Abstract PR012: Novel strategy for RAS-pathway targeting: Initial results from a phase 1b/2 clinical trial of the oral HDAC inhibitor bocodepsin (OKI-179) combined with binimetinib in patients with RAS-pathway mutated solid tumors and NRAS-mutated me

Abstract

Background: Activating RAS pathway mutations occur in > 30% of human cancers, including NRAS mutations in 15-20% of advanced melanoma. MEK inhibitors have modest single agent activity in NRAS-mutated melanoma, showing a 15% overall response rate and 2.8 month progression free survival. Bocodepsin (OKI-179) is a novel Class I-selective, oral histone deacetylase inhibitor (HDACi). The combination of bocodepsin and binimetinib is preferentially synergistic in RAS pathway mutated tumor models, leading to the unique mechanism of double strand DNA breaks and cellular apoptosis. Here we present the initial results of the Nautilus phase 1b/2 trial of bocodepsin and binimetinib (NCT05340621). Materials and Methods:  In Phase 1b, patients with previously treated advanced solid tumors with any activating RAS pathway mutation were treated with binimetinib oral 45 mg twice daily with bocodepsin 200 mg (cohort 1) or 300 mg (cohort 2) oral daily 4 days on 3 days off in 28-day cycles. In Phase 2, patients with NRAS-mutated melanoma previously treated with immunotherapy were treated with bocodepsin 300 mg with binimetinib in a Simon optimal 2-stage study with a primary endpoint of objective response rate. Secondary endpoints included safety and PK. Results: As of July 6, 2023, 14 patients were enrolled in Phase 1b in 2 cohorts and across multiple tumor types (colorectal, n=4; melanoma, n=3; NSCLC, n=2; pancreatic, n=2; other, n=3) and RAS-pathway mutations (KRAS, n=9; NRAS, n=3; BRAF, n=1; NF1, n=1). The median age was 70 (41-76) and median number of prior therapies was 6 (1-13). No DLTs were observed. Bocodepsin 300 mg was identified as the RP2D in combination with standard dose binimetinib. The most common treatment-emergent adverse events were consistent with either binimetinib or bocodepsin alone known adverse events and included diarrhea (N=11, 78.57%), nausea (N=9, 64.29%), anemia (N=8, 57.14%), and dermatitis acneiform (N=8, 57.14%). The most common grade 3/4 events included anemia (N=4, 28.57%) and syncope (N=2, 14.29%). Of the 14 evaluable patients in Phase 1, the best response was partial response (PR) in 1 pt (NRAS-mutated melanoma) and stable disease (SD) in 6 pts, with a median time on study of 120 days (50-260). Phase 2 enrollment is ongoing. At the data cutoff, in the 9 response evaluable NRAS melanoma patients (between Ph1 and Ph2), 3 PR and 3 SD were observed.  Conclusions:  The combination of bocodepsin and binimetinib in patients with RAS-mutated advanced cancers is tolerable with manageable AEs.  Initial response data in NRAS melanoma are supportive of potential combinatorial activity of binimetinib and bocodepsin. The data for Phase 2 will be updated at the time of presentation.

Citation Format: Rodabe N Amaria, Herbert Duvivier, Katy Tsai, Robert Galamaga, Parisa Momtaz, Evan Pisick, Natalie Langr, Harish Dave, Duncan Walker, Jennifer Diamond, Kevin Litwiler, Ryan Sullivan. Novel strategy for RAS-pathway targeting: Initial results from a phase 1b/2 clinical trial of the oral HDAC inhibitor bocodepsin (OKI-179) combined with binimetinib in patients with RAS-pathway mutated solid tumors and NRAS-mutated melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR012.