4048 Background: Cadonilimab (AK104), an anti-PD-1/CTLA-4 bispecific antibody, plus chemotherapy significantly improved OS versus chemotherapy and had a tolerable safety profile in first-line (1L) treatment of advanced G/GEJA patients (pts), including those with low PD-L1 expression. Currently, it has been approved by NMPA. Ivonescimab (AK112), also approved in China, is a novel bispecific antibody against PD-1 and VEGF and has shown a clinically significant improvement in efficacy with favorable safety for advanced NSCLC in two phase 3 studies (HARMONi-2 and HARMONi-A). Here, we presented the updated data for the safety and efficacy of AK104 combined with AK112 and chemotherapy as 1L treatment in advanced G/GEJA. Methods: Pts with previously untreated advanced G/GEJA were enrolled. The phase II trial consisted of a dose-escalation part (part 1) and a dose expansion part (part 2). Eligible pts were firstly enrolled into sequential part1 including 10mg/kg and 15mg/kg AK104 (Q6W, D8) combined with AK112 (20mg/kg, Q3W, D1) and chemotherapy (SOX or XELOX) following the conventional 3+3 design. If the starting dose of 10mg/kg AK104 led to ≥2 dose-limiting toxicities (DLTs), 6mg/kg AK104 would be administered. After the part 1 completed, eligible pts were enrolled into the part 2 and received AK104 (the recommended dose, Q6W, D8) combined with AK112 (20 mg/kg, Q3W, D1) and chemotherapy (SOX or XELOX). The primary outcomes were safety and ORR. Secondary endpoints included DCR, PFS, OS, biomarkers of drug activity and pharmacokinetics. Results: As of 19 January 2026, 54 pts were enrolled with a median age of 60 years (range: 39-75). 55.6% were PD-L1 CPS＜5, 42.6% had liver metastases and 40.7% had peritoneal metastases. Among efficacy evaluable pts, the ORR was 71.7% and DCR was 95.7%. The median PFS (mPFS) was 8.4 months (mo) (95%Cl: 6.0-13.1) and OS analysis was immature. In the pts with liver metastases, the ORR was 81.8%, DCR was 90.9% and mPFS was 10.7 mo (95%Cl: 5.7-13.1). In the pts with peritoneal metastases, the ORR was 72.2%, DCR was 100.0% and mPFS was 6.4 mo (95%Cl: 5.45-NR). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 18.5% pts, mainly including hypokalemia (5.6%), decreased neutrophil count (3.7%), decreased platelet count (3.7%) and hyperbilirubinemia (3.7%). There were no grade 4/5 TRAEs or treatment-related deaths. Conclusions: Updated results demonstrated that AK104 combined with AK112 and chemotherapy as 1L treatment continued to show highly encouraging anti-tumor activity with a manageable safety profile in pts with advanced G/GEJA, including those with liver or peritoneal metastases. Clinical trial information: NCT06196697 .
Wang et al. (Wed,) studied this question.