Editor’s pick of Jeroen Mebis, MD, PhD, Medical Oncologist, Jessa Hospital, Hasselt
Patients with HLA-A*02:01–positive previously untreated metastatic uveal melanoma generally respond poor to systemic treatment and face a poor prognosis. However, treatment with tebentafusp, a soluble T-cell receptor and CD3-directed bispecific fusion protein, now demonstrated to result in significantly longer overall survival than the investigator’s choice of treatment with pembrolizumab, ipilimumab, or dacarbazine.
Uveal melanoma is the most common intraocular cancer in adults, representing approximately 3-5% of all melanomas. Although uveal melanoma arises from melanocytes, it is distinct from cutaneous melanoma and has different molecular drivers, metastatic patterns and tumour-immune microenvironment. These differences also contribute to its poor response to systemic treatment. The one-year overall survival (OS) is approximately 50% in patients with metastatic disease and data showing a proven OS benefit with a systemic treatment are lacking. Tebentafusp (formerly IMCgp100) consists of a soluble affinity-enhanced HLA-A*02:01– restricted T-cell receptor that is specific for the glycoprotein 100 (gp100) peptide YLEPGPVTA and is fused to an anti-CD3 single-chain variable fragment. In a previous phase II trial, monotherapy with tebentafusp demonstrated more promising OS than historical controls. A multicentre, randomised phase III trial now compared tebentafusp with investigator’s choice of treatment as first-line systemic therapy in patients with metastatic uveal melanoma.
In total, 378 patients were randomly assigned in a 2:1 ratio to receive tebentafusp or the investigator’s choice of treatment with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group). As intra-patient dose escalation of tebentafusp has previously demonstrated to reduce toxic effects, patients received intravenous tebentafusp at a dose of 20 μg on day 1, 30 μg on day 8, and 68 μg weekly thereafter. Patients were monitored overnight after treatment for the first three weeks during dose escalation. Treatment (except for ipilimumab, which was given for a maximum of four doses) was continued until the occurrence of radiographic progression, the development of unacceptable toxic effects, a decision by the investigator, or withdrawal of consent by the patient. In order to be eligible, patients were required to have histologic or cytologic confirmation of metastatic uveal melanoma, were at least 18 years of age and were HLA-A*02:01–positive. Furthermore, patients could not have received previous systemic or liver-directed therapy for metastatic disease, must have an ECOG performance- status score of 0 or 1 and had at least one measurable lesion, according to RECIST, version 1.1.2. Patients were stratified according to the lactate dehydrogenase level.
In the intention-to-treat population, overall survival at one year was 73% in the tebentafusp group and 59% in the control group (HR[95%CI]: 0.51[0.37-0.71], p< 0.001). Importantly, this treatment effect was generally observed across the prespecified subgroups. Furthermore, treatment with tebentafusp resulted in a significant progression-free survival benefit in the intention-to-treat population. At six months, the estimated PFS was 31%, as compared with 19% in the control group (HR[95%CI]: 0.73[0.58-0.94], p= 0.01). The objective response rate was 9% in the tebentafusp arm and 5% in the control group while the median duration of response was similar between both arms (9.9 vs. 9.7 months for the tebentafusp and control arms, respectively).
The most common treatment-related adverse events (TRAEs) of any grade in the tebentafusp group were cytokine-related adverse events, such as pyrexia (76%), chills (47%), and hypotension (38%), and skin-related adverse events, such as rash (83%), pruritus (69%), and erythema (23%). TRAEs of grade 3 or 4 were reported in 44% of patients in the tebentafusp group, as compared to 17% of patients in the control group. In a majority of patients in the tebentafusp group (57%), the TRAEs occurred in the first four weeks of treatment during intra-patient dose escalation. Thereafter, the incidence and severity of such events decreased with repeated dosing and infrequently led to discontinuation of the trial treatment (2%). Cytokine release syndrome occurred in 89% of the patients in the tebentafusp group, although mostly of grade 1 (12%) or grade 2 (76%). No treatment-related deaths were reported.
In this randomised, phase III trial, treatment with tebentafusp, a soluble T-cell receptor and CD3-directed bispecific fusion protein, was associated with longer overall survival than the investigator’s choice of therapy in HLA-A*02:01–positive patients with metastatic uveal melanoma.
Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021;385:1196-206.