Abstract C016: Evaluating clinical biomarkers of FHD-286, a potent and selective inhibitor of BRG1/BRM, in metastatic uveal melanoma

Abstract

Abstract The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates chromatin accessibility and gene expression through its ATP-dependent remodeling activity. FHD-286, a first-in-class compound that potently and selectively inhibits the ATPase components of the BAF complex, BRG1 and BRM, was evaluated in a Phase I dose escalation in subjects with metastatic uveal melanoma (mUM) (FHD-286-001). The pharmacodynamics of FHD-286 were assessed to demonstrate proof-of-mechanism and understand the downstream molecular and clinical impact of BRG1/BRM inhibition. In addition, circulating tumor DNA (ctDNA) was evaluated as an early predictor of overall survival benefit. Seventy-three subjects were on a daily dosing regimen ranging from 2.5 to 10 mg or an intermittent regimen of 1-week on/1-week-off ranging from 10 to 22.5 mg. Tumor biopsies were collected at screening and either Cycle 3, or end of treatment. Biomarker changes in the tumor were observed by histological assessment, by IHC/IF biomarker assays, and RNA sequencing. Observations were suggestive of a differentiation effect by FHD-286 on the tumor cells, including a decrease in stemness genes and an increase in mature melanocytic markers. Evidence of necrosis and a trend of decreasing tumor cell density were also seen. In addition, ctDNA was measured in serial plasma samples using a targeted NGS panel. A reduction in ctDNA was shown in approximately 50% of subjects, which correlated with an increased overall survival benefit. Lastly, serial blood samples collected in Paxgene RNA tubes were analyzed by RNA sequencing. A robust dose-dependent gene signature was identified as a peripheral readout of target engagement at steady-state in both dosing regimens and across dose cohorts. In summary, we observed changes in the tumor cells at the biopsy site and ctDNA that suggest FHD-286 has a biological impact on uveal melanoma that may lead to clinical benefit. Given the limitations and challenges to obtain tumor biopsies from every subject and at a frequent rate, the identified PD gene signature in the blood is a valuable tool to measure target engagement in this study, and other potential solid tumor indications. Citation Format: Jessica Wan, Kim Horrigan, GiNell Elliott, Liv Johannessen, Mike Collins, Alexander J. Lazar, Dillon Corrigan, Caitlin Patriquin, Sam Agresta, Jessica Piel, Martin Hentemann. Evaluating clinical biomarkers of FHD-286, a potent and selective inhibitor of BRG1/BRM, in metastatic uveal 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 C016.