Dr Nathan on the Rationale For Investigating Tebentafusp in Uveal Melanoma

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the rationale for launching the phase 3 IMCgp100-202 trial (NCT03070392) evaluating tebentafusp-tebn (Kimmtrak) in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma, as well as the mechanism of action of the agent.

Notably, the open-label clinical investigation randomly assigned patients to receive tebentafusp vs the investigator's choice of pembrolizumab (Keytruda), ipilimumab (Yervoy) or dacarbazine. In January of 2023, the FDA approved tebentafusp for the treatment of adult patients with HLA-A*02:01–positive unresectable or metastatic uveal melanoma. This regulatory decision was supported by findings from the IMCgp100-202 trial.

Nathan begins by stating that uveal melanoma differs significantly from cutaneous melanoma, which has seen substantial progress. Up to 50% of patients with metastatic cutaneous melanoma experience favorable outcomes at 5 years. However, eye melanoma, originating from melanocytes, is biologically and genetically distinct from cutaneous melanoma, proving resistant to most conventional therapies, Nathan explains. Only a small subset of patients with metastatic eye melanoma derives long-term benefits from the current standard-of-care treatments effective for patients with cutaneous melanoma, he states. Given this clinical gap and the unique challenges of managing uveal melanoma, IMCgp100-202 trial investigators sought a drug that could be a groundbreaking intervention, potentially enhancing survival outcomes for patients with eye melanoma, Nathan emphasizes.

Tebentafusp, which is categorized as an ImmTAC, comprises 2 parts. It has a T-cell receptor at 1 end and anti-CD3 Fe fragments at the other end, forming a molecular bridge, Nathan continues. This investigational drug activates T cells in the tumor microenvironment without relying on T-cell receptor specificity, allowing non–tumor-specific T cells to be activated and directed to the tumor, he says. Tebentafusp's T-cell receptor end binds to a peptide presented in the context of HLA on the tumor cell surface, a crucial interaction dependent on the patient's specific HLA haplotype, Nathan notes. Consequently, patient selection is crucial to ensure the appropriate HLA haplotype for effective binding, he concludes.