ASCO 2025 | Phase I trial of DYP688 in uveal melanoma and other GNAQ/11-mutant melanomas

DYP is a really novel compound. It really brings two things together. It brings a targeted therapy, which I’ll touch on in a second, with an antibody drug conjugate, which we’ve all seen. In uveal melanoma, GNAQ and GNA11 mutations are found in the vast majority of patients. There’s lots of studies targeting downstream of this mutation, but targeting the mutation directly has been really difficult. There are drugs that do target this mutation directly, but when they’re used in animal models, they’re undeliverable. One of these drugs causes profound bleeding and hypotension. What DYP does is takes an antibody drug conjugate, so an antibody that binds to S100. S100 is expressed on most melanoma cells and delivers the targeted therapy. So unlike normal antibody drug conjugates, which deliver chemotherapy, this delivers the targeted therapy. So it’s targeted twice, if you like. Because of that, the study has had some really interesting results. The first is how well tolerated this drug is. Because it’s targeted twice, we get a fantastic safety profile. The rate of grade three toxicities that were treatment-related was low, with approximately 7.5% of patients having a grade 3 treatment-related toxicity. That included an asymptomatic hypercalcemia, so that was felt to be related to the mechanism of action, one episode of hypotension, and so really very well tolerated. In terms of efficacy, we saw responses in 12 patients in our study. Responses were seen in all but our two lowest dosing cohorts, and clinical activity was seen beyond these responses. Three-quarters of all patients treated had a reduction in their tumour size and this was a really heavily pre-treated patient population. So in summary we’ve got an active drug that’s very well tolerated mainly due to its really novel mechanism of action.

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