Abstract PO1-26-02: Enfortumab vedotin (EV): Correlation of estrogen receptor status and Nectin-4 expression with single agent efficacy in breast XPDX models
Authors: Moreno Crystal , Flores Johnnie , Simonson Alyssa , DeBoer Maci , Banos Natalia , III Armando Diaz , Lynch Morgan , Lund Jim , Leykum Leonora , Rouzbahan Tahmi , Pedregal Manuel , Papadopoulos Kyriakos P. , Lang Amy , Rosenthal Arthur , Rasco Drew , Rodriguez Gladys , Rodriguez Luis , Lakhani Nehal , Beeram Muralidhar , Patnaik Amita , De Miguel Maria , Drengler Ronald , Abbate Steven , Uribe Bernard Doger de Speville , Wick Michael 
Published: May 2024

Abstract
EV is a Nectin-4 targeting antibody-drug conjugate (ADC) with an MMAE payload, recently approved for treatment of bladder cancer patients. To better understand the potential for EV in treatment of breast cancer, we evaluated 175 breast XPDX models, including hormone receptor positive and negative cancer, some with actionable mutations, representing primary and metastatic disease from naïve or clinically treated patients. Each model was stained and scored for Nectin-4 protein and evaluated in vivo against single agent EV and activity correlated with ER status, Nectin-4 staining and known variants.
175 breast XPDX models were evaluated in this study, approximately 35% representing estrogen receptor positive and 20% clinically HER2+ cancers. Nectin-4 protein expression based on intensity and proportion was determined on a scale of 0+-3+, and models profiled using WES and RNAseq. For in vivo studies, models were evaluated against single agent EV administered by intravenous injection once weekly for three cycles at 3 mg/kg. Endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C&lt; 0%) versus Day 0 tumor volume was also reported.
Overall, 40% of breast models stained positive for Nectin-4 including 50% of ER- and 20% of ER+ and 50% of HER2+ models. For ER- models, 50% were negative and 40% stained 1+ while 80% of ER+ models were negative and 15% stained 1+. In vivo, 25% of models were sensitive to EV, with 65% of these models ER- and &lt; 10% HER2+. Nectin-4 staining did not directly correlate to model sensitivity although models with known drivers such as AKT1 and ESR1 were insensitive as were several models established from post CDK4/6i patients.
We have characterized a panel of breast XPDX models based on Nectin-4 staining and in vivo sensitivity to EV and correlated activity with protein and receptor staining and known mutations. This data is a valuable tool in further developing EV and identifying its potential in treating breast cancer.
Citation Format: Crystal Moreno, Johnnie Flores, Alyssa Simonson, Maci DeBoer, Natalia Banos, Armando Diaz III, Morgan Lynch, Jim Lund, Leonora Leykum, Tahmi Rouzbahan, Manuel Pedregal, Kyriakos P. Papadopoulos, Amy Lang, Arthur Rosenthal, Drew Rasco, Gladys Rodriguez, Luis Rodriguez, Nehal Lakhani, Muralidhar Beeram, Amita Patnaik, Maria De Miguel, Ronald Drengler, Steven Abbate, Bernard Doger de Speville Uribe, Michael Wick. Enfortumab vedotin (EV): Correlation of estrogen receptor status and Nectin-4 expression with single agent efficacy in breast XPDX models [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-26-02.