The Scottish Medicines Consortium (SMC) has accepted tebentafusp (Kimmtrak, Immunocore Ltd) for use within NHS Scotland as monotherapy for adults with HLA-A*02:01-positive unresectable or metastatic uveal melanoma.

The decision follows a second resubmission assessed under the SMC's end-of-life and orphan medicine process and applies only in the context of an approved NHS Scotland Patient Access Scheme underpinning the cost-effectiveness case.

About Uveal Melanoma

Uveal melanoma is a rare but aggressive cancer arising from melanocytes in the uveal tract. Up to half of patients with localised disease eventually develop metastases, with the liver being the first site of spread in around 90% of cases. About 45% of patients with metastatic disease are HLA-A*02:01-positive and thus eligible for tebentafusp. Median survival after metastasis is around 12 months.

How Tebentafusp Works

Tebentafusp is a first-in-class bispecific fusion protein comprising a high-affinity T-cell receptor linked to an anti-CD3 antibody fragment. The T-cell receptor binds the gp100 peptide presented by HLA-A*02:01 on uveal melanoma cells, while the anti-CD3 domain recruits and activates polyclonal T cells, triggering cytokine release and direct tumour cell lysis. 

Treatment is administered intravenously at 20 μg on day 1, 30 μg on day 8, 68 μg on day 15, and 68 μg once weekly thereafter until disease progression or unacceptable toxicity.

Survival Benefit in Metastatic Uveal Melanoma

The SMC decision was primarily based on the phase 3 IMCgp100-202 trial, which enrolled 378 HLA-A*02:01-positive adults with previously untreated metastatic uveal melanoma. Participants were randomised in a 2:1 ratio to receive tebentafusp (n = 252) or investigator's choice of therapy (n = 126), 82% of whom received pembrolizumab. Smaller numbers  of patients received ipilimumab or dacarbazine.

At the primary interim analysis, tebentafusp significantly improved overall survival (OS): median, 21.7 vs 16.0 months for investigator's choice of therapy (hazard ratio [HR], 0.51; 95% CI, 0.37-0.71; P < .001). At a later follow-up (median, 43.3 months), the benefit persisted (median OS, 21.6 vs 16.9 months; HR, 0.68). A post hoc 5-year analysis reported 60-month OS rates of 15% vs 8%. Progression-free survival was also improved (median, 3.3 vs 2.9 months; HR, 0.73; P= .014), though the SMC considered the 0.4-month difference of limited clinical significance. Indirect comparisons suggested improved OS and progression-free survival compared with nivolumab plus ipilimumab, but the SMC noted limitations in these analyses.

Existing systemic therapies produce objective responses in fewer than 10% of patients with metastatic uveal melanoma. SMC Chair Dr Rob Peel said: "Tebentafusp is the first licensed treatment available for advanced uveal melanoma that offers a survival benefit, and we know our decision will be welcomed by patients and their families."

Safety Profile

Treatment-related adverse events (AEs) occurred in 99% of patients receiving tebentafusp. Among these, 45% experienced grade 3 or higher treatment-related AEs (compared with 17% in the comparator arm). In 57% of patients, treatment-related AEs occurred during the first 4 weeks and decreased in frequency and severity with subsequent doses.

The most common grade 3 or higher treatment-related AEs included rash, pruritus, elevated liver enzymes, pyrexia, hypotension, hypertension, and cytokine release syndrome. Serious treatment-related AEs occurred more frequently with tebentafusp than with investigator's choice of therapy (22% vs 7%), but regulators concluded that the toxicity profile was manageable in the context of this life-threatening disease.

Clinical Impact and Implementation

The SMC concluded that tebentafusp addresses a major unmet need as the first licensed therapy for HLA-A*02:01-positive metastatic uveal melanoma with demonstrated OS benefit. Clinical experts considered it a therapeutic advance in a disease in which currently used systemic therapies achieve objective responses in less than 10% of patients. 

Implementation will require specialised service delivery. The first three infusions must be administered in hospital with overnight monitoring for signs and symptoms of cytokine release syndrome for at least 16 hours, and eligible patients require HLA-A*02:01 testing before treatment initiation. 

During the SMC's Patient and Clinician Engagement meeting, clinicians and patient representatives described tebentafusp as the first clinically effective treatment for metastatic uveal melanoma, highlighting its potential to prolong survival, preserve quality of life, and improve psychological well-being for patients and their families.