Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. DESTINY-Gastric01 study showed significantly higher objective response rate with T-DXd than physician's choice of chemotherapy (51.3%, vs. 14.3%, Shitara K, et al. NEJM 2020) as well as prolonged overall survival (median 12.5 vs. 8.4 months, hazard ratio 0.59). Considering that high response rate or major pathological response (MPR), which is defined as the proportion of subjects with < 10% residual tumor may be associated with favorable survival outcomes after preoperative chemotherapy, T-DXd could be a promising neoadjuvant treatment for patients with gastric and gastroesophageal junction (GEJ) cancer. However, to our knowledge, there is no currently ongoing study of T-DXd as a neoadjuvant setting for patients with gastric and GEJ cancers. Methods: This is an open-label, single-arm, multicenter, investigator initiated phase 2 trial to evaluate antitumor activity of T-DXd as the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma. Eligible patients should have previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort will enroll patients with HER2 overexpression defined as immunohistochemistry （IHC）3+ or IHC2+/ in situ hybridization（ISH）+ by local assessment. According to the results of exploratory biomarker analysis of DESTINY-Gastric01 study (Shitara K, et al. ESMO-GI2021), patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with HER2-extra cellular domein (ECD) higher than 11.6 ng/ml also will be enrolled into the exploratory cohort. Patients will receive 3 cycles of T-DXd (6.4mg/kg) by intravenous infusion every 3 weeks followed by surgery at 3 to 8 weeks after last T-DXd infusion.The primary endpoint is MPR rate. The threshold in the main cohort is defined as 20%, and the expected MPR rate was set at 45%. The minimum sample size of this trial is 23 patients in the main cohort (α- and β-error probabilities, 0.1 and 0.15, respectively). Total number of patients will be increased up to 27 patients depending on the enrollment. In addition, 10 patients will be recruited into the exploratory cohort. Secondary endpoints are pathologic complete response (pCR) rate, curative resection rate, and adverse event rate. Biomarker analyses including whole exome sequencing, RNA sequencing, proteomics, and ctDNA changes will also be conducted using pre- and post-treatment tumor and blood samples. Enrollment is ongoing at six sites in Japan from November 2021. Clinical trial information: NCT05034887.