp.

Exploratory circulating tumor DNA (ctDNA) analyses suggested that on-treatment molecular response may be a more sensitive marker of benefit than imaging. Of 202 ctDNA-evaluable patients in the tebentafusp group, 123 (61%) had detectable ctDNA at baseline; of these, 88% had some reduction by week 9 and 37% achieved complete clearance. Patients with undetectable baseline ctDNA had a median OS of 27.3 months (95% CI, 24.1-34.3) and an estimated 5-year OS rate of 27% (95% CI, 17%-38%), similar to those who cleared ctDNA by week 9, who had a median OS of 29.6 months (95% CI, 23-37) and estimated 5-year OS rate of 19% (95% CI, 9%-33%). A reduction of at least 50% in ctDNA was also associated with longer OS (HR, 0.41; 95% CI, 0.26-0.67). These reductions occurred across all RECIST categories and were not associated with baseline tumor size.

What was the trial design ofIMCgp100-202?

In the trial, 378 patients were randomly assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine (n = 126), with stratification by lactate dehydrogenase level. Tebentafusp was given intravenously at 68 µg weekly after step-up doses of 20 µg on day 1 and 30 µg on day 8. Eligible patients were at least 18 years old with HLA-A*02:01–positive metastatic uveal melanoma by central assay who were treatment-naive for metastatic disease and had an ECOG performance status of 0 or 1. The median follow-up was 62.4 months. No new safety data were available for this analysis.

The authors acknowledged that a high unmet need remains, noting that patients who are HLA-A*02:01–negative, who comprised 49% of those prescreened, lack an established standard of care. They added that prospective validation of ctDNA-guided monitoring is needed to improve early assessments and guide treatment beyond progression.

References

1. Piperno-Neumann S, Rutkowski P, Hassel JC, et al. Five-year survival with tebentafusp in metastatic uveal melanoma. Ann Oncol. 2026;37(9):1266-1277. doi:10.1016/j.annonc.2026.05.695
2. 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. Abstract presented at: American Association for Cancer Research Annual Meeting 2026; April 17-22, 2026; San Diego, CA. Abstract CT029.