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

Background: Durvalumab combined with fluorouracil, leucovorin, oxaliplatin, and docetaxel (D-FLOT) has demonstrated significant improvement in event-free survival (EFS) among patients with resectable gastric and gastroesophageal junction adenocarcinoma (GEJA) and is expected to become a new standard of care. Nevertheless, surgical resection remains requisite and is associated with substantial morbidity and deterioration in quality of life for GEJA. Given that D-FLOT achieves a pathological complete response in ∼20% of patients, intensification of total neoadjuvant therapy with short-course radiation (SRT) could further increase clinical CR (cCR) rates and facilitate non-operative management (NOM) in selected GEJA patients. Trial design: EPOC2301 is a single-arm, phase II study evaluating the efficacy and safety of pembrolizumab with FLOT plus SRT as total neoadjuvant therapy for resectable GEJA. Patients receive two cycles of FLOT and one dose of pembrolizumab, followed by 25 Gy radiotherapy, then two more cycles of FLOT and one dose of pembrolizumab. Response is assessed by computed tomography, positron emission tomography-computed tomography, endoscopy with bite-on-bite biopsy, and whole-genome circulating tumor DNA analysis. Patients achieving cCR or near-cCR continue NOM with pembrolizumab and FLOT, whereas those without adequate response undergo surgery followed by adjuvant pembrolizumab and FLOT. The primary endpoint is 3-year EFS.