Tebentafusp improves OS: A First in Metastatic Uveal Melanoma

Walter Alexander

April 16, 2021

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator's choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).

Prolonged OS Despite Low Response Rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator's choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator's choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator's choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator's choice arm. Rates of progressive disease were 52% and 62%, respectively.

Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator's choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

"So this drug is slowing down developing disease," she said.

"Manageable" Adverse Events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator's choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.

"Practice-Changing" Results

"This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results," said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn't work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. "There still remains an unmet need for patients who do not have this particular surface protein," she said.

The study was sponsored by Immunocore. Hassel disclosed relationships with Immunocore and other companies. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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