Abstract A047: MT1-MMP Immunohistochemistry (IHC) analysis of tumor microarrays (TMAs) using a novel scoring system guides patient selection for BT1718 expansion cohorts

Abstract

Abstract Introduction: BT1718 is a targeted Bicycle peptide-conjugate designed to deliver the anti-tubulin agent, DM1 to tumors expressing membrane type 1-matrix metalloprotease (MT1-MMP; MMP14; MT1). In vivo preclinical studies demonstrated that anti-tumor activity of BT1718 is dependent on the level of tumor MT1-MMP expression. In patient tumors MT1-MMP expression has been reported in tumor and stromal cells, both of which may contribute to the potential for anti-tumor effects following BT1718 dosing. BT1718 is currently being investigated in a Phase 1/2 clinical trial, which includes both dose escalation (ongoing) and dose expansion cohorts enrolling patients with advanced solid tumors that have exhausted standard therapeutic options. The dose expansion cohorts will enroll patients with tumors expressing high levels of MT1-MMP following establishment of the recommended Phase 2 dose. Here we describe the analysis of TMAs stained using a clinical grade MT1-MMP IHC assay to guide which patient populations to include in BT1718 dose expansion cohorts. Methods: A clinical grade MT1-MMP IHC assay was developed on the Ventana platform using a Millipore MT1-MMP primary antibody (MAB3328) at 1:6000 and detected using Optiview chemistry. Cancer indications reported in the literature with high MT1-MMP expression including ovarian, bladder, triple negative breast, esophageal, and NSCLC were stained and MT1-MMP expression levels estimated by consensus review of two pathologists using an H-score scale (staining intensity*percent positivity). H-scores (0-300) were derived separately for tumor membrane (TM), cytoplasm (TC), and stroma (TS) for each case. Results: MT1-MMP expression in TM/TS, but not TC is likely to yield the greatest potential for BT1718 binding and subsequent anti-tumor activity. Therefore, analyses of TM/TS H-scores were used to identify BT1718 dose expansion cohorts. Histograms were generated separately for TM and TS H-scores with a bin-width of 50. The distribution of MT1-MMP staining in TM and TS was different (Table 1) with H-score between 0-49 being the most frequently populated TM bin, regardless of indication. In contrast, TS scores were typically higher (e.g. H-score=100-149), with the clearest example being ovarian cancer (89% of cases TM 0-49 & only 20% of cases TS 0-49). In addition, within NSCLC, tumor subtype analysis demonstrated that cases of squamous histology appeared enriched for higher TM H-scores (TM≥150=36%) compared to adenocarcinoma cases (TM≥150=2%). Moreover, various TM and/or TS H-score boundaries were modelled with the aim of delivering a proposed cut-off for recruiting patients with high MT1-MMP expression to the expansion cohorts, the results of this modelling will be presented. Table 1: Distribution of MT1-MMP TM and TS H-scores across multiple indications p> Citation Format: Tara Gelb, Chris Bacon, Philip Sloan, Mike Rigby, Stephanie Guerrera, Fiona Kelly, Stefan Symeonides, Stephen J Blakemore. MT1-MMP Immunohistochemistry (IHC) analysis of tumor microarrays (TMAs) using a novel scoring system guides patient selection for BT1718 expansion cohorts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A047. doi:10.1158/1535-7163.TARG-19-A047