Abstract C013: Clinical biomarkers based on PK/PD modeling to guide the development for a first-in-class, highly selective SMARCA2 (BRM) degrader, PRT3789

Abstract

Abstract Background: The SWI/SNF family of chromatin-remodeling complexes is frequently dysregulated in multiple tumor types, resulting in aberrant expression of genes. Damaging mutations resulting in loss of function of one of its core catalytic subunits SMARCA4 (BRG1) occur in multiple tumor types, including in 5-10% of non-small cell lung cancer (NSCLC). SMARCA4-deleted cells become highly dependent on the other catalytic subunit, SMARCA2 (BRM), for their survival, therefore selective degradation of SMARCA2 has therapeutic potential in these cancer types.  PRT3789 is a first-in-class, potent and selective SMARCA2 degrader that is currently under evaluation in a Phase 1 study in patients with advanced solid tumors with loss of SMARCA4 (NCT05639751). We deeply characterized the degradation kinetic parameters of PRT3789 based on preclinical PK/PD studies, which enabled dose-selection. Based on this modeling, we developed a suite of biomarker assays that can be used to assess target engagement in this Phase 1 study. Methods: A sensitive and quantitative plate-based immunoassay utilizing the MSD® platform was developed for the measurement of SMARCA2 protein in human PBMCs following treatment with PRT3789. A secondary, qPCR-based assay was developed for assessment of SMARCA2 transcriptional targets in peripheral blood that may be associated with response to SMARCA2 degradation by PRT3789. Additionally, an immunohistochemistry (IHC) assay for the assessment of SMARCA2 and SMARCA4 protein expression in tumor tissue was developed on the Leica BOND III platform using commercially available antibodies. Results: Detailed in vitro enzymology characterized the degradation kinetic parameters of PRT3789 and was successfully used to predict the PRT3789 effects observed in PK/PD and xenograft efficacy studies in mice. The MSD® assay demonstrated a wide dynamic range of detection for SMARCA2 with a lower level of quantification of 23 pg/mL, as well as exhibiting acceptable spike recovery and minimal cross-reactivity to SMARCA4. Based on the qPCR assay, we developed a differential gene expression (DGE) score based on expression of an 8-gene panel that correlates with SMARCA2 protein degradation in PBMCs. The IHC assay demonstrated discrete and robust nuclear tumor staining with a dynamic intensity range and limited cytoplasmic background for both SMARCA2 and SMARCA4. A panel of NSCLC tumor samples with known SMARCA4 mutations were further evaluated in this assay. Loss of SMARCA4 protein expression in tumor cells by IHC was associated with nonsense and frameshift mutations in the SMARCA4 gene. Conclusions: We demonstrate the sensitive assessment of SMARAC2 protein degradation and effects on downstream gene expression in PBMCs, which will be used to assess target engagement following treatment with PRT3789 in a Phase 1 clinical study. Citation Format: Min Wang, Andrew Moore, Alexander Grego, Miles Cowart, Joseph Rager, Gina Paris, Koichi Ito, Naveen Babbar, Sandy Geeganage, Peegy Scherle, Neha Bhagwat. Clinical biomarkers based on PK/PD modeling to guide the development for a first-in-class, highly selective SMARCA2 (BRM) degrader, PRT3789 [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 C013.