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

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

Dermatological involvement is common and manageable, highlighting the need for early dermatological input in patients receiving tebentafusp. Emerging data suggest a possible association between rash and response, which warrants further investigation.

Additionally, circulating tumor DNA (ctDNA) may serve as a more sensitive efficacy biomarker than radiological responses, warranting further investigation. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251084090.

For patients with metastatic uveal melanoma (UM), tebentafusp is currently the only systemic therapy approved by the EMA and FDA, but its use is limited to HLA-A*02:01-positive individuals...These findings indicate that patients responding to ICB display tumors with enhanced immune activation. CD28 and CCL8 emerged as promising candidates and should be validated in prospective studies to determine their clinical utility.

P2, N=47, Recruiting, Sarcoma Alliance for Research through Collaboration | Not yet recruiting --> Recruiting

P1/2, N=109, Not yet recruiting, Thomas Jefferson University | Trial completion date: Feb 2027 --> Mar 2032 | Trial primary completion date: Jan 2027 --> May 2030

Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma...Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.

P1, N=8, Recruiting, St Vincent's Hospital, Sydney

CLT with tebentafusp was well-tolerated, extending the duration of tebentafusp benefit in a highly selected mUM population. This merits further studies to assess clinical utility.