Abstract 1197: A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection

Introduction: Bicycles® are a novel class of fully synthetic, short, constrained peptides. BT8009 consists of a bicyclic peptide targeting the tumor antigen Nectin-4, linked to the cytotoxin monomethyl auristatin E (MMAE) via a molecular spacer and cleavable linker. Nectin-4 is a validated tumor target and is highly expressed in a wide range of tumors. A Phase I/II dose escalation/expansion study, BT8009-100 (NCT04561362), enrolling patients with advanced solid tumors associated with Nectin-4 expression is ongoing in the US. Here we report the analysis of tumor tissue microarrays (TMAs) stained with a Nectin-4 immunohistochemistry (IHC) assay to support patient selection for the BT8009-100 study. Methods: We developed a clinical grade Nectin-4 IHC assay on the Leica platform using a proprietary rabbit monoclonal α-Nectin-4 primary antibody (Abcam, Burlingame, CA) and the BOND Polymer Refine detection kit. TMAs of cancer types reported to have high Nectin-4 expression, including esophageal, pancreatic, bladder, head & neck, stomach, non-small cell lung, breast, and ovarian cancer, were stained and manually scored for Nectin-4 levels, with the tumor microenvironment evaluated in a subset of samples. Nectin-4 H-scores (stain intensity on a scale of 0-3 x percent positive tumor cells) were generated by a pathologist independently for tumor cell membrane and tumor cytoplasm. H-scores ≥ 100 in the tumor membrane or cytoplasm were considered positive. Results: In all indications tested, a greater degree of Nectin-4 positivity was observed in the tumor cytoplasm as compared to tumor membrane. Breast and bladder cancer had the greatest frequency of Nectin-4 positivity. Subtype analysis in breast cancer identified enrichment of Nectin-4 expression in hormone receptor negative and human epidermal growth factor receptor 2 positive tumors. Conclusion: The frequency of Nectin-4 expression as measured by IHC across multiple tumor types may guide clinical strategy for the BT8009 program. TableIndicationTotal cores (n)Percent Tumor Membrane PositivePercent Tumor Cytoplasm PositivePercent Tumor Membrane or Cytoplasm PositiveBreast225164957Bladder142274256Esophagus14073032Head & Neck69102532Lung15731717Ovarian8921315Pancreas96123Stomach131022 Citation Format: Carly T. Campbell, Robert Smale, Michael Rigby, Shawn Watson, Amy Dickson, Tara Gelb, Heather Cohen, Pierre Lee, Josette William Ragheb, Stephen J. Blakemore. A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1197.