Background: Anti-PD-1 monoclonal antibodies plus chemo as first-line therapy for advanced G/GEJ cancer yields OS and PFS benefits compared to chemo alone while the survival benefits are limited, especially in patients with low PD-L1 expression (CPS<5). Simultaneous blockade of the PD-1 and CTLA-4 pathways has shown synergistic anti-tumor activity and has been proven effective across multiple cancer types. This phase Ib/Ⅱ dose-escalation study evaluated the safety and efficacy of AK104, a PD-1/CTLA-4 bispecific antibody, combined with XELOX or modified XELOX (mXELOX) in the first-line treatment of G/GEJ cancer cohorts (NCT03852251). Methods: Pts with unresectable advanced G/GEJ adenocarcinoma and no prior systemic therapy, regardless of PD-L1 status, were enrolled, excluding known HER2-positive pts. Enrolled patients received AK104 (4 mg/kg, 6 mg/kg or 10 mg/kg Q2W, 10 mg/kg or 15mg/kg Q3W) + chemo (mXELOX Q2W or XELOX Q3W). The primary endpoint was safety and the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 31 Oct. 2022, 98 pts were enrolled with only 4 pts in 10 mg/kg Q3W, the safety and efficacy of the regimen of 10mg/kg Q3W will be reported in the phase III study and not be reported here. 94 pts were enrolled with median age of 62.7 years (range: 29–75), 70.2% male, 62.8% ECOG PS 1, and 45.7% liver metastasis. The median follow-up was 24.0 months (range: 0.5-33.3). 88 patients (94%) had at least one post-baseline tumor evaluation. The ORR was 68.2% (60/88), with 5 (5.7%) complete responses and 55 (62.5%) partial responses. The disease control rate (DCR) was 92.0% (81/88). The median duration of response (DoR) was 9.69 months (95%CI, 5.82 to 14.00). The median PFS was 9.20 months (95%CI, 6.67 to 10.48). The median OS was 17.41 months (95%CI, 12.35 to 29.77). In pts with PD-L1 CPS≥5 and CPS＜5, the median OS was 20.24 months and 17.28 months, respectively. Treatment-related adverse events (TRAEs) occurred in 97.9% of pts. The most frequent were platelet count decreased (62.8%), white blood cell count decreased (61.7%), neutrophil count decreased (59.6%), anemia (51.1%), aspartate aminotransferase increased (33.0%), nausea (30.9%), and vomiting (30.9%). Grade ≥3 TRAEs occurred in 69.4% of pts. No new safety signals were identified. Conclusions: AK104, combined with mXELOX/XELOX, showed promising activity and manageable safety in previously untreated patients with advanced G/GEJ adenocarcinoma. AK104 + chemo represents a potential new first-line treatment option for these pts. A phase III study of AK104 combined with chemo as first-line therapy for G/GEJ cancer is underway (NCT05008783). Clinical trial information: NCT03852251.