Background: For HER2-positive (IHC 2+/FISH-, IHC 3+) advanced gastric cancer/gastroesophageal junction cancer (GC/GEJ), trastuzumab in combination with chemotherapy is the standard first-line treatment. Adding pembrolizumab to trastuzumab and chemotherapy significantly improves objective response rate. However, the overall survival results did not meet statistical significance. DV, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE) via a cleavable linker. We aimed to evaluate DV combined with toripalimab and chemotherapy/ trastuzumab as first-line treatment for HER2-expressed (IHC 1+, 2+ or 3+) locally advanced or metastatic GC/GEJ. Methods: This is a randomized, seamless phase II/III trial. Key eligibility criteria include participants confirmed GC/GEJ and systemic treatment naïve. In phase II period, participants will be divided into two cohorts. Ninety participants with HER2-positive (IHC2+ FISH+ or IHC3+) will be randomly (1:1:1) assigned to receive DV every 2 weeks (Q2W) plus toripalimab Q2W and oxaliplatin and capecitabine (CAPOX) every 3 weeks (Q3W), or DV plus toripalimab and trastuzumab Q3W, versus toripalimab plus trastuzumab and CAPOX. Forty participants with HER2-low (IHC1+ or IHC2+/FISH-) will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX, versus toripalimab and CAPOX. In phase III period, HER2-positive participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX or trastuzumab versus CAPOX plus trastuzumab±anti-PD-1 antibody, based on results from phase II, and evolution of treatment landscape. HER2-low participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX versus CAPOX±anti-PD-1 antibody based on evolution of stand of care. The primary endpoint is PFS by IRC in PD-L1 CPS ≥5 population. To the best of our knowledge, this is the first Phase III clinical trial exploring the combination of anti-HER2 ADC with trastuzumab and chemotherapy in first-line GC/GEJ. This trial began in August 2023 and has enrolled 4 patients at the time of submission. Clinical trial information: NCT05980481.