Background: Despite attempts, no HER2-directed therapies have been approved for gastric or GEJ cancer after disease progression on trastuzumab. [Fam-] trastuzumab deruxtecan (T-DXd, DS-8201a) is a novel HER2-targeted antibody-drug conjugate composed of a humanized monoclonal antibody specifically targeting HER2, a cleavable tetrapeptide-based linker (drug-to-antibody ratio of ≈8), and a potent topoisomerase I inhibitor payload. In a phase 1 study, T-DXd (5.4 or 6.4 mg/kg) showed promising antitumor activity in a variety of tumor types, including a confirmed objective response rate (ORR) of 43% among subjects with extensively pretreated HER2-positive gastric cancer (Shitara et al. Lancet Oncol. 2019;20(6):827-836). Here we describe the phase 2 trial evaluating the efficacy and safety of T-DXd in subjects with HER2-positive gastric/GEJ cancer previously treated with trastuzumab (NCT04014075). Methods: This is a single-arm, open-label, multicenter, phase 2 study in subjects with centrally confirmed, HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive), unresectable or metastatic gastric/GEJ cancer that progressed on or after first-line therapy with a trastuzumab-containing regimen. HER2 status will be confirmed by a fresh biopsy before enrollment. Subjects are excluded if they received anticancer therapy after a first-line trastuzumab-containing regimen. The study began in August 2019 and will recruit ≈ 72 subjects from 25 to 30 sites in North America and Europe. T-DXd at 6.4 mg/kg will be administered intravenously once every 3 weeks until disease progression. The primary efficacy endpoint is confirmed ORR by independent central review (ICR) using RECIST v1.1 criteria. Secondary endpoints include duration of response and progression-free survival by ICR and investigator assessment, ORR by investigator assessment, and overall survival. Additional endpoints include safety, disease control rate, and pharmacokinetic analyses. Health-related quality of life will also be measured. Clinical trial information: NCT04014075