Background: Gastric and gastroesophageal junction cancers (GC, GEJC) are the fifth most common cancer types and the third leading cause of cancer-related deaths globally (Globocan 2020). Standard of care for resectable GC/GEJC includes neoadjuvant-adjuvant FLOT chemotherapy (5-fluorouracil + leucovorin + oxaliplatin + docetaxel) combined with surgery and lymph node dissection for some regions of the world. While treatment advances have improved survival, the 5-year recurrence rate remains high and 5-year overall survival (OS) is poor for patients with resectable disease. Evidence suggests cytotoxic chemotherapy can promote antitumor immunity, thus the combination of immune checkpoint inhibitors, such as durvalumab (an anti–PD-L1 antibody), with cytotoxic chemotherapy may result in increased efficacy (Yu et al. Cancer Lett. 2019; Li et al. Mol Cancer. 2021). MATTERHORN (NCT04592913) is a phase 3, multicenter study evaluating the efficacy and safety of neoadjuvant-adjuvant durvalumab or placebo with FLOT followed by adjuvant durvalumab or placebo in patients with resectable GC/GEJC. Methods: Approximately 900 adult patients will be randomized 1:1 to Arm A or Arm B for 2 neoadjuvant and 2 adjuvant cycles (single cycle defined as durvalumab or placebo every 4 weeks [Q4W] + FLOT [Q2W × 2]); followed by durvalumab or placebo Q4W for 10 cycles. Eligible patients must have histologically confirmed, resectable, stage II or higher GC or GEJC not treated with anticancer therapy, ECOG performance status 0 or 1, and adequate organ function. Complete surgical resection of the primary tumor must be achievable. A tumor tissue sample will be taken at screening or <3 months prior to enrollment. Key exclusion criteria are any prior immune-mediated therapy, peritoneal dissemination or distant metastasis, (adeno)squamous cell carcinoma, or gastrointestinal stromal tumor. The primary endpoint is event-free survival (EFS) assessed by blinded independent central radiology review (BICR) and/or local pathology testing. Secondary endpoints include OS and pathological complete response rate (pCR). Safety and tolerability will be evaluated by adverse events, vital signs, laboratory parameters, and electrocardiogram. Enrollment is ongoing. Funding: AstraZeneca. Clinical trial information: NCT04592913