LY4052031 shows early promise in post-EV urothelial cancer

Initial results from the NEXUS-01 phase 1 trial (NCT06465069) of LY4052031, an antibody-drug conjugate (ADC) targeting Nectin-4 with a novel topoisomerase-I (Topo-I) payload, revealed an objective response rate (ORR) of 42% in Topo-I–naive patients with metastatic urothelial carcinoma (mUC)—including those with prior enfortumab vedotin-ejfv (EV, Padcev) exposure—with a generally favorable tolerability profile in patients with normal CYP2D6 metabolic function.

Gopa Iyer, MD, a genitourinary medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, presented the data at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Background and rationale

EV plus pembrolizumab (EVP) is the current first-line standard of care for locally advanced or mUC, establishing Nectin-4 as a clinically important target. Treatment options following progression on EVP are limited, and clinical outcomes are poor. Preclinical data suggest that EV resistance may be mediated by P-glycoprotein–mediated payload efflux, supporting continued investigation of Nectin-4 targeting with alternative ADC payloads.

LY4052031 is a humanized IgG1 antibody linked via a cleavable cathepsin peptide linker to camptothecin-98 (camp98), a novel Topo-I inhibitor, at a homogeneous drug-to-antibody ratio of 8. Clearance of camp98 is predominantly mediated by the hepatic CYP2D6 enzyme—a pharmacokinetic feature with direct implications for patient safety, as Iyer explained during his presentation.

Trial design and patient population

NEXUS-01 is a phase 1a dose-escalation and optimization study. Cohort A1 (n=105) enrolled patients with mUC and select solid tumors known to express Nectin-4 across dose levels from 0.6 mg/kg to 5.4 mg/kg, using a Bayesian Optimal Interval design with a 21-day dose-limiting toxicity evaluation period. Cohort A2 (n=32) was a randomized dose-optimization cohort enrolling patients with mUC, randomly assigned to 2.4, 3.6, 4.2, or 4.8 mg/kg every 3 weeks. Prior EV therapy was permitted. After a protocol amendment, CYP2D6 activity score (AS) became a key eligibility criterion.

As of the April 29, 2026, data cutoff, 137 participants were enrolled. The median age was 67 years (range, 31-86), and 107 (79%) had mUC. The mUC cohort was heavily pretreated, with a median of 3 prior systemic regimens (range, 1-9); 67% had received EV with or without pembrolizumab, 39% had received EVP specifically, and 23% had received a prior Topo-I ADC. Visceral metastases were present in 59% and liver metastases in 31%.

CYP2D6 genotyping and pharmacogenomic risk stratification

Early in the trial, patients with poor or absent CYP2D6 metabolic activity were found to have markedly higher camp98 plasma exposure and a substantially increased risk of severe toxicity. A CYP2D6 AS is generated from germline genotyping and reflects the metabolic activity of the enzyme; scores of 0.0 or 0.25 indicate absent or minimal activity. Prospective CYP2D6 genotyping was subsequently made mandatory for all enrollees, and a dedicated substudy was opened, assigning patients with AS 0.0 to 1.2 mg/kg and those with AS 0.25 to 2.4 mg/kg. Only patients with AS of at least 0.5—indicating normal CYP2D6 function—were eligible for the randomized dose-optimization cohort.

Median payload average concentration per dose was substantially higher among patients with AS 0.0 (0.015 nM/mg; quartile range, 0.00995-0.0305) and AS 0.25 (0.00479 nM/mg; quartile range, 0.00251-0.00675) compared with those with AS of at least 0.5 (0.00264 nM/mg; quartile range, 0.00224-0.0035). In the AS 0.0 group (n=4), rates of any-grade mucositis, neutropenia, and febrile neutropenia were each 50%, and sepsis occurred in 25%; 75% of these patients discontinued treatment due to treatment-emergent adverse effects (TEAEs). In the AS 0.25 group (n=6), any-grade febrile neutropenia was 17%, with a 33% dose-reduction rate and a 17% discontinuation rate.

Three treatment-related deaths occurred: 1 case of aspiration pneumonia in a patient with AS 0.25 receiving 4.8 mg/kg, and 2 cases of sepsis—1 in a patient with AS 0.0 receiving 1.2 mg/kg and 1 in a patient with unknown AS receiving 3.6 mg/kg. Enrollment of patients with AS 0.0 has been suspended; pharmacogenomic-guided dosing for those with AS 0.25 is ongoing.

