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.