Nectin-4 ADC LY4052031 Yields 33% ORR After Enfortumab Vedotin in Urothelial Cancer

LY4052031, an investigational next-generation Nectin-4 antibody-drug conjugate (ADC), produced confirmed responses in one-third of patients with metastatic urothelial carcinoma (mUC) who had progressed on prior enfortumab vedotin (Padcev)-based therapy, according to first-in-human results from the phase 1 NEXUS-01 study (NCT06465836) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Among 36 evaluable mUC participants with 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. Overall, 67% of responses remained ongoing at a data cutoff of April 29, 2026. At the 3.6 mg/kg dose level, ORR climbed to 47% in 15 post-EV-exposed patients. Investigators also identified CYP2D6 metabolizer status as a pharmacogenomic biomarker for severe toxicity risk, prompting a mid-study protocol amendment.

"LY4052031 demonstrated promising clinical activity across multiple dose levels, suggesting Nectin-4 remains an important therapeutic target following progression on EV-based therapy," lead investigator Gopa Iyer, MD, of the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York, said during a presentation of the data. “The drug was generally well tolerated, and the most common treatment-emergent adverse events were grades 1 to 2 in participants with normal CYP2D6 function.”

Why test another Nectin-4 ADC after enfortumab vedotin?

EV plus pembrolizumab (Keytruda) is now the standard first-line treatment for locally advanced or mUC, validating Nectin-4 as a clinically important therapeutic target. However, treatment options after progression on EV-based therapy remain limited and clinical outcomes remain poor, marking it as an area of substantial unmet need. Preclinical work has implicated P-glycoprotein-mediated efflux of MMAE, which is the cytotoxic payload of EV, as one mechanism of EV resistance, raising the question of whether a Nectin-4 ADC built around a different payload could retain activity in the post-EV setting, Iyer noted.

LY4052031 is designed to test this hypothesis directly. It is a humanized IgG1 antibody linked through a cathepsin-cleavable GGFG peptide linker to camptothecin-98 (camp98), a novel topoisomerase 1 inhibitor, at a homogeneous drug-antibody ratio of 8. Hepatic CYP2D6 is the primary clearance enzyme for the payload.

How was NEXUS-01 designed and who enrolled?

NEXUS-01 is a multi-arm phase 1 study comprising a dose escalation cohort (cohort A1, n = 105) that included both patients with mUC and those with select Nectin-4-expressing solid tumors. The study uses a Bayesian optimal interval design with backfilling across seven dose levels (0.6-5.4 mg/kg every 3 weeks). The study also included a randomized dose optimization cohort (cohort A2, n = 32) in mUC with CYP2D6 activity score (AS) ≥0.5 testing 4 dose levels (2.4, 3.6, 4.2, and 4.8 mg/kg). Substudies were also included for participants with low CYP2D6 activity and for those with renal insufficiency (creatinine clearance 30-49 mL/min). Eligible patients had an ECOG performance status of 0 or 1, measurable or non-measurable disease per RECIST v1.1, and could have received prior EV-based therapy.

A total of 137 participants had been treated as of the April 29, 2026, data cutoff, with 107 (79%) having mUC. At the cutoff, 65 (47%) remained on treatment. The mUC population was heavily pretreated, with a median of 3 prior systemic regimens (range, 1-9), which included prior platinum chemotherapy for 88%. Additionally, 67% had received EV with or without pembrolizumab, 94% had received an immune checkpoint inhibitor, and 23% had received a prior topoisomerase 1-payload ADC. Visceral metastases were present in 59% of mUC participants, and 31% had liver metastases. CYP2D6 activity scores of 0 or 0.25, which indicated to poor or intermediate-low metabolizer status, were present in fewer than 10% of enrolled participants overall, consistent with the global prevalence of those phenotypes, Iyer noted.

How active was LY4052031 after progression on EV?

In the prespecified efficacy population of 48 mUC participants with intact CYP2D6 function (AS ≥0.5) and no prior topoisomerase 1-payload ADC, ORR by investigator assessment per RECIST v1.1 was 42% (20/48), with a 4% complete response rate (2/48) and a 79% disease control rate (38/48). Among the 36 patients in this population who had received prior EV-based therapy, ORR was 33% (12/36), DCR was 75% (27/36), and median DOR was 7.4 months among 9 confirmed responders, with 67% of responses ongoing. At the 3.6 mg/kg dose level specifically, ORR was 47% (7/15).

