Kimmtrak (tebentafusp-tebn)

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

Clinically, the bispecific T-cell redirection drug Tebentafusp has achieved a major breakthrough in metastatic uveal melanoma immunotherapy. This review systematically elucidates key driver gene mutations, chromosomal abnormalities, epigenetic alterations, and the unique immunosuppressive microenvironment of uveal melanoma, providing new insights into mechanisms of treatment resistance and guiding the development of innovative therapeutic strategies.

P2, N=44, Recruiting, Diwakar Davar | Trial completion date: Mar 2030 --> Sep 2030 | Trial primary completion date: Mar 2028 --> Sep 2028

UM is a rare but aggressive malignancy with limited treatment options once metastatic. Liver-directed strategies remain the mainstay of management, while novel systemic approaches, including tebentafusp, represent promising advances. Further research is required to improve survival and expand therapeutic opportunities.

This review synthesizes the current understanding of UM epidemiology, characteristics, prognostic biomarkers, immune biology, and contemporary management for both localized and metastatic disease. While survival gains remain modest, the rapid expansion of biologically informed and immune-based strategies offers cautious optimism for improving outcomes in this historically treatment-refractory disease.

Low HLA-A*02:01 positivity and limited access to tebentafusp remain major challenges in Türkiye. These findings provide an essential benchmark for improving treatment strategies in metastatic UM.

Plasma analysis identified a pathogenic SPEN variant and human leukocyte antigen (HLA) genotype (HLA-A*02:17 and HLA-A*02:01 alleles), conferring therapeutic eligibility for tebentafusp, and molecular evidence supportive of metastatic uveal melanoma, enabling initiation of appropriate systemic therapy before additional tissue sampling...While the liquid biopsy and ablation of one of the lesions confirmed the diagnosis, the liquid biopsy was a key first step that provided a comprehensive diagnostic and prognostic picture without the need for an invasive procedure. This case highlights how integrating liquid biopsy into the diagnostic pathway for uveal melanoma can lead to earlier, more informed treatment decisions.