Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.

3151 Background: SYS6002 (CRB-701) is a novel, nectin-4 targeting antibody drug conjugate (ADC) that take advantage of a third generation, site-specific cleavable linker with novel conjugation chemistry. This technology is designed to establish a stable linker across antibody and payload, to produce an ADC with a homogenous drug antibody ratio of 2.0, with the additional aim to reduce the concentration of free-MMAE and thereby improve known payload related toxicities. SYS6002 (CRB-701) also contains a novel monoclonal antibody with a prolonged half-life that can support Q3W dosing. Methods: This is a multicenter, open-label, single-arm, phase I study using Bayesian optimal interval design. Eligible patients were aged ≥18 years with histologically confirmed Nectin-4 positive solid tumors (no Nectin-4 testing was required for urothelial carcinoma UC) who had failed or were intolerant to standard of care options. In the dose escalation, patients were given SYS6002 (dose level 0.2, 0.6, 1.2, 1.8, 2.7, 3.6, and 4.5 mg/kg) administered Q3W by intravenous infusion. The primary endpoints were safety, tolerability, and the recommended phase 2 dose. Results: As of January 2024, SYS6002 (CRB-701) has established a differentiated safety profile across a broad dose range (0.2-3.6 mg/kg) with no dose limiting toxicities and the majority of adverse events representing grade 1 or 2. No low-grade peripheral neuropathy, skin rash or fatigue, known toxicities that rate limit the usage of enfortumab vedotin (EV) have occurred. Herein, we report the anti-tumor activity of SYS6002 (CRB-701) in patients with nectin-4 positive solid tumors with a median of 4 prior therapies. The first confirmed stable disease was observed at 0.6 mg/kg and the first confirmed partial response was at 1.2 mg/kg. Anti-tumor activity in nectin-4 positive patients at doses ≥ 2.7 mg/kg ( n=6) would suggest an overall unconfirmed objective response rate of 50%, and among them, the ORR of patients with UC was 50% (1/2), and that of patients with cervical cancer reached 67% (2/3). Across this group of patients, 4/6 had moderate to high nectin-4 expression (H-score ≥ 150) and 3 achieved a partial response, suggesting SYS6002 (CRB-701) could achieve a highly differentiated ORR of 75% in patients with moderate to high Nectin-4 expression. After single IV infusion of SYS6002 0.2-3.6 mg/kg, the exposure of TAb, ADC and MMAE generally increased in a dose proportional manner. The half-lives of TAb, ADC and MMAE were 4-6 days, 4-5 days and 5-10 days, respectively. SYS6002 (CRB-701) exhibited a longer ADC half-life and lower free-MMAE exposures relative to EV at comparable dose levels. Conclusions: SYS6002 (CRB-701) demonstrates promising anti-tumor activity with a well-tolerated safety profile in patients with advanced nectin-4 positive solid tumors. Dose escalation at 4.5 mg/kg Q3W and dose expansion at 3.6 mg/kg Q3W are ongoing. Clinical trial information: ChiCTR2200066256.