Gopa Iyer, MD, highlights data on anti-Nectin-4 ADC for metastatic urothelial carcinoma

In the following interview, conducted at the 2026 American Society of Clinical Oncology Annual Meeting, Gopa Iyer, MD, discusses early findings from the phase 1 NEXUS-01 trial (NCT06465069).¹ The study is evaluating the investigational anti–Nectin-4 antibody-drug conjugate LY4052031 in patients with locally advanced or metastatic urothelial carcinoma, including those previously treated with enfortumab vedotin-ejfv (Padcev).

Iyer is a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

Iyer explains that although enfortumab vedotin plus pembrolizumab (Keytruda) has become the standard first-line treatment for metastatic urothelial carcinoma, there remains no established standard of care after progression on this regimen. He noted that platinum-based chemotherapy is often the preferred option, but it offers modest and often short-lived responses. NEXUS-01 was designed to address this unmet need by evaluating LY4052031, a next-generation anti–Nectin-4 antibody-drug conjugate with a novel topoisomerase I inhibitor payload. The phase 1 trial included both dose-escalation and dose-optimization components to assess the agent's safety, pharmacokinetics, and preliminary antitumor activity across multiple dose levels.

Iyer explained that an important finding early in the study was the influence of CYP2D6 activity on drug metabolism. Investigators observed that patients with low CYP2D6 activity experienced higher rates of toxicity, prompting a protocol amendment requiring prospective CYP2D6 genotyping. Patients with normal CYP2D6 activity entered the randomized dose-optimization portion of the trial, whereas those with low activity (< 0.5) were assigned to a separate lower-dose cohort to evaluate whether treatment could be administered more safely.

Among patients with normal CYP2D6 activity, Iyer said LY4052031 demonstrated a favorable safety profile, with predominantly low-grade, reversible adverse events (AEs) such as nausea, alopecia, fatigue, and dysgeusia. Rates of neutropenia were relatively low, and AEs commonly associated with enfortumab vedotin—including peripheral neuropathy, skin and ocular toxicities, and hyperglycemia—were uncommon.

The study also showed encouraging preliminary efficacy, with an objective response rate of 48% and a disease control rate of 81% among efficacy-evaluable patients with metastatic urothelial carcinoma treated at doses of 2.4 to 4.8 mg/kg, including responses in patients previously treated with enfortumab vedotin. Iyer emphasized, however, that patients with low CYP2D6 activity experienced substantially greater toxicity, underscoring the importance of genotype-guided dosing as development of the agent continues.

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