SYS6010 combined with SYH2051 in advanced solid tumors: Results from a phase Ib/II trial.

4044 Background: SYS6010 is an antibody-drug conjugate (ADC) composed of an epidermal growth factor receptor (EGFR)-specific antibody, a cleavable linker, and the topoisomerase I inhibitor JS-1. SYH2051 is an ATM inhibitor that disrupts DNA repair. The combination of SYS6010 and SYH2051 has shown preliminary antitumor activity (ASCO 2025) in advanced gastrointestinal tumors, particularly gastric cancer (GC). Here, we report the safety and preliminary efficacy of SYS6010 plus SYH2051 in patients with advanced solid tumors in phase Ⅰb. Methods: This was a multi-center, open-label study. Phase Ⅰb enrolled patients with advanced, EGFR-positive or EGFR-mutant solid tumors, including gastric cancer (GC) with EGFR expression (≥1+) in ≥30% of tumor cells, who were refractory or intolerant to standard treatment. Phase Ⅰb consisted of dose escalation and expansion parts. Dose escalation followed a 3+3 design, exploring SYS6010 at doses of 3.2 mg/kg and 3.6 mg/kg (both Q2W) in combination with SYH2051 at 20 mg, 40 mg, 60 mg, and 80 mg (QD). The primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase Ⅱ dose (RP2D). Results: As of October 31, 2025, a total of 117 patients (median age, 58 years; male, 73.5%; ECOG PS 1, 72.6%; metastasis, 100%) were enrolled. Most common tumor types included gastric cancer (GC, n = 66), colon cancer (n = 24), and rectal cancer (n = 15). One dose-limiting toxicity (grade 4 thrombocytopenia) was reported in the regimen of SYS6010 3.2 mg/kg plus SYH2051 60 mg. The RP2D was determined to be SYS6010 3.6 mg/kg plus SYH2051 40 mg. Overall, 94.0% (110/117) of enrolled patients reported at least one treatment-related adverse event (TRAE). The common TRAEs (≥30%) were anemia (68.4%), leukopenia (50.4%), neutropenia (48.7%), decreased appetite (47.0%), nausea (43.6%), hypoalbuminemia (40.2%), fatigue (39.3%), and thrombocytopenia (33.3%). Grade ≥ 3 TRAEs occurred in 44.4% (52/117) of patients. Treatment discontinuations due to TRAEs were reported in 0.9% (1/117) of patients for SYS6010 and in 0.9% (1/117) for SYH2051. No deaths were reported due to TRAEs. Among all efficacy-evaluable GC patients treated with the RP2D regimen (n = 33), the confirmed objective response rate (cORR) was 15.2%, disease control rate (DCR) was 69.7%, and median progression-free survival (mPFS) was 4.5 mo (95% CI, 2.1–5.7). For the 17 patients receiving RP2D regimen as ≥3rd-line therapy, cORR was 23.5%, DCR was 88.2%, and mPFS was 5.4 mo (95% CI, 2.5–NR). The 3-mo and 6-mo PFS rates were 72.4% and 36.2%, respectively. Overall survival data were immature. Conclusions: The combination of SYS6010 and SYH2051 showed acceptable safety and tolerability in patients with advanced solid tumors. Promising antitumor activity was observed in patients with advanced GC, particularly among those receiving the regimen as ≥3rd-line therapy. Clinical trial information: NCT07104877 .