Kimmtrak (tebentafusp-tebn)

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.

Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40-70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events.

Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3months of treatment-start, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a non-invasive tool for disease monitoring.

P2, N=18, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

This is the first published case suggesting a potential role for leukotriene receptor antagonists in CYSLTR2-mutant UM. These findings support further preclinical and clinical investigation of montelukast as a repurposed therapy in this challenging disease entity.

Tebentafusp for patients with HLA-A*02:01-positive mUM is associated with improved survival outcomes and manageable toxicity. These findings support tebentafusp as the standard of care for this patient population.

P1/2, N=109, Recruiting, Thomas Jefferson University | Not yet recruiting --> Recruiting | Trial completion date: Mar 2032 --> Aug 2032 | Trial primary completion date: May 2030 --> Oct 2030