Phase 3 Data Show Long-Term Survival Benefit of Tebentafusp in Metastatic Uveal Melanoma

A recent phase 3 trial published in The New England Journal of Medicine reinforced the long-term survival benefits of tebentafusp in patients with metastatic uveal melanoma who are HLA-A*02:01 positive.

Tebentafusp is a T-cell receptor-bispecific molecule designed to specifically target cluster of differentiation 3 (CD3) and glycoprotein 100 (gp100). At present, this is the only approved treatment for patients with metastatic uveal melanoma and a HLA-02:01-positive status.

T-Cell Receptor Model | image credit: AIGen -stock.adobe.com

In around 50% of patients with uveal melanoma, a metastatic disease develops, leading to worsened prognosis and dire expected survival outcomes of approximately 1 year. The emergence of tebentafusp has shown lots of promise for patient survival outcomes in its previous trials.

This development has been important considering that immune-checkpoint inhibitors—which can drastically alter outcomes in cutaneous melanoma—are relatively ineffective in cases of metastatic uveal melanoma. In this report, researchers provided an updated analysis from the phase 3 IMCgp11-202 trial that showcased the safety and efficacy of tebentafusp in this patient population after a 3-year follow-up.

Between March 2017 and June 2020, 378 HLA-A*02:01-positive patients were randomly assigned to a group treated with tebentafusp (n = 252) and a control group (n = 126; patients treated with dacarbazine, ipilimumab, or pembrolizumab). With a follow-up of at least 3 years, the tebentafusp group exhibited a median survival of 21.6 months, whereas the control group exhibited a median survival rate of 16.9 months (HR, 0.68; 95% CI, 0.54-0.87). At 1, 2, and 3 years, the percentage of surviving patients who received tebentafusp was 72%, 45% and 27%, respectfully. The control group had a survival rate at these intervals of 60%, 30%, and 18%, respectfully. Additionally, the researchers noted that a higher proportion of patients treated with tebentafusp than those in the control group experienced any shrinkage of tumors (40% vs 24%).

Some adverse side effects were observed in the tebentafusp group. Among these effects, the most prevalent were hypotension (38%), pruritus (70%), pyrexia (76%), and rash (83%). Patients typically experienced these events early on in tebentafusp therapy; no new events arose with long-term use and no treatment-related deaths took place.

In their concluding remarks, Hassel and colleagues reflected on their data regarding reduced circulating tumor DNA (ctDNA) at the 9-week mark before any treatment response was clear in their patients. As they observed a reduction in ctDNA correlating with overall survival—at rates that mimicked those witnessed in their phase 2 trial of tebentafusp—the authors believe these findings reinforce the need for additional investigations on the relationship between reduced ctDNA levels and tebentafusp. While their phase 3 results support the long-term benefits of tebentafusp in HLA-A*02:01-positive patients with metastatic uveal melanoma, they conclude by emphasizing avenues for future research efforts.

Reference

Hassel JC, Piperno-Neumann S, Rutkowski P, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023;389(24):2256-2266. doi:10.1056/NEJMoa2304753.