First-in-human trial of SYS6010 combined with SYH2051 in patients with advanced gastrointestinal tumors.

3037 Background: SYS6010 is an antibody-drug conjugate (ADC) composed of an EGFR-specific antibody, a cleavable linker, and JS-1, a topoisomerase I inhibitor, as its cytotoxic payload. It targets EGFR, a transmembrane receptor tyrosine kinase overexpressed in malignancies such as lung, breast, gastric, and colorectal cancers. SYS6010 induces DNA damage leading to apoptosis, while resistance may occur through ATM-mediated DNA repair. SYH2051, an ATM inhibitor, disrupts DNA repair, enhancing SYS6010-induced apoptosis. This combination is hypothesized to exert synergistic anti-tumor effects. Methods: This first-in-human clinical trial employed a single-center, open-label, non-randomized design to evaluate the safety, tolerability, and preliminary efficacy of SYS6010 combined with SYH2051. Patients with advanced gastrointestinal tumors expressing EGFR who had progressed on at least one prior line of standard therapy were enrolled. SYS6010 was administered intravenously at a dose of 3.2 mg/kg on day 1 of each 14-day cycle, while SYH2051 was given orally at doses of 40 mg or 80 mg, once daily, for five consecutive days within the same cycle. Safety was assessed using CTCAE v5.0, and efficacy was evaluated according to RECIST v1.1 criteria. Results: As of December 31, 2024, 25 patients were enrolled, including 18 with colorectal cancer and 7 with gastric cancer. Twelve patients had received ≥3 prior lines of therapy. Among 6 evaluable gastric cancer patients, 3 achieved partial response (PR) and 3 stable disease (SD), resulting in an objective response rate (ORR) of 50% and a disease control rate (DCR) of 100%. The median progression-free survival (PFS) was approximately 5.8 months (data not mature), and 3 patients remained on treatment. Among 18 colorectal cancer patients (9 with KRAS mutations and 9 wild-type), preliminary analysis showed a median PFS of approximately 4.2 months in wild-type KRAS patients (data not mature). Common treatment-related adverse events (TRAEs) included hematologic toxicity, gastrointestinal symptoms, and fatigue. Frequently observed TRAEs were fatigue (60%), decreased appetite (56%), leukopenia (56%), anemia (48%), neutropenia (48%), nausea (48%), thrombocytopenia (36%), and hypoalbuminemia (32%). Grade ≥3 TRAEs occurred in 12 patients (48%), including neutropenia (7 patients), anemia (6 patients), thrombocytopenia (3 patients), vomiting (3 patients), leukopenia (2 patients), interstitial lung disease (1 patient), infection (1 patient), and elevated bilirubin (1 patient). No treatment-related deaths were reported. Conclusions: SYS6010 combined with SYH2051 was well tolerated and demonstrated preliminary antitumor activity in advanced gastrointestinal tumors, particularly in gastric cancer. Further evaluation is ongoing.