Nautilus, a phase 1b/2 trial of combining oral HDAC inhibitor (HDACi) with MEK inhibitor (MEKi) in patients with NRAS-mutated metastatic melanoma (MM)
Recommended Citation
Amaria RN, Duvivier HL, Tsai KK, Momtaz P, Galamaga RW, Pisick EP, Doonan BP, Weise AM, Langr N, Winkler JD, Dave HP, Robinson Diamond J, Sullivan RJ. Nautilus, a phase 1b/2 trial of combining oral HDAC inhibitor (HDACi) with MEK inhibitor (MEKi) in patients with NRAS-mutated metastatic melanoma (MM). 2025; (16_suppl).
Document Type
Conference Proceeding
Publication Date
5-28-2025
Abstract
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 Iselective, oral histone deacetylase inhibitor that was found to have synergistic efficacy with MEKi in preclinical models of NRAS-mutated melanoma. Cells displayed unrepaired double strandDNAbreaks 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 NRASmutantMM( 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 (300mgdaily, 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 asMMpatients with disease progression after immunotherapy remain in need of rational therapeutic options. Thus, MEKi + HDACi warrants further study in a larger patient cohort.
Issue
16_suppl
