NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4 in participants with advanced or metastatic urothelial carcinoma or other solid tumors.
Authors: Gao Xin , Patnaik Amita , Lakhani Nehal J. , Call Justin A , Galsky Matthew D. , Garmezy Benjamin , Wei Alexander Z , Carter Louise , Powles Thomas , Siefker-Radtke Arlene O. , O'Donnell Peter H. , Kitano Shigehisa , Castellano Daniel , Shinde Rajiv , Joshua Anthony M. , Balbas Minna , Han Hongmei , Chang Amy E. , Baldini Capucine , Iyer Gopa 
Published: February 2025

TPS900

Background:
Nectin-4 is a cell surface antigen overexpressed in multiple tumor types including urothelial cancer. Enfortumab vedotin (EV) is a first generation anti-nectin-4 antibody-drug conjugate (ADC) comprising a fully humanized antibody conjugated to an MMAE payload with heterogeneous DAR 4 and is approved in metastatic urothelial carcinoma (mUC) both as a single agent in treatment refractory disease and as first-line treatment in combination with pembrolizumab. Persistent nectin-4 expression despite progression on EV has been demonstrated in preclinical tumor models suggesting payload mediated treatment resistance. LY4052031 is a next generation anti-nectin-4 ADC, consisting of a Fc-silent IgG1 antibody conjugated to a novel topoisomerase I (TOPO 1) inhibitor camp98 (LSN3889710) via a cleavable peptide linker with improved stability and a homogeneous drug antibody ratio (DAR) of 8. LY4052031 has demonstrated robust
in vivo
efficacy in tumor models across a range of nectin-4 expression levels and in MMAE-resistance.
Methods:
NEXUS-01 (NCT06465069) is a first-in-human, open-label, multi-center, phase 1 study of LY4052031 in patients (pts) with advanced or metastatic UC or other solid tumors known to express nectin-4. LY4052031 is administered intravenously once every 3 weeks. Eligible pts have ECOG PS 0-1 with a histologic diagnosis of advanced UC, triple-negative breast, non-small cell lung, esophageal, pancreatic, gastric (Japan only), ovarian, cervical, head and neck squamous cell carcinoma, or prostate cancer. Pts must have progressed on or be ineligible for all available standard therapies, with no limit on the number of prior therapies. The study consists of phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation will utilize a Bayesian optimal interval design. Additional pts will backfill previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. Optional dose optimization will involve randomized evaluation of 2 or more dose levels selected in the dose escalation phase. Dose expansion will enroll pts with UC who are EV-naïve (cohort B1) and with prior EV treatment (cohort B2), or with non-UC solid tumors (cohort C). Primary objectives are to determine the recommended phase 2 dose (RP2D) and assess the safety of LY4052031. Key secondary objectives are to evaluate the pharmacokinetic profile, immunogenicity, and antitumor activity of LY4052031 per RECIST v1.1. Nectin-4 expression and other biomarker data will be generated and correlated with clinical activity. Clinical trial information:
NCT06465069
.