A swimmer plot of treatment duration in the post-EV subset showed responses concentrated at the 3.6 mg/kg dose level and treatment durations extending to approximately 13 months. Notably, several partial responses developed late after initial stable disease, with some emerging beyond 4 months on treatment, which suggests that the depth of response continues to evolve with longer exposure, said Iyer. Responses were observed across all 4 dose levels tested in the optimization cohort (2.4-4.8 mg/kg).

Among 12 EV-naive participants in the efficacy population, ORR was 67% (8/12), including one complete response, and DCR was 92% (11/12).

Among 18 mUC participants who had received a prior topoisomerase 1-payload ADC, such as trastuzumab deruxtecan (Enhertu), datopotamab deruxtecan (Datroway), or sacituzumab govitecan (Trodelvy), there were no confirmed responses observed. "Very interestingly, there were 18 patients who were enrolled onto this study who had received a prior topoisomerase 1-containing ADC before enrollment," Iyer said. "There were no confirmed responses observed in that patient population."

Why did the trial add CYP2D6 genotyping mid-study?

Early in NEXUS-01, investigators identified a subset of participants who developed prolonged severe neutropenia, complicated in some cases by febrile neutropenia and sepsis. Pharmacokinetic analysis traced the signal to camp98 metabolism and found that patients with poor or intermediate-low CYP2D6 metabolizer status showed dramatically higher payload exposure. Median payload Cavg was 0.00254 nM in participants with AS ≥0.5 (n = 95) vs 0.00479 nM in those with AS 0.25 (n = 6) and 0.015 nM in those with AS 0.0 (n = 4). This equated to roughly a fivefold increase in payload exposure in poor metabolizers.

Rates of grade ≥3 toxicity tracked the exposure differential. In AS 0.0 participants (n = 4), grade ≥3 mucositis occurred in 50%, grade ≥3 neutropenia in 50%, febrile neutropenia in 50%, and sepsis in 25%. In AS 0.25 participants (n = 6), grade ≥3 mucositis occurred in 17%, neutropenia of any grade in 17% (none were grade ≥3), febrile neutropenia in 17%, and sepsis in no patients. In AS ≥0.5 participants (n = 122), the corresponding rates of grade ≥3 AEs were 3%, 5%, less than 1%, and 2% for mucositis, neutropenia, febrile neutropenia, and sepsis, respectively. Dose reduction rates were 33% in AS 0.25 participants versus 13% in AS ≥0.5 participants.

In response, the protocol was amended to require prospective germline CYP2D6 genotyping for all participants. Enrollment of patients with AS 0.0 has been halted. Patients with AS 0.25 are now dosed at a reduced level (2.4 mg/kg) in a dedicated CYP2D6 substudy, while CYP2D6 AS-specific dose optimization in the AS ≥0.5 population continues. Three treatment-related deaths were reported across the full safety population: one grade 5 aspiration pneumonia in a patient with AS 0.25 dosed at 4.8 mg/kg, and two grade 5 sepsis events (one in a patient with AS 0.0 dosed at 1.2 mg/kg and one in a patient with unknown AS dosed at 3.6 mg/kg).

In the AS ≥0.5 population (n = 122), LY4052031 was generally well tolerated. The most common any-grade treatment-emergent adverse events were nausea (40%; grade ≥3, 3%), dysgeusia (38%), alopecia (37%), fatigue (30%; grade ≥3, 5%), anemia (25%; grade ≥3, 13%), and constipation (25%). Diarrhea, which is a known on-target effect of topoisomerase 1 inhibitors, occurred in 18% of patients and was grade ≥3 in 3%. Neutropenia occurred in 12% (grade ≥3, 5%) of patients. Notably, EV-associated adverse events, such as skin toxicity, peripheral neuropathy, ocular toxicity, and hyperglycemia, were rare with LY4052031. Dose reductions occurred in 13% of these participants, and 3% discontinued because of TEAEs.

What's the path forward?

The NEXUS-01 data, Iyer concluded, underscore Nectin-4 as a "clinically relevant and therapeutically tractable target" after progression on EV-based therapy, with the optimized 3.6 mg/kg dose level, the activity demonstrated in the post-EV setting, and the pharmacogenomic risk-stratification framework setting the stage for further development. Dose optimization in the AS ≥0.5 population is ongoing, and the CYP2D6 substudy continues to enroll patients with AS 0.25 using the pharmacogenomic-guided dosing approach.

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