Background: Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. A phase 2 study demonstrated remarkable clinical activity of lenvatinib plus pembrolizumab for advanced gastric cancer with objective response rate of 69% (Kawazoe A, et al. Lancet Oncol. 2020), leading to the global phase 3 LEAP-015 trial at first-line (NCT04662710). The objective of this study is to evaluate anti-tumor activity of lenvatinib with pembrolizumab as neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma. Methods: The study is an open-label, single-arm, single-center, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Patients will receive 3 cycles of 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of lenvatinib plus pembrolizumab followed by 11 cycles of pembrolizumab monotherapy as the adjuvant treatment. The primary endpoint is major pathological response rate, and the secondary endpoints are pathological complete response rate, tumor shrinkage effect on primary lesions, radical resection rate, treatment completion rate until surgery or adjuvant treatment, event-free survival, overall survival, and incidence of adverse events. We also investigate several biomarkers using pre- and post-treatment tumor and blood samples. First patient will be enrolled in November 2021. Clinical trial information: NCT04745988.