In an interim analysis of the phase III IMCgp100-202 trial reported in The New England Journal of Medicine, Nathan et al found that tebentafusp, a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector, significantly improved overall survival vs investigator choice of single-agent therapy with pembrolizumab, ipilimumab, or dacarbazine in patients with previously untreated metastatic uveal melanoma.

As related by the investigators, “Molecules termed immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) are a new class of T-cell–redirecting bispecific fusion proteins that use an engineered high-affinity T-cell receptor to target any protein, including intracellular antigens, that is presented as a peptide-HLA complex on the target cell surface. Tebentafusp consists of a soluble affinity-enhanced HLA-A*02:01–restricted T-cell receptor that is specific for the glycoprotein 100 peptide YLEPGPVTA and is fused to an anti-CD3 single-chain variable fragment. Once ImmTAC molecules are bound to their specific peptide-HLA complexes on the target cell surface, they recruit and activate polyclonal T cells, through CD3, to release cytokines and cytolytic mediators against target cells.”

Study Details

In the international open-label trial, 378 HLAA*02:01–positive patients were randomly assigned 2:1 between March 2017 and June 2020 to receive tebentafusp (n = 252) or investigator choice of singe-agent treatment with pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7). Random assignment was stratified by lactate dehydrogenase level. Tebentafusp was given intravenously at 20 μg on day 1, 30 μg on day 8, and 68 μg weekly thereafter. Pembrolizumab was given at 2 mg/kg to a maximum of 200 mg per dose or at a fixed dose of 200 mg on day 1, ipilimumab at 3 mg/kg day 1 for a maximum of four doses, and dacarbazine at 1,000 mg/m² on day 1, each in 21-day cycles.

The primary endpoint was overall survival in the intention-to-treat population. 

Overall Survival

At the clinical data cutoff for the first interim analysis (October 2020), median follow-up was 14.1 months. Estimated overall survival at 1 year was 73% (95% confidence interval [CI] = 66%–79%) in the tebentafusp group vs 59% (95% CI = 48%–67%) in the control group, and estimated median overall survival was 21.7 months (95% CI = 18.6–28.6 months) vs 16.0 months (95% CI = 9.7–18.4 months), with a stratified hazard ratio (HR) of 0.51 (95% CI = 0.37–0.71, P < .001).

At 6 months, estimated progression-free survival was 31% vs 19% (stratified HR = 0.73, 95% CI = 0.58–0.94, P = .01). Median progression-free survival was 3.3 months (95% CI = 3.0–5.0 months) vs 2.9 months (95% CI = 2.8–3.0 months). Objective response was observed in 9% (median duration = 9.9 months) vs 5% (median duration = 9.7 months). Disease control rates were 46% vs 27%.

Adverse Events

The most common treatment-related adverse events of any grade in the tebentafusp group were cytokine-related adverse events, including pyrexia (76%), chills (47%), and hypotension (38%), and skin-related events, including rash (83%), pruritus (69%), and erythema (23%). Treatment-related grade 3 or 4 adverse events occurred in 44% of the tebentafusp group vs 17% of the control group. The most common in the tebentafusp group was rash (18%), followed by pyrexia, pruritus, increased aspartate aminotransferase, increased lipase, and hypertension (4% each); the most common in the control group were increased lipase (5%) and diarrhea (3%). Treatment-related adverse events led to discontinuation of treatment in 5% vs 3% of patients. No treatment-related deaths were reported.

The investigators concluded, “Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma.”

Disclosure: The study was funded by Immunocore. For full disclosures of the study authors, visit nejm.org.