An open label phase 2 study of total neoadjuvant therapy (TNT) consisting of FLOT with pembrolizumab and short radiation for patients with locally advanced gastroesophageal junction adenocarcinoma (EPOC2301).

TPS464 Background: Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the standard of care for resectable upper gastrointestinal adenocarcinoma, based on the FLOT4 and ESOPEC trials. The phase III MATTERHORN trial further demonstrated that adding durvalumab to FLOT (D-FLOT) improves event-free survival (EFS) in patients with resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. While effective, surgical resection remains necessary for all patients and is associated with substantial postoperative morbidity and impaired quality of life (QOL). Notably, D-FLOT achieved a pathological complete response (pCR) in approximately 20% of patients, raising the possibility that some may be cured without surgery. Increasing the rate of clinical complete response (cCR) through intensified total neoadjuvant therapy—including the addition of short-course radiation—may enable organ preservation and non-operative management in carefully selected patients. Methods: EPOC2301 is a multi-center, open-label phase II trial evaluating TNT comprising FLOT plus pembrolizumab and short-course radiotherapy in patients with resectable GEJ adenocarcinoma (Siewert type I–III, cT≥2 and/or N+, M0). Patients receive two cycles of FLOT and two dose of pembrolizumab, followed by 25 Gy radiotherapy, then two more cycles of FLOT and one dose of pembrolizumab. Response is assessed by CT, PET-CT, endoscopy with bite-on-bite biopsy, and tumor-informed whole-genome-based circulating tumor DNA analysis. Patients achieving cCR or near-cCR continue non-operative management with pembrolizumab (Q3W ×14) and FLOT (Q2W ×4). Those without adequate response undergo surgery followed by adjuvant pembrolizumab and FLOT. The primary endpoint is EFS. With an expected EFS of 70% (threshold 46%, one-sided α=10%, power 80%), the planned sample size is 26 patients. Secondary endpoints include organ-sparing survival, overall survival, pathological responses, ctDNA clearance rate, TNT completion rate and QOL. Enrollment began in July 2025. The trial is funded by MSD and registered at ClinicalTrials.gov (NCT07018570). Clinical trial information: NCT07018570 .