Phase II trial of SYS6010, an EGFR antibody-drug conjugate (ADC) in patients with advanced esophageal squamous cell carcinoma (ESCC).

4047 Background: SYS6010 is an EGFR- ADC composed of an EGFR-specific antibody, a cleavable linker, and the topoisomerase I inhibitor (TOPOi) JS-1. Preliminary clinical data from the phase I study of SYS6010 monotherapy in patients with solid tumors showed an acceptable safety and encouraging preliminary efficacy (ChiCTR2300072141). Here, we report the efficacy and safety results of SYS6010 in patients with ESCC in the phase II trial. Methods: Patients with advanced ESCC that was refractory or intolerant to standard therapy were enrolled. In the dose-expansion part, SYS6010 was administered intravenously at a dose of 3.6 mg/kg every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) assessed by the investigator. Results: As of Jan 14, 2026, 48 patients with ESCC (median age, 64.5 years; male, 89.6%; ECOG PS 1, 87.5%; metastatic disease, 93.8%) were enrolled and received SYS6010. Ten patients (20.8%) had received ≥3 prior lines of systemic therapy. The median follow-up was 3.9 months (mo; Q1-Q3: 3.1-5.6). Among 40 efficacy-evaluable patients, the confirmed ORR (cORR) was 35% (95%CI 20.6-51.7), and the disease control rate (DCR) was 67.5% (95%CI 50.9-81.4). Median progression-free survival (mPFS) was 4.6 mo (95% CI, 2.7–NR; 48% maturity). The 3-mo and 6-mo PFS rates were 56.3% and 41.4%, respectively. 15 patients remain on treatment with SYS6010. For TOPOi-naïve patients (n = 34), cORR and DCR were 41.2% (95%CI 24.7-59.3) and 70.6% (95%CI 52.5-84.9), respectively. mPFS was 4.6 mo (95%CI 2.8-NR; 45% maturity), with 3-mo and 6-mo PFS rates of 62.5% and 43.2%, respectively. 14 patients remain on treatment with SYS6010. Overall, 97.9% (47/48) of patients experienced treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 31 (64.6%) patients. Common grade ≥3 TRAEs (≥5%) included neutropenia (29.2%), anemia (18.8%), leukopenia (18.8%), thrombocytopenia (12.5%), lymphocytopenia (8.3%), vomiting (8.3%), and nausea (6.3%). TRAEs led to treatment discontinuation in 4 (8.3%) patients. One death of unknown reason was reported and assessed by the investigator as related to the study drug. Conclusions: SYS6010 demonstrated a manageable safety profile and promising antitumor activity, supporting further development in patients with advanced ESCC, especially TOPOi-naïve patients. A phase 3 study is planned to compare SYS6010 with standard of care (SOC) in patients with TOPOi-naïve ESCC. Clinical trial information: ChiCTR2500099933.