Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.
Authors: Ye Ding-Wei , Zhang Jian , Yang Hua , Yang Jin , Zheng Tongsen , Sun Hongmei , Sun Yuping , Li Guiling , Liu Funan , Wan Xuechao , Ge Lan , Sun Guilan , Zhang Xiao , Wang Lei , BRAKE RACHAEL 
Published: August 2024

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.