Dr Nathan on the Significance of Tebentafusp in HLA-A*02:01+ Uveal Melanoma

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the clinical significance of updated data from the phase 3 IMCgp100-202 trial (NCT03070392) of tebentafusp-tebn (Kimmtrak) in previously untreated, HLA-A*02:01–positive metastatic uveal melanoma, as well as next steps planned for this research.

The randomized IMCgp100-202 study assessed tebentafusp in patients with metastatic uveal melanoma vs standard of care pembrolizumab (Keytruda), ipilimumab (Yervoy) or dacarbazine. Updated findings from a 3-year analysis showed that tebentafusp produced a median overall survival (OS) of (95% CI, 19.0-24.3) vs 16.9 months (95% CI, 12.9-19.5) with the agents in the comparator arm (n = 126; HR, 0.68; 95% CI, 0.54-0.87), demonstrating a significant survival benefit. This benefit was consistently observed across patients with poor prognostic factors. Tebentafusp also maintained superior 1– and 2-year progression-free survival (PFS) rates compared with the control arm.

Although it is a classically immunologically cold tumor with a low tumor mutational burden, uveal melanoma presents a high clinical need, and patients often experience limited responses to immune checkpoint inhibitors, Nathan begins. The success of tebentafusp in inducing clinically meaningful activity in this challenging-to-treat patient population suggests a paradigm shift in the treatment of uveal melanoma and has implications for other tumor types as well, he explains.

Moving forward, the investigation of tebentafusp at future timepoints will be important to further cement the agent's benefit in this population, Nathan states. Additionally, the next important area of investigation for tebentafusp in uveal melanoma is in small-volume or microscopic disease, he adds.

An academic study is currently exploring minimal residual disease (MRD) detected by circulating tumor DNA (ctDNA) to identify patients who may benefit from tebentafusp, Nathan continues, adding that the study has reported a change in ctDNA levels as being a sensitive way of identifying patients who experience OS benefit from the drug. This approach aims to determine whether tebentafusp could offer a benefit over other therapies in this setting, he says. Additionally, exploring tebentafusp in even earlier disease stages remains of great interest, Nathan concludes.

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Paul D. Nathan, MBBS, PhD, FRCP, discusses the clinical significance of updated data on tebentafusp in metastatic uveal melanoma.

Rationale For Investigating Tebentafusp in Uveal Melanoma

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, 

 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.

Paul D. Nathan, MBBS, PhD, FRCP, discusses the rationale for launching the phase 3 IMCgp100-202 trial evaluating tebentafus in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma, as well as the mechanism of action of the agent.


Paul Nathan, MBBS, PhD, FRCP, Mount Vernon Cancer Centre

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Dr Nathan on the Significance of Tebentafusp in HLA-A*02:01+ Uveal Melanoma

Dr Nathan on the Rationale For Investigating Tebentafusp in Uveal Melanoma