"CYP2D6 is the hepatic enzyme that is primarily responsible for clearing the topoisomerase-1 payload from the body, and prospective CYP2D6 genotyping is very effective at identifying patients who are at risk for severe toxicity because of lower metabolic function of the enzyme, and this enables a pharmacogenomic-guided dose optimization approach," Iyer said.

Safety in patients with normal CYP2D6 function

Among the 122 patients with CYP2D6 AS of at least 0.5, 61 (50%) remained on treatment at the data cutoff, with a median treatment duration of 2 months (range, 0.3-16). The most common TEAEs of any grade were nausea (40%), dysgeusia (38%), alopecia (37%), fatigue (30%), anemia (25%), and constipation (25%). Most were grade 1 or 2. Diarrhea, a known class effect of Topo-I inhibitors, occurred in 18% of patients and was predominantly low grade. Notably, adverse events (AEs) associated with EV—including peripheral neuropathy, skin toxicities, ocular toxicity, and hyperglycemia—were rare.

Grade 3 or higher AEs in this population included anemia (13%), fatigue (5%), and neutropenia (5%). Only 3 patients (2.5%) with AS of at least 0.5 experienced grade 4 AEs (neutropenia or white blood cell decrease), all at the 2 highest dose levels. Dose reductions and discontinuations due to TEAEs were uncommon, occurring in 13% and 3% of patients, respectively.

"In general, dose reductions and discontinuations were infrequent," Iyer said, adding that EV-associated adverse events "were all quite rare with this drug."

Antitumor activity in mUC

Efficacy data are reported in Topo-I–naive patients with mUC and CYP2D6 AS of at least 0.5 treated at 2.4 to 4.8 mg/kg every 3 weeks. In 48 efficacy-evaluable patients (EV-naive and EV-pretreated combined), the ORR was 42% (20/48), and the disease control rate (DCR) was 79% (38/48). Among 12 EV-naive patients, the ORR was 67% (8/12), and the DCR was 92% (11/12). Responses were observed across all dose levels. No confirmed responses were observed among the 18 patients who had previously received a Topo-I–containing ADC.

In the 36 EV-pretreated efficacy-evaluable patients, the ORR was 33% (12/36), and the DCR was 75% (27/36). At the 3.6 mg/kg dose level in the post-EV population (n=15), the ORR was 47% (7/15). The median duration of response among 9 confirmed post-EV responders was 7.4 months (95% CI, 2.7-not estimable), and 67% of responders remained on treatment at the data cutoff.

"LY4052031 demonstrated promising clinical activity across several dose levels, and it underscores that Nectin-4 is a clinically relevant and therapeutically tractable target after progression on EV-based therapy," Iyer said. He also noted that "some of these partial responses occurred fairly late in the treatment duration—out to about 4 months after being on treatment—indicating that some patients who had initial stable disease were able to convert to partial responses later on."

Conclusions

Iyer concluded that LY4052031 represents a promising next-generation Nectin-4 ADC with a distinct payload mechanism that may overcome EV resistance in mUC. He emphasized that the favorable tolerability profile in patients with normal CYP2D6 function—characterized by low rates of myelosuppression, diarrhea, and EV-class toxicities—alongside the infrequent need for dose modification, distinguishes the drug from EV. The integration of prospective CYP2D6 germline genotyping as a mandatory eligibility screen was highlighted as a key precision medicine strategy to mitigate severe toxicity risk. CYP2D6 AS-specific dose optimization and enrollment in the pharmacogenomic substudy are ongoing.

DISCLOSURES: Iyer reported disclosures related to AstraZeneca, Biohaven Pharmaceuticals, EMD Serono, Flare Therapeutics, Janssen, Loxo/Lilly, Mirati Therapeutics, AADi Bioscience, Pfizer, and DAVA Oncology.

REFERENCE

1. Iyer G, Gao X, Wei AZ, et al. 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. J Clin Oncol. 2026;44(suppl 16):4508. doi:10.1200/JCO.2026.44.16_suppl.4508