The phase 1 NEXUS-01 trial demonstrated encouraging activity for LY4052031, a next-generation Nectin-4-targeting antibody-drug conjugate (ADC) for metastatic urothelial carcinoma.
Designed to overcome resistance to enfortumab vedotin (EV), LY4052031 uses a novel topoisomerase 1 inhibitor payload. Among heavily pretreated patients previously exposed to EV, the drug achieved an objective response rate (ORR) of 33% and a disease control rate of 75%, with responses lasting a median of 7.4 months. At the optimized 3.6 mg/kg dose, the ORR increased to 47%. EV-naïve patients achieved an ORR of 67%.
A key finding was the strong link between CYP2D6 enzyme activity and toxicity. Patients with low CYP2D6 activity experienced significantly higher drug exposure and increased risks of severe neutropenia, mucositis, and sepsis, prompting the introduction of genetic screening and dose adjustments.
In patients with normal CYP2D6 function, LY4052031 was generally well tolerated, with nausea, altered taste, hair loss, and fatigue being the most common side effects.