First-in-human study of SYS6043, a novel B7-H3–targeting antibody-drug conjugate, in patients with advanced pan-tumor malignancies.

Abstract

3002 Background: B7-H3, a tumor-associated immune checkpoint, is broadly overexpressed in multiple solid tumors and associated with aggressive disease biology and treatment resistance. SYS6043, a novel ADC targeting B7-H3, is designed to selectively deliver a cytotoxic payload to B7-H3 expressing tumors. Preclinical trials showed potent antitumor activity across diverse solid tumor models. Here, we report safety and efficacy results from a phase 1/2 trial of SYS6043 in patients with advanced solid tumors. Methods: Eligible patients (18–75 years) had advanced solid tumors refractory to or progressing after standard therapies. The study included a phases 1 dose-escalation and PK expansion phase, followed by a phase 2 cohort expansion. Phase 1 used a BOIN design to evaluate SYS6043 at a dose of 1.2-10.0 mg/kg Q3W and 4.0-6.0 mg/kg Q2W, with PK expansion at selected doses. Phase 2 evaluated SYS6043 at 8.0 mg/kg Q3W and 6.0 mg/kg Q3W and Q2W across tumor-specific cohorts. Primary endpoints were safety, tolerability, and determination of the RP2D in Phase 1, and objective response rate (ORR) in Phase 2. Results: As of November 28 2025, 502 patients were enrolled, including ovarian cancer (OC, n = 68), small cell lung cancer (SCLC, n = 57), breast cancer (BC, n = 55), cervical cancer (CC, n = 42), nasopharyngeal carcinoma (NPC, n = 40), non-squamous non-small lung cancer (nsq-NSCLC, n = 34), endometrial cancer (EC, n = 21), and other solid tumors ( n = 185). Dose-limiting toxicities (grade 3 gastrointestinal disease, and grade 4 febrile neutropenia) occurred at 10.0 mg/kg Q3W. Treatment-related adverse events (TRAEs) occurred in 94.2% of patients, with ≥grade 3 TRAEs in 28.5%. The most common TRAEs were anemia (52.0%), nausea (44.4%), fragile (42.8%), leukemia (41.6%), neutropenia (36.9%), decreased appetite (35.3%), and hypoalbuminemia (25.3%). Efficacy analyses focused on Q3W cohorts. SYS6043 demonstrated rapid and deep antitumor activity across multiple tumor types. In heavily pretreated SCLC ( n = 50), ORR was 64.0% (95% CI, 49.2-77.1) with DCR of 92.0% (95% CI, 80.8-97.8). At 6 mg/kg Q3W ( n = 28), ORR reached 75.0% (95% CI, 55.1-89.3), including one complete response. In OC, ORR and DCR were 46.2% and 87.2%, respectively with median PFS of 5.6 months at 6 mg/kg Q3W. Notably high response rates were also observed in BC (ORR 83.8%, DCR 100%), nsq-NSCLC (ORR, 57.1%), CC (ORR, 38.5%), NPC (ORR, 37.9%), and EC (ORR, 30.0%), indicating broad and consistent antitumor activity. Conclusions: SYS6043 demonstrated a manageable safety profile and robust, cross-tumor antitumor activity in a large population of patients with advanced solid tumors. The magnitude and consistency of responses across multiple histologies, including treatment-refractory tumors such as SCLC, support SYS6043 as a promising therapeutic candidate warranting further clinical and translational investigation. Clinical trial information: ChiCTR2400094683.