Background: Gastric or gastroesophageal junction (GEJ) cancers are usually diagnosed at advanced stages with poor prognoses and 5-year survival rates. Standard-of-care first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic disease is chemotherapy and trastuzumab, plus pembrolizumab for programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] tumors. Trastuzumab deruxtecan (T-DXd) 6.4 mg/kg monotherapy is approved as second-line treatment for patients with HER2-positive gastric or GEJ cancer. DESTINY-Gastric03 (NCT04379596) showed that first-line T-DXd 5.4 mg/kg plus chemotherapy with or without pembrolizumab in the advanced setting had manageable safety and promising efficacy in HER2-positive gastric or GEJ cancer. Aim: To investigate a first-line T-DXd plus platinum-free chemotherapy with pembrolizumab treatment approach for patients with HER2-positive gastric or GEJ cancer. Trial design: DESTINY-Gastric05 (NCT06731478) is a global, multicenter, open-label, randomized, phase III trial to evaluate the efficacy and safety of first-line T-DXd 5.4 mg/kg plus 5-fluorouracil or capecitabine and pembrolizumab versus platinum-based chemotherapy with trastuzumab and pembrolizumab in patients with unresectable, locally advanced or metastatic, centrally confirmed HER2-positive (immunohistochemistry 3+ or immunohistochemistry 2+/in situ hybridization positive) gastric or GEJ cancer with a PD-L1 CPS ≥1. An exploratory cohort is to evaluate T-DXd plus 5-fluorouracil or capecitabine in patients with PD-L1 CPS <1.