ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15th, 2019, and March 14th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval CI: 20.7%–57.7%) and the disease control rate is 55.2% (95% CI: 35.7%–73.6%). With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4–6.4) and 10.7 months (95% CI: 4.8–not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1–18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639). Display omitted •ARX788 is an anti-HER2 antibody-drug conjugate with AS269 as cytotoxic payload•ARX788 is well tolerated and has promising anti-tumor activity in this phase 1b study•Mutation rate of ERBB2 was higher in the responders than in the nonresponders Zhang et al. demonstrate the safety, efficacy, and survival of an anti-HER2 antibody-drug conjugate, ARX788, in patients with HER2-positive advanced gastric adenocarcinoma. They show that ARX788 is well tolerated and has promising anti-tumor activities for HER2-positive advanced gastric adenocarcinoma.