Early ctDNA Reduction Predicts Survival Benefit from Tebentafusp in Uveal Melanoma
In a phase 2 trial of tebentafusp (gp100xCD3 bispecific) in 127 patients with treatment-refractory metastatic uveal melanoma, the one-year overall survival rate reached 62% despite a low radiographic response rate of only 5%. Exploratory ctDNA analysis revealed that early on-treatment ctDNA reduction was strongly associated with overall survival, even in patients showing radiographic progression. The findings highlight ctDNA as a potential early response biomarker for immunotherapies where conventional imaging underestimates clinical benefit.
The original study
Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial.
- Authors
- Carvajal RD, Butler MO, Shoushtari AN, Hassel JC, Ikeguchi A, Hernandez-Aya L, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase II, Multicenter Study, Journal Article, Research Support, N.I.H., Extramural
- PMID
- 36229663
Original 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.