Efficacy, safety and DNA methylation analysis of cadonilimab combined with taxane and cisplatin as the first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC): An open-label, multicenter phase II trial– Updated results from AK104-IIT-014.

e16064 Background: Immune checkpoint inhibitors combined with chemotherapy has become the current first-line standard treatment for advanced ESCC, while still having a lot of room for improvements in objective responses and survival. Cadonilimab, a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumour activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of Cadonilimab combination therapy as the first-line treatment in advanced ESCC. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were eligible for inclusion. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m 2 , iv, d1, q3w) and cisplatin (65 to 75 mg/m 2 , iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for DNA methylation level sequencing. Results: At updated analysis (cut-off: February 5, 2024), 35 pts were enrolled with a median age of 61 years (range 44-75), 82.9% were male, 57.1% had PD-L1 CPS<10 and 88.6% had distant metastases. In the efficacy-evaluable population (n = 29), 5 pts reached complete response (CR), 21 pts had partial response (PR) and 3 pts had stable disease (SD). The ORR was 89.7% (95%Cl: 71.5%-97.3%) and the DCR was 100.0% (95%Cl: 85.4%-100.0%). Among evaluable pts with PD-L1 CPS≥10 and PD-L1 CPS<10, the ORR were 100.0% (12/12) and 81.3% (13/16), respectively. SEPT9 methylation was significantly higher in patients with CR or PR compared to patients with SD (33.28% vs 3.87%, p < 0.001). The median PFS and OS was still not reached. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 9 (25.7%) pts. The most common TRAEs were neutropenia (17.1%), leukopenia (5.7%) and hyponatremia (5.7%). Immune-related adverse events were observed in 9 pts (25.7%). Three pts (8.6%) suffered from serious adverse events, and no grade 5 TRAEs or death were observed. Conclusions: The updated results suggested that bispecific antibody AK104 combined with taxane and cisplatin as first-line treatment showed promising anti-tumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Follow-up is ongoing for survival analysis. Clinical trial information: NCT05522894 .