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NEXUS-01 — LY4052031 (Nectin-4 topoisomerase-I ADC), advanced/metastatic urothelial carcinoma, post-EV

Abstract: 4508 · Session: Genitourinary Cancer—Kidney & Bladder, Oral Abstract Session, 2026 ASCO Annual Meeting · Presenter: Gopa Iyer, MD (Memorial Sloan Kettering Cancer Center) · Citation: J Clin Oncol 2026;44(suppl 16):4508

At a glance

  • Sponsor: Eli Lilly and Company
  • PI / presenter: Gopa Iyer, MD — Memorial Sloan Kettering Cancer Center
  • NCT ID: NCT06465069
  • Phase: 1 (first-in-human, phase 1a/1b dose escalation + expansion)
  • Design: Open-label, multicenter; Bayesian optimal interval (BOIN) dose escalation; IV Q3W. Advanced/metastatic urothelial carcinoma and other Nectin-4–expressing solid tumors
  • N: 36 evaluable post-EV metastatic urothelial carcinoma participants (efficacy subset)
  • Primary endpoint(s): Safety/tolerability, dose-limiting toxicities, RP2D (with preliminary antitumor activity)
  • Comparator: None (single-arm, first-in-human)
  • Indication: Advanced or metastatic urothelial carcinoma
  • Line: Post–enfortumab vedotin (EV) / heavily pretreated

Headline result

Among 36 evaluable participants with metastatic urothelial carcinoma and prior EV-based therapy, LY4052031 produced an objective response rate (ORR) of 33% with a 75% disease-control rate and a median duration of response of 7.4 months (per 9 confirmed responders; 67% of responses ongoing). Activity was dose- and biomarker-dependent: at the 3.6 mg/kg dose level, ORR reached 47% in 15 post-EV participants, and among topoisomerase-I ADC–naïve participants with CYP2D6 activity score ≥0.5, ORR was 42% overall (33% EV-pretreated, 67% EV-naïve), DCR 79%. No confirmed responses were seen among 18 participants previously exposed to a topoisomerase-I ADC, suggesting payload-class cross-resistance. Safety was favorable — predominantly grade 1–2 toxicities, dose reductions 13%, treatment discontinuations 3%. Investigators identified CYP2D6 metabolizer status as a pharmacogenomic biomarker for severe-toxicity risk, prompting a mid-study protocol amendment. No formal comparator, HR, or p-values (single-arm phase 1).

Mechanism / class

LY4052031 is a next-generation anti–Nectin-4 antibody-drug conjugate: an Fc-silent humanized IgG1 antibody conjugated via a cleavable peptide linker to camp98, a novel camptothecin-derived topoisomerase-I inhibitor payload, with a homogeneous drug-to-antibody ratio of 8. Nectin-4 is the validated target of enfortumab vedotin (Padcev, an MMAE/microtubule-payload ADC approved in metastatic urothelial carcinoma). LY4052031 keeps the Nectin-4 target but swaps to a topoisomerase-I payload, positioning it as a potential post-EV / next-generation Nectin-4 ADC.

Discussant takeaway

Discussant Andrea Apolo, MD framed the GU oral session ("Living Longer, Living Better: Can We Have It All?"), synthesizing Nectin-4 ADC data across the urothelial continuum and highlighting LY4052031 activity following prior EV exposure as evidence that re-targeting Nectin-4 with a new payload can overcome EV resistance, while noting the lack of response after prior topoisomerase-I ADC exposure as a class-cross-resistance signal.

Practice-changing?

Pending. Early but encouraging phase 1 signal of a next-generation Nectin-4 ADC retaining activity after EV (33% ORR post-EV; 47% at 3.6 mg/kg), with a favorable safety profile and a pharmacogenomic (CYP2D6) toxicity biomarker. Single-arm, small N, no comparator. Lilly is advancing to phase 1b dose expansion, with potential to move directly toward phase 3 — not practice-changing today but a candidate to watch in the post-EV space.

  • Other ASCO 2026 trials: other GU/urothelial ADC abstracts in trials/

Sources

  • ASCO Meeting Library: https://www.asco.org/abstracts-presentations/260954/abstract
  • ASCO poster/abstract record: https://www.asco.org/posters/POSTER479608
  • ClinicalTrials.gov (NCT06465069): https://clinicaltrials.gov/study/NCT06465069
  • OncLive: https://www.onclive.com/view/nectin-4-adc-ly4052031-yields-33-orr-after-enfortumab-vedotin-in-urothelial-cancer
  • UroToday (results): https://www.urotoday.com/conference-highlights/asco-2026/asco-2026-bladder-cancer/169394-asco-2026-initial-results-from-nexus-01-a-phase-1-study-of-ly4052031-an-adc-targeting-nectin-4-in-participants-with-advanced-or-metastatic-urothelial-carcinoma.html
  • UroToday (discussant — Nectin-4 ADCs: Past, Present, Future): https://www.urotoday.com/conference-highlights/asco-2026/asco-2026-bladder-cancer/169469-asco-2026-discussant-nectin-4-antibody-drug-conjugates-the-past-present-and-future.html
  • Urology Times: https://www.urologytimes.com/view/ly4052031-shows-early-promise-in-post-ev-urothelial-cancer
  • FierceBiotech: https://www.fiercebiotech.com/biotech/asco-lilly-debuts-bladder-cancer-data-potential-padcev-challenger