AACR Adaptive Biomarker-Driven Organ Preservation Trial in Gastroesophageal Adenocarcinomas

This is a two-stage, prospective, multi-center, perioperative, biomarker-driven, open-label study. The trial design consists of a screening phase (Stage I) and a testing phase (Stage II). Stage I: Eligible patients will provide screening consent and research tissue for biomarker assessment. While awaiting results, they may receive one cycle of FLOT or mFOLFOX6. Once a biomarker included in the study platform is identified, patients will sign a second consent and be assigned to the corresponding subgroup. They will continue treatment with the chemotherapy backbone (mFOLFOX6) plus an immune checkpoint inhibitor and a biomarker-targeted agent. Patients who began on FLOT will switch to mFOLFOX6 once a targeted agent is added. If no actionable biomarker is detected, patients will continue standard-of-care therapy off-study. Patients receiving the chemotherapy + immune checkpoint inhibitor + targeted agent combination will complete 4 months of preoperative therapy, followed by surgery and postoperative therapy for a total treatment duration of up to one year. Once 24 patients in a given biomarker subgroup have undergone surgery, continuation to Stage II will depend on meeting predefined efficacy thresholds. Only regimens demonstrating sufficient efficacy will advance. Stage II: Effective therapies identified in Stage I will be further evaluated to establish predictive markers of pathological complete response (pathCR) and identify patients who may safely avoid surgery. Patients will provide tissue for central biomarker testing and may receive a chemotherapy cycle while awaiting results. Once assigned to an eligible biomarker subgroup, they will receive mFOLFOX6 + immune checkpoint inhibitor plus the targeted agent for 4 months. Response will be assessed through clinical, endoscopic, and radiologic evaluation. Patients showing no residual disease after preoperative therapy will forgo surgery and continue maintenance therapy (immune checkpoint inhibitor plus the targeted agent) for an additional 8 months with regular surveillance. Those with residual disease will proceed to surgery, followed by postoperative therapy and follow-up for up to one year.