Nautilus, a phase 1b/2 trial of combining oral HDAC inhibitor (HDACi) with MEK inhibitor (MEKi) in patients with NRAS-mutated metastatic melanoma (MM).

Abstract

9552 Background: Activating NRAS mutations occur in 15-20% of MM cases. The MEK inhibitor binimetinib has modest single agent activity with 15% objective response rate (ORR) and 2.8 month progression-free survival (PFS). Bocodepsin (OKI-179) is a novel Class I-selective, oral histone deacetylase inhibitor that was found to have synergistic efficacy with MEKi in preclinical models of NRAS-mutated melanoma. Cells displayed unrepaired double strand DNA breaks and cellular apoptosis, while regressions were observed in xenograft models. Here we present the results of the phase 2 portion of a clinical trial of this combination in NRAS-mutant MM (NCT05340621). Methods: In this Phase 2 study, only patients with NRAS-mutant MM previously treated with immunotherapy were enrolled and treated with bocodepsin at the recommended phase 2 dose (300 mg daily, 4 days on, 3 days off, continuously) with binimetinib (45 mg twice daily, continuously). Primary endpoint was ORR, with secondary endpoints including safety and PK analyses. Results: As of 1/3/2025, 36 total patients were enrolled; 14 in phase 1b dose escalation and 22 in phase 2, including a total of 24 NRAS-mutant melanoma patients. Median age of NRAS-mutant MM patients was 69 years, and 47% of patients were males. Median numbers of prior therapies was 3 and LDH elevations were found in 41% of patients. There were no grade 3/4 toxicities seen in >10% of patients, including no episodes of high grade rash. Of the 20 evaluable patients with NRAS-mutant MM, ORR was 30%. The median PFS was 7.25 months (5-92 weeks). Conclusions: The combination of bocodepsin and binimetinib in patients with NRAS-mutant melanoma is tolerable with manageable AEs and no high grade rash. Initial response data in patients with NRAS-mutant melanoma are supportive of potential combinatorial activity of a MEK inhibitor and HDACi bocodepsin. Further investigation is crucial as MM patients with disease progression after immunotherapy remain in need of rational therapeutic options. Thus, MEKi + HDACi warrants further study in a larger patient cohort. Clinical trial information: NCT05340621 .