A phase 1b study of SYS6002 in advanced solid tumors.

Abstract

4579 Background: SYS6002 is a next-generation Nectin-4-targeting antibody-drug conjugate (ADC) utilizing a novel site-specific enzymatic conjugation technology to link monomethyl auristatin E (MMAE) with a uniform drug-antibody ratio of 2. This design aims to enhance linker stability, minimize free payload release, and improve the therapeutic window. Methods: This phase 1 study (ChiCTR2200066256) included dose escalation (0.2–4.5 mg/kg Q3W; 2.4–2.7 mg/kg Q2W), pharmacokinetic (PK) expansion, and cohort expansion phases. Eligible patients had advanced solid tumors refractory to standard therapies. The primary endpoints were safety and recommended phase 2 dose (RP2D). Secondary endpoints included PK profile and efficacy, with the latter reported herein were specific to the pretreated advanced urothelial carcinoma (aUC) cohort. Results: As of Dec 19, 2025, 150 patients were enrolled (dose escalation n=32; PK expansion n=70; cohort expansion n=48). The maximum tolerated dose was not reached up to 4.5 mg/kg. The RP2D in aUC patients was determined as 3.6 mg/kg Q3W. SYS6002 exhibited a manageable safety profile in all 150 patients. With a median follow-up of 11.5 months (IQR 6.5-15.5), 2 (1.3%) patients discontinued treatment due to treatment-related adverse events (TRAEs) and no TRAE led to death. The most common TRAEs were ocular disorders (e.g., corneal disorder, dry eye), which were predominantly Grade 1-2. While ocular events were frequent (consistent with on-target effects), they were reversible and effectively managed with prophylaxis, resulting in no treatment discontinuations due to ocular toxicity. Notably, TRAEs typically associated with payload shedding were characterized by low incidence, with peripheral neuropathy reported in 11.3% of patients (no Grade ≥3) and rash in 20.7% (2.0% Grade ≥3), which compared favorably to historical data of other MMAE-based ADCs. Furthermore, no Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis reported. In 85 efficacy-evaluable aUC patients across all tested doses, the objective response rate (ORR) was 37.6% (95%CI 27.4-48.8) and disease control rate (DCR) was 77.6% (95%CI 67.3-86.0), with a median duration of response of 6.2 months (95%CI 4.3-10.4) and median overall survival of 13.2 months (95%CI 10.6-14.9). At the RP2D (n=39), the ORR reached 41.0% (95%CI 25.6-57.9). Encouragingly, in heavily pretreated patients with prior MMAE-based ADC exposure (n=25), SYS6002 maintained activity with an ORR of 24.0% (95%CI 9.4-45.1) and DCR of 72.0% (95%CI 50.6-87.9), suggesting potential to overcome resistance. Conclusions: SYS6002 demonstrated a distinct safety profile from other Nectin-4 ADCs. Its promising efficacy in aUC patients, extending to those progressing on prior MMAE-based ADCs, supports further phase 3 trials. Clinical trial information: ChiCTR2200066256.