Tebentafusp is a novel bispecific molecule consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100-positive cells. The agent showed clinical benefit, including target lesion reduction, in patients with metastatic uveal melanoma, according to phase II study findings presented by Sacco et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Virtual Congress 2020 (Abstract 64MO).

The study authors noted that high expression of gp100 is seen in melanocytes and melanoma cells.

Phase II Trial

Researchers conducted a phase II multicenter study evaluating safety and efficacy of tebentafusp in HLA-A*0201–positive patients with metastatic uveal melanoma. Phase I of this study determined the phase II dose as 68 μg.

All patients received treatment at 24 centers with a regimen of weekly intravenous doses of 20 μg for cycle 1, day 1; 30 μg for cycle 1, day 8; and 68 μg for cycle 1, day 15+.

Of the 127 patients treated, 50% were male, 70% had an Eastern Cooperative Oncology Group performance status of 0, and 58% had baseline lactate hydrogenase exceeding the upper limit of normal. All of the patients had received at least one prior therapy in the metastatic setting, if not more. Many (34%) patients had received two or more prior treatments, including liver-directed therapy in 45% of patients. Seventy-three percent of patients had received immunotherapy; of these, 65% received anti–PD-1 and 31% received anti–CTLA-4 therapies.

Objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 assessed by independent central review served as the primary study endpoint; secondary endpoints included safety, overall survival, and progression-free survival.

Results

Following treatment with tebentafusp, the objective response rate was 5% (95% confidence interval [CI] 1.8%­–10.0%), all of which were partial responses. Stable disease was achieved by 45% of patients.

The median duration of response was 8.7 months. Of the 116 patients with evaluable tumors, 44% demonstrated a reduction in target lesions that included immune-related responses.

With a median follow-up of 19.6 months, the median overall survival was 16.8 months (95% CI = 12.9–21.3). The 12- and 18-month overall survival rates were 62% and 45%, respectively.

Median progression-free survival was 2.8 months. In patients demonstrating any reduction in a target lesion, the 12-month overall survival rate improved to 86%.

The most commonly reported treatment-related adverse events were generally cutaneous and likely linked to targeting gp100-positive melanocytes, or cytokine-mediated due to T-cell activation. Treatment-related adverse events included pyrexia (in 80% of patients), pruritus (67%), and chills (64%). Grade ≥ 3 treatment-related adverse events included maculopapular rash in 13% of patients, hypotension in 8%, and increased AST and hypophosphatemia in 5% of patients each. In most patients, treatment-related adverse events decreased in frequency and severity after the first three doses of tebentafusp.

Cytokine-release syndrome (Lee 2019 criteria) was reported in 86% of patients; grade 3 cytokine-release syndrome was reported in 3% of patients, and 1% of patients experienced grade 4 cytokine-release syndrome. There were no reported grade 5 treatment-related adverse events.

Interestingly, the 64% of patients who developed a rash within 7 days of tebentafusp initiation demonstrated superior median overall survival—22.5 months compared to 10.3 months in patients who did not develop a rash.

The investigators noted that although the primary endpoint showed only a 5% objective response rate, this was accompanied by a reduction in target lesion for 44% of patients. They further pointed out that the 12-month overall survival rate of 62% in patients overall was increased to 86% in patients achieving target lesion reduction.

According to the authors, treatment-related adverse events were generally predictable and manageable; furthermore, they decreased in frequency and severity following the first few doses and were consistent with the proposed mechanism of action.

Tebentafusp is being studied further and is currently being evaluated in a randomized pivotal study with a primary endpoint of overall survival.

Disclosure: Funding was reported from Immunocore Ltd. For full disclosures of the study authors, visit oncologypro.esmo.org.