Tebentafusp-tebn Doubles 5-Year Survival in Metastatic Uveal Melanoma

Five-year overall survival (OS) data from the pivotal phase 3 randomized trial of tebentafusp-tebn (Kimmtrak) in HLA-A*02:01–positive patients with metastatic uveal melanoma (mUM) demonstrate that the bispecific T-cell receptor therapy doubled the likelihood of survival at 5 years compared with investigator’s choice, according to findings presented at the American Association for Cancer Research (AACR) Annual Meeting 2026.^1,2

In the phase 3 IMCgp100-202 trial (NCT03070392), the 5-year OS rate was 16% (95% CI, 11%-21%) in the tebentafusp arm vs 8% (95% CI, 4%-14%) in the control arm (stratified HR, 0.67; 95% CI, 0.54-0.85).¹ Median OS was 21.6 months with tebentafusp vs 16.9 months with investigator’s choice, of which 82% received pembrolizumab (Keytruda). These data represent the longest prospective OS follow-up reported in any randomized trial in mUM and the longest follow-up for any T-cell engager in a solid tumor. Historically, 5-year survival in mUM has been less than 10%.^1,3

The Kaplan-Meier survival curves separated early and remained separated throughout the observation period, confirming durability of benefit with extended follow-up. This update builds on prior data showing an OS HR of 0.51 at the primary analysis and 0.68 at the 3-year follow-up, at which point 3-year OS rates were 27% for tebentafusp vs 18% for investigator’s choice.^4,5

“These long-term overall survival results further solidify [tebentafusp] as the first-line standard of care for HLA-A*02:01–positive patients with metastatic uveal melanoma,” said Mohammed Dar, MD, chief medical officer of Immunocore, in a news release. “The survival benefit was evident even in patients with known poor prognostic factors, including those with large tumors and extrahepatic disease.”²

Subgroup and Biomarker Findings

The OS benefit with tebentafusp was consistent across clinically relevant subgroups with known poor prognostic factors, including patients with high tumor burden (at least 10 cm), elevated lactate dehydrogenase (LDH), hepatic-only disease, and combined hepatic and extrahepatic disease.^1,2 Notably, a survival advantage was also observed among patients whose best response was progressive disease, including those with greater than 20% tumor growth as their best change from baseline, a finding that challenges conventional reliance on radiographic response as a surrogate for clinical benefit.

Among 5-year survivors in the tebentafusp arm, 44% received tebentafusp as their only therapy. In contrast, 86% of control arm survivors subsequently received tebentafusp, suggesting the OS benefit in the experimental arm was driven primarily by tebentafusp rather than by crossover or salvage regimens.

Circulating tumor DNA (ctDNA) data provided additional mechanistic insight. Longer OS was associated with undetectable ctDNA at baseline or ctDNA reductions of at least 50% by week 9. Among the 21 ctDNA-evaluable patients surviving at least 5 years, 15 had undetectable baseline ctDNA and the remaining 6 achieved ctDNA clearance by week 9. Importantly, deep ctDNA reductions were observed regardless of baseline tumor burden and across all RECIST response categories, further supporting ctDNA molecular response as a more sensitive indicator of tebentafusp activity than radiographic measurement.

Treatment Beyond Progression

A key signal in the data involved continuation of therapy past initial tumor progression. More patients in the tebentafusp arm continued treatment beyond progression compared with the control arm (57% vs 25%). In a Cox model adjusted for baseline and time-varying covariates at progression, treatment beyond progression (TBP) in the tebentafusp arm was associated with significantly better post-progression OS compared with stopping treatment (HR, 0.61; 95% CI, 0.44-0.83). Patients continuing tebentafusp beyond progression also achieved a nearly 7-fold higher rate of tumor reduction compared with control arm patients who continued treatment (27% vs 4%), lending support to a strategy of treatment continuation in select patients.

Context and Clinical Significance

Uveal melanoma is a rare and aggressive intraocular malignancy; up to 50% of patients develop metastatic disease, which until recently had no approved systemic therapy.³ Tebentafusp is a bispecific fusion protein comprised of a soluble T-cell receptor targeting the melanocyte lineage antigen gp100 fused to an anti-CD3 effector domain, enabling redirection and activation of T cells against tumor cells regardless of mutational burden or immune infiltration status.

The FDA approved tebentafusp-tebn in January 2022 for HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma.

Safety

The established safety profile of tebentafusp was consistent with prior reports. Cytokine release syndrome occurred in 89% of patients (grade 3/4: 0.8%) and requires monitoring for at least 16 hours following the first 3 infusions.² Skin reactions occurred in 91% of patients. Elevations in liver enzymes were reported in 65% of patients.

REFERENCES

1. Nathan P, Piperno-Neumann S, Hassel JS, et al. Five-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial. Cancer Res. 2026;86(suppl 8):CT029. doi:10.1158/1538-7445.AM2026-CT029

2. KIMMTRAK doubles the likelihood of being alive at five years for first line HLA-A*02:01+ patients with metastatic uveal melanoma. News release. Immunocore. April 19, 2026. Accessed April 22, 2026. https://tinyurl.com/2a9yw9xc

3. Zahra FT, Ali H, Mohsin F, et al. Trends in mortality, incidence, and survival of uveal melanoma: A SEER-based retrospective analysis. J Clin Oncol. 2025;43(suppl 16):e21581. doi:10.1200/JCO.2025.43.16_suppl.e21581

4. 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

5. Hassel JC, Piperno-Neumann S, Rutkowski P, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023;389(24):2256-2266. doi:10.1056/NEJMoa2304753