Phase I dose-escalation study of the next-generation nectin-4 targeting antibody–drug conjugate CRB-701 (SYS6002) in US and UK patients with urothelial cancer and other solid tumors.

807 Background: Linker conjugation chemistry is a key determinant of antibody–drug conjugate (ADC) activity and tolerability. Linkers must be stable in the systemic circulation and allow efficient drug release at the target site for maximal intra-tumoral drug delivery. CRB-701, a next-generation nectin-4 targeted ADC, has third-generation linker technology that is specifically designed to reduce the dose-limiting toxicities (DLTs) reported with ADCs (e.g. enfortumab vedotin [EV]). In nonclinical studies, CRB-701 demonstrates preferential internalization-mediated payload release and a longer half-life than EV, which may reduce free monomethyl auristatin E (MMAE)-related toxicities and enable less frequent dosing. Following the first-in-human study (SYS6002-01), we present results of a phase I dose-escalation study conducted in a Western population. Methods: A Bayesian Optimal Interval design with 4 dose groups (1.8, 2.7, 3.6 and 4.5 mg/kg; each once every 3 weeks) was used to determine the maximum tolerated dose and the optimal doses for phase II evaluation (CRB-701-01; ClinicalTrials.gov identifier, NCT06265727). Patients with advanced solid tumors who failed or were intolerant to standard treatment were enrolled. Retrospective H-scores were obtained to confirm nectin-4 positivity. Safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity were assessed. Results: Patients with metastatic urothelial cancer, cervical cancer, endometrial cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer or triple-negative breast cancer were enrolled (N = 31). Patients had failed all potentially available, appropriate prior therapies. All 4 dose cohorts were enrolled; maximum patient follow-up was 23 weeks. No DLTs occurred. Most adverse events (AEs) were grade 1 or 2 in severity. Grade 1 or 2 treatment-related AEs reported in >20% of patients included corneal epithelial lesions, hematuria, hypertriglyceridemia, hyponatremia, proteinuria, anemia and dry eye. Skin rash (grade 1 or 2), neutropenia, fatigue and peripheral neuropathy were less frequent than expected for an MMAE-based ADC; longer-term data will be reported at the congress. CRB-701 demonstrated linear PK across all doses with limited accumulation. Antitumor responses were observed at multiple doses, with the first partial response at the lowest 1.8 mg/kg dose (confirmed responses will be presented). Conclusions: PK, safety andefficacy observations are consistent with those from a previous study in Han Chinese patients. CRB-701 was well tolerated and, relative to EV at similar doses, demonstrated signs of a differentiated PK profile, including a longer half-life and lower free MMAE levels. CRB-701 development will continue to dose expansion. Clinical trial information: NCT06265727 .