PURPOSE: Tebentafusp is a first-in-class bispecific fusion protein designed to 
target gp100 (a melanoma-associated antigen) through a high affinity T-cell 
receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which 
redirects T cells to kill gp100-expressing tumor cells. Here, we report a 
multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) 
focusing on the mechanism of action of tebentafusp.
PATIENTS AND METHODS: Eighty-four patients with advanced melanoma received 
tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker 
assessments were performed for blood-derived and tumor biopsy samples obtained 
at baseline and on-treatment.
RESULTS: Tebentafusp was generally well-tolerated and active in both patients 
with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. 
A 1-year overall survival rate of 65% was achieved for both patient cohorts. 
On-treatment cytokine measurements were consistent with the induction of IFNγ 
pathway-related markers in the periphery and tumor. Notably, tebentafusp induced 
an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating 
CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor 
microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash 
(likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) 
showed a positive association with patient survival.
CONCLUSIONS: These data suggest that redirecting T cells using a gp100-targeting 
TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with 
metastatic melanoma. Furthermore, the activity observed in these two molecularly 
disparate melanoma classes hints at the broad therapeutic potential of 
tebentafusp.