Kimmtrak (tebentafusp-tebn)

These data provide new insights into Gαq-driven modulators of UM phenotype of relevance for studies of tumor-microenvironment interaction and metastasis.

Ipilimumab combined with nivolumab has demonstrated superior outcomes, earning a median overall survival surpassing 70 months...The advent of new ICIs, such as relatlimab, introduces additional complexities in decision-making for first-line therapy...The FDA approval of tebentafusp and lifileucel has demonstrated potential in extending the survival time of patients with metastatic uveal melanoma...It aims to facilitate informed treatment decisions and enhance understanding of the multifaceted challenges in effectively managing advanced melanoma. As new therapies emerge, continuous education and adaptability will be key to optimising patient outcomes.

T-cell engager therapies, including bispecific T-cell engagers and the immune-mobilizing monoclonal T-cell receptor against cancer tebentafusp, are an emerging class of anticancer immunotherapy, with rapid expansion of the class since initial approval of blinatumomab in 2014 and with distinct dermatologic adverse events increasingly recognized across agents. Tebentafusp and talquetamab demonstrate highest rates of notable dermatologic toxicity reflecting on-target off-tumor cutaneous effects...Across agents, most dermatologic adverse events can be managed with topical corticosteroids, emollients, antihistamines, or brief courses of systemic corticosteroids without requiring treatment discontinuation. Recognition of these agent-specific and mechanistically linked patterns is essential for dermatologists as T-cell engager therapies become increasingly integrated into oncology practice.

Genomic loss of the HLA-haplotype carrying the HLA-A*02:01 restriction element was detected in a progressive metastasis, resulting in loss of presentation of tebentafusp's target antigen. Understanding mechanisms of resistance against synthetic cancer immunotherapies will be key to monitoring disease control and development of early intervention strategies towards cure.

Ongoing research explores tebentafusp in other settings, including cutaneous melanoma. Other ImmTACs, e.g. brenetefusp is being developed, underscoring the potential of this modality in cancer immunotherapy.

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.

Local RT may enhance antigen release and T-cell recruitment, amplifying tebentafusp efficacy and inducing abscopal-like effects. Prospective studies are warranted to evaluate this combination and identify biomarkers predictive of response.

P2, N=19, Recruiting, Grupo Español Multidisciplinar de Melanoma

Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and PRAME among others. Collectively, next-generation TCEs guided by rational target selection, context-dependent activation, and biomarker-driven patient stratification, are poised to broaden the reach of immunotherapy in solid tumors. In this review, we synthesize the recent advances that aim to expand the therapeutic window of TCEs for the treatment of solid tumors.

P2, N=378, Completed, Immunocore Ltd | Active, not recruiting --> Completed

In 2022, tebentafusp became the first approved systemic therapy to improve overall survival in metastatic UM...As half of the patients are HLA A02:01 negative, alternative strategies are under investigation, including the protein kinase C inhibitor darovasertib in the NADOM neoadjuvant/adjuvant trial and in combination with crizotinib in metastatic UM. DYP688, a first-in-class PMEL17-targeting antibody-drug conjugate that inhibits GNAQ/11 signaling, has shown promise in metastatic UM and other GNAQ/11-mutant melanomas. The landscape of UM treatment is rapidly evolving following the identification of new targets and pathways such as PKC or PRAME. Combination of liver-directed therapies with personalized systemic immunotherapies or targeted agents in the metastatic disease, as well as the early use of systemic therapies in the primary tumor setting will refine treatment strategies in UM and suggest improved outcomes in the near future.

P1/2, N=410, Active, not recruiting, Immunocore Ltd | Recruiting --> Active, not recruiting | N=727 --> 410 | Trial completion date: Aug 2026 --> Dec 2027 | Trial primary completion date: Feb 2026 --> Oct 2026