Background: Anti-PD-1 agent plus chemo as first-line therapy for advanced G/GEJ cancer (Checkmate-649) yields OS and PFS benefits compared to chemo alone, indicating synergistic activity between immune checkpoint inhibitors and chemo. The combination of anti-PD-1 and anti-CTLA-4 has consistently demonstrated higher response rate compared to PD-1 monotherapy but higher toxicity. Here, we performed this phase Ib/II study to evaluate the efficacy and safety of AK104, a PD-1/CTLA-4 bispecific antibody, combined with XELOX (capecitabine combined with oxaliplatin) or modified XELOX (mXELOX) in the first-setting of G/GEJ cancer cohorts. This study is registered on ClinicalTrials.gov (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, 10 mg/kg, Q2W or 10 mg/kg, 15mg/kg Q3W) + chemo (mXELOX Q2W or XELOX Q3W). The primary endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 13 Aug 2021, 96 pts were enrolled with median age 62.7 years (range: 29–75), 70.8% male, 62.5% ECOG PS 1, 44.8% liver metastasis. The median follow-up was 9.95 months (range, 0.4-26.8). 88 patients (92%) had at least one post-baseline tumor evaluation. The ORR was 65.9% (58/88) with 2 (2.3%) complete responses and 56 (63.6%) partial responses. The disease control rate (DCR) was 92.0% (81/88). The median duration of response (DoR) was 6.93 months (95%CI, 4.60 to 11.20). The median PFS was 7.10 months (95%CI, 5.55 to 10.48). The median OS was 17.41 months (95%CI, 12.35 to NE). In pts with PD-L1 CPS≥1 vs CPS＜1, median OS was 17.41 months and 14.65 months, respectively. Treatment-related adverse events (TRAEs) occurred in 97.9% of pts, and the most frequent were platelet count decreased (60.4%), white blood cell count decreased (58.3%), neutrophil count decreased (56.3%), anaemia (47.9%), nausea (30.2%), vomiting (30.2%), aspartate aminotransferase increased (30.2%). Grade ≥3 TRAEs occurred in 62.5% pts. No new safety signals were identified. Conclusions: AK104 in combination with mXELOX/XELOX showed promising activity and manageable safety in previously untreated pts 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. Clinical trial information: NCT03852251.