Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial

Abstract

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

Tebentafusp: a first-in-class treatment for metastatic uveal melanoma

“…Of note, in the phase I dose escalation study, among patients who received ICPIs following tebentafusp, there were a group who had a superior than expected response to ICPIs. 42 This may be due to upregulation of PD-1 and PD-L1; epitope spreading by tebentafusp and potentially an increased presence of TILs. ICPIs in UM may therefore possess greater efficacy if given following tebentafusp delivery.…”

Mechanistically modeling peripheral cytokine dynamics following bispecific dosing in solid tumors

“…Conversely, model simulations imply that efficacy is not likely to be impacted by step‐up dosing; step‐up dosing reduced tumor trimer formation <20% at 8 weeks compared with flat dosing, with tumor trimer formation between the two dose regimens becoming more similar as the number of doses increases. Given the median follow‐up duration for a phase II tebentafusp study was 19.5 months, 45 it is therefore likely that step‐up dosing would not impact tebentafusp efficacy. Indeed, clinical studies with tebentafusp and other bispecifics have found that step‐up dosing improves safety without compromising efficacy 46,47 .…”

Enhanced Vaccine Immunogenicity Enabled by Targeted Cytosolic Delivery of Tumor Antigens into Dendritic Cells

“…Recently, a T cell engager medication comprising a bispecific fusion anti-CD3 protein targeting gp100 membrane antigen (Tebentafusp) has shown potent antitumor response with significant improvement of overall survival at 1 year in patients with metastatic refractory melanoma , and HLA-A*02:01-positive uveal melanoma patients for which it gained FDA approval in 2022. We have therefore selected gp100, but also Trp1 tumor-specific antigens, for the construction of a dual LF N conjugate and assessed DCs targeting efficacy in an aggressive melanoma model.…”