An anti-PMEL antibody-drug conjugate with a G(q/1)(1) inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial
- Author(s)
- Carlino, MS; Kapiteijn, E; Piperno-Neumann, S; Sullivan, RJ; Carvajal, R; Dummer, R; Gromke, T; Hassel, JC; Kee, D; Ramelyte, E; Shoushtari, AN; Wei, AZ; Enk, A; Handel, EE; Montazeri, K; Ramon-Patino, J; Richly, H; Rodrigues, M; Sandhu, S; Smithy, J; Speetjens, FM; Milanez-Almeida, P; Chaudhury, A; Hoffmaster, K; Ising, M; Otero, JA; RamKumar, T; Reynolds, A; Sharaby, S; Werner, L; Yerramilli-Rao, P; Calvo, E;
- Journal Title
- Nature Medicine
- Publication Type
- Online publication before print
- Abstract
- Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gα(q)/Gα(11) (G(q/11)) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1038/s41591-026-04518-z
- Open Access at Publisher's Site
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Creation Date: 2026-08-11 02:01:20
Last Modified: 2026-08-11 02:01:47