Background: Efficacy and prognosis of chemotherapy in first-line setting for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma was dismal currently. PD-1 blockades combined with chemotherapy as first-line regimen exhibited superior efficacy for pts with G/GEJ adenocarcinoma recently, and the efficacy of tumor regression still needs to be improved. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been approved for treatment of considerable malignancies in China. We aimed to investigate the efficacy and safety of TQB2450 (PD-L1 blockade) plus anlotinib combined with CAPEOX (oxaliplatin and capecitabine) as first-line regimen for advanced G/GEJ adenocarcinoma and report the preliminary results timely. Methods: Pts with HER2-negative unresectable locally advanced or metastatic G/GEJ adenocarcinoma who did not expose to previous systemic treatment were recruited in this study. Eligible pts received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with oxaliplatin (130mg/m², d1, iv, q3w) and capecitabine (1000mg/m², po, bid, d1~14, q3w) for 6 cycles as initial therapy. For those without disease progression (PD), maintenance therapy was adopted with TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The calculated sample size was 25. The primary endpoint was ORR, secondary endpoints were DoR, PFS, OS, DCR and safety. Results: From Apr 2021 to Jul 2022, a total of 20 pts were enrolled and available for efficacy evaluation. In best overall response assessment, there were 15 PR (75.0%), 4 SD (20.0%) and 1 NE (5.0%). In consequence, the preliminary ORR was 75.0% (95%CI: 50.9%~91.3%), DCR was 95.0% (95%CI: 75.1%~99.9%). Median PFS of the 20 pts was not yet reached. Furthermore, the most common treatment-emergent adverse events with the incidence >40% were thrombocytopenia (80%), anemia (75%), leukopenia (65%), decreased total protein (45%) and decreased total protein (45%). The common grade ≥3 treatment-emergent adverse events were neutropenia (15%), lymphocyte count decreased (10%), anemia (5%), leukopenia (5%), elevated aspartate aminotransferase (5%) and elevated alkaline phosphatase (5%). Conclusions: Preliminary results suggested that TQB2450 plus anlotinib combined with CAPEOX in first-line setting for advanced G/GEJ adenocarcinoma exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04891900.