A Phase 1a/1b Study of LY4052031, an Antibody-Drug Conjugate Targeting Nectin-4, in Participants With Advanced or Metastatic Urothelial Carcinoma or Other Solid Tumors

More details:

Overview

LY4052031 is an investigational, next-generation antibody–drug conjugate (ADC) targeting Nectin-4, a cell-surface protein overexpressed in urothelial and several other cancers. It is being evaluated in the first-in-human, open-label phase 1 NEXUS-01 trial (NCT06465069), which is enrolling patients with advanced or metastatic urothelial carcinoma and selected solid tumors. No peer-reviewed full-length clinical publication has yet been reported. (ascopubs.org)

Mechanism of action

LY4052031 comprises a humanized IgG1 anti–Nectin-4 antibody linked through a cleavable peptide linker to Camp98 (LSN3889710), a camptothecin-derived topoisomerase I inhibitor. It has a homogeneous drug-to-antibody ratio of 8. After binding Nectin-4 and internalization, the payload is released, inhibiting topoisomerase I and thereby causing DNA damage, cell-cycle arrest, and tumor-cell death. (cancer.gov)

Efficacy

Initial phase 1 results were reported at ASCO 2026. As of November 25, 2025, 70 patients had received 0.6–5.4 mg/kg intravenously every three weeks, including 47 with metastatic urothelial carcinoma.

Among 21 efficacy-evaluable urothelial-cancer patients with adequate CYP2D6 activity treated at 2.4–4.8 mg/kg:

• Objective response rate: 48% (10/21), including one complete and nine partial responses.
• Disease-control rate: 81% (17/21).
• Median duration of response: 7 months.
• Among 15 patients previously treated with enfortumab vedotin, the response rate was 40%; among six enfortumab-naive patients, it was 67%.

These are preliminary results from small, nonrandomized dose-escalation cohorts and do not establish comparative efficacy. (ascopubs.org)

Safety

The most frequent treatment-emergent adverse events were nausea (43%), alopecia (39%), fatigue (37%), decreased appetite (29%), and constipation, diarrhea, altered taste, mucositis, and vomiting (27% each). Anemia occurred in 24% and was the most common grade 3 or higher event (13%).

Reduced CYP2D6 metabolic activity was associated with greater payload exposure and more dose-limiting toxicity at higher doses. The protocol was consequently amended to require CYP2D6 genotyping and separate dose finding for patients with low activity scores. Dose optimization remains ongoing. (ascopubs.org)

Further reading

• ASCO 2026 clinical-results abstract
• NEXUS-01 trial record from Lilly
• NCI Drug Dictionary entry
• AACR 2024 preclinical abstract collection

Last updated: Sep 2026

Inclusion Criteria:

* Have one of the following solid tumor cancers:

* Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer

* Cohort A2/B1/B2: urothelial carcinoma

* Cohort C: triple negative breast cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, HNSCC (head and neck squamous cell carcinoma), esophageal cancer, pancreatic cancer, or prostate cancer

* Prior Systemic Therapy Criteria:

* Cohort A1/C: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies

* Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.

* Prior enfortumab vedotin specific requirements:

* Cohorts A1/A2/C: prior treatment with enfortumab vedotin is allowed, but not required

* Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting

* Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.

* Measurability of disease

* Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)

* Cohorts A2, B1, B2, C: measurable disease required as defined by RECIST v1.1

* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations

Exclusion Criteria:

* Individual with known or suspected uncontrolled CNS metastases

* Individual with uncontrolled hypercalcemia

* Individual with uncontrolled diabetes

* Individual with evidence of corneal keratopathy or keratitis, and history of corneal transplant

* Any serious unresolved toxicities from prior therapy

* Significant cardiovascular disease

* Recent thromboembolic event or bleeding disorder

* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms

* History of pneumonitis/interstitial lung disease

* History of Grade ≥3 skin toxicity when receiving enfortumab vedotin

* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention