Phase 1 study of drug for uveal melanoma showed measurable anti-tumor activity

A press release issued by Northwell Health’s Feinstein Institutes for Medical Research in Manhasset, NY, announced positive phase 1 results from a clinical trial of DYP688 (NCT05415072), a first-in-class drug, for metastatic uveal melanoma, which has limited treatment options. The investigators led by Matteo Carlino, MD, published the results in Nature Medicine.¹

The study indicated that DYP688 demonstrated measurable anti-tumor activity and was well-tolerated by patients, according to the press release.

Richard D. Carvajal, MD, commented, “This first-in-class antibody-drug conjugate is a smart, targeted therapy designed to kill only diseased cells, a novel approach that differs from conventional cytotoxic drugs. We observed promising results alongside an exceptionally high degree of patient tolerability. While Novartis has made a business decision to halt its development, the academic and patient communities recognize its potential.” He is the deputy physician-in-chief and director of medical oncology at the Northwell Health Cancer Institute and the Roy J. and Tara Zuckerberg Professor in Medical Oncology.

Kevin Tracey, MD, president and CEO of the Feinstein Institutes and Karches Family Distinguished Chair in Medical Research, commented on the advantages of targeted therapy. “Precision medicine is the key to better treatment,” he stated.

How the drug works

DYP688 is described as an antibody-drug conjugate (ADC). In contrast to other ADCs that exert broad toxic chemotherapy, this approach identifies the diseased cells with a Gq/11 inhibitor designed to specifically block the cancer’s growth pathway, the press release explained.

The investigators pointed out in their study that 85% to 90% of tumors have activating GNAQ and GNA11 mutations. The uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688 works by binding surface PMEL and delivers the Gα_q/Gα₁₁ (G_q/11) inhibitor SDZ475.

In the dose-escalating phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas, the safety and the pharmacokinetics were assessed as the first and second study endpoints, respectively. Sixty-six patients were included in the study and received varying doses of DYP688 and schedules.

What did the results show?

The investigators reported that grade 3 treatment-related adverse events developed in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. “Objective responses were seen in 13 of 66 patients (19.7%) and tumor reduction in 47 of 66 patients (71.2%). Median progression-free survival was 7.2 months (95% confidence interval, 5.3–7.8) months,” the study reported.

“The observed activity and favorable safety profile support further investigation of DYP688 as both a single agent and, potentially, in combination regimens for patients with metastatic uveal melanoma,”¹ the investigators commented.

Reference

1. Carlino MS, Kapiteijn E, Piperno-Neumann S, et al. An anti-PMEL antibody−drug conjugate with a G_q/11 inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial. Nat Med. 2026; published online July 13, 2026. https://www.nature.com/articles/s41591-026-04518-z