Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma.

Abstract

4508 Background: Enfortumab vedotin plus pembrolizumab (EVP) is the current first-line standard of care for locally advanced / metastatic urothelial carcinoma (mUC). However, subsequent treatment options are limited, representing an urgent and growing unmet need. Preclinical data suggest that EV resistance may be payload mediated and consequently Nectin-4 remains a viable target for alternative therapies. LY4052031 is a next generation anti-Nectin-4 ADC, comprising a humanized IgG1 antibody conjugated to Camp98, a novel topoisomerase I inhibitor, via a cleavable peptide linker with homogeneous drug antibody ratio of 8. Here, we report the initial clinical data from the phase 1 dose escalation cohort of NEXUS-01 (NCT06465069). Methods: Adults with locally advanced / mUC or other selected solid tumors were eligible. Participants (pts) must have received or were ineligible for available standard therapies, and have ECOG PS 0-1. Dose escalation utilized a Bayesian optimal interval design. Key endpoints were safety, PK, and antitumor activity of LY4052031 per RECIST v1.1. Results: As of 25 Nov 2025, 70 pts (47 mUC, 23 non-UC) received LY4052031 doses ranging from 0.6-5.4 mg/kg IV Q3W. Median age was 66 years (range, 31-82); 60% had ECOG PS 1. Among pts with mUC, 70% (33/47) had prior EV (6% [2/33] had discontinued EV due to treatment-related toxicity). LY4052031, total antibody, and Camp98 exhibited mostly linear, dose-proportional PK, except at 4.8-5.4 mg/kg for payload. The most common treatment-emergent AEs (TEAEs) were nausea (43%), alopecia (39%), fatigue (37%), decreased appetite (29%), constipation, diarrhea, dysgeusia, mucositis, vomiting (27% each), and anemia (24%). The most common grade ≥3 TEAE was anemia (13%). Low activity scores (AS) for CYP2D6, the metabolic clearance pathway for Camp98, were associated with increased dose-limiting toxicity at higher dose levels. Thus, the study was amended to require CYP2D6 genotyping prior to treatment with dedicated dose finding in pts with low AS ( < 0.5). Response was assessed in efficacy evaluable pts, defined as all treated pts who had at least 1 post-baseline response assessment or who discontinued prior to the first post-baseline response assessment. In 21 efficacy evaluable mUC pts (AS ≥0.5) treated with 2.4-4.8 mg/kg, ORR was 48% (10/21) and DCR was 81% (17/21) with 1 CR, 9 PR, and 7 SD. Among those who had prior EV (8 EV and 7 EV/P), ORR was 40% (6/15) and DCR was 80% (12/15) with 1 CR, 5 PR, and 6 SD; in the EV naïve pts, ORR was 67% (4/6) and DCR was 83% (5/6) with 4 PR and 1 SD. Median follow-up was 7 months (95% CI, 2.79-NE); median DoR was 7 months (95% CI, 2.7-NE). Conclusions: LY4052031 demonstrated promising clinical activity at multiple dose levels, including in EV pre-treated mUC. CYP2D6 AS specific dose optimization is ongoing and updated results will be presented. Clinical trial information: NCT06465069 .