Abstract CT084: A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress)

Abstract

Abstract Background: Nectin-4 is a cell adhesion molecule expressed in multiple tumor types.1 Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) comprising a fully humanized nectin-4 antibody conjugated to the microtubule inhibitor, monomethyl auristatin E (MMAE), is approved for the treatment of advanced urothelial cancer (UC). However, skin toxicity, peripheral neuropathy, and hyperglycemia are clinically significant toxicities with EV. LY4101174 (ETx-22) is a next-generation nectin-4 targeting ADC comprising a humanized IgG1 Fc-silent monoclonal antibody linked to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker with improved stability and a homogeneous drug-antibody ratio (DAR) of 8. Preclinically, LY4101174 has demonstrated robust in vivo efficacy in tumor models across a range of nectin-4 expression levels and in the nectin-4-MMAE ADC treated resistant tumor model.2 Methods: LOXO-ENC-23001 is a global, open-label, multi-center, first-in-human phase 1 study of LY4101174 in patients (pts) with advanced or metastatic solid tumors known to express nectin-4. LY4101174 will be administered intravenously and evaluated initially on either every 2 weeks or 3 weeks schedule. Eligible pts (≥18 years) must have good performance status (ECOG PS 0-1) with metastatic UC, head and neck squamous cell carcinoma, esophageal, pancreatic, prostate, non-small cell lung, cervical, ovarian, or triple-negative breast cancer, and must have received or not be a candidate for available standard therapies. The study will be conducted in 2 phases: phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. The dose-limiting toxicity evaluation period will be 21 or 28 days based on dosing schedules. Phase 1b dose expansion cohorts will enroll pts with selected tumor types: mUC with no prior EV treatment (cohort B1), mUC with prior EV treatment (cohort B2), and other selected non-UC tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4101174. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4101174 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. 1Challita-Eid PM et al. 2016 Cancer Res 76(10):3003-13. 2Azim H et al. 2023 Mol Cancer Ther 22(12_Suppl):B128. Citation Format: Jonathan Rosenberg, Renaud Sabatier, Armelle Viceneux, Thibault de La Motte Rouge, Stephane Champiat, Loic Lebellec, Philippe Barthélémy, Guru Sonpavde, Xin Gao, Scot Niglio, Tian Zhang, Craig Gedye, Matthew Galsky, Matthew Milowsky, Melissa Reimers, Andrew Weickhardt, Enrique Grande, Daniel E. Castellano, Mehmet Bilen, Amita Patnaik, Robert Zerbib, Minna Balbas, Xiaojian Xu, Kaitlyn Aptaker, Arjun V. Balar, Ahmad H. Awada. A phase 1 study of LY4101174 (ETx-22), an antibody-drug conjugate targeting nectin-4, in patients with advanced or metastatic urothelial cancer and other solid tumors (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT084.