Abstract 6899: Enfortumab vedotin (EV): Efficacy comparison with trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) and its potential for combination benefit in bladder cancer XPDX models

Abstract EV is a Nectin-4 targeting antibody-drug conjugate (ADC) with an MMAE payload, recently approved for bladder cancer treatment. We established and characterized 18 bladder XPDX models representing primary and metastatic disease from naïve or clinically treated patients, some with actionable mutations. To better understand the potential additive benefit of EV in bladder cancer, we evaluated the ADC alone and in combination with agents targeting ERBB2, PIK3CA or FGFR3. In addition, we tested EV alone in ST5420B, a model established from a patient who progressed on EV after five cycles, as well as ST975B, a model which harbors a novel NECTIN4 fusion. 18 bladder XPDX models were established in immune-deficient mice, including 5 from newly diagnosed patients (2 from primary site), and 13 from recurrent disease (2 from primary site). Nectin-4, Trop2 protein and ERBB2 receptor expression was tested, and models profiled using WES and RNAseq. For in vivo studies, all models were evaluated against cisplatin, T-DXd, SG, and EV. Models with actionable mutations were tested with alpelisib, erdafitinib, and neratinib alone and in combination with EV. Endpoints in all studies 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<0%) versus Day 0 tumor volume was also reported. Most models stained positive for Nectin-4 and Trop-2. FGFR3 variants were found in five models and ERBB2 mutations in two while several models reported PIK3CA variants; deletions in RB1 and CDKN2A were common. In vivo studies reported differential responses to cisplatin with the most sensitive models established from treatment-naïve patients. EV and SG tested alone reported activity in several models; EV added benefit in some combination treatments. We have characterized a panel of bladder XPDX models and benchmarked them against T-DXd, EV and SG alone and EV in combination with targeted therapies. This data is a valuable tool in further developing EV and identifying novel therapies for bladder cancer. Citation Format: Johnnie Flores, Heaven Sessions, Alyssa Simonson, Natalia Banos, Tahmineh Rouzbahani, Armando Diaz III, Jim Lund, Emiliano Calvo, Victor Moreno, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Scott Ulmer, Luis Rodriguez, Michael Wick. Enfortumab vedotin (EV): Efficacy comparison with trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) and its potential for combination benefit in bladder cancer XPDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6899.