Practice-Changing Trials in Gastrointestinal Cancers at ASCO 2025: A Critical Review and Clinical Context

The ASCO 2025 meeting featured several phase III trials with the potential to impact gastrointestinal cancer management. CheckMate 577 reported mature overall survival (OS) data for adjuvant nivolumab in esophageal/GEJ cancer; however, OS benefit was not statistically significant in the intent-to-treat population and appeared restricted to PD-L1-positive tumors. MATTERHORN demonstrated significant improvements in event-free survival and OS with perioperative durvalumab plus FLOT in gastric/GEJ cancer. In stage III dMMR colon cancer, ATOMIC supported adjuvant atezolizumab plus chemotherapy, though questions persist about chemotherapy necessity and neoadjuvant immunotherapy. For advanced disease, BREAKWATER established encorafenib-based triplet therapy as first-line standard for BRAF V600E-mutant metastatic colorectal cancer, while DESTINY-Gastric04 confirmed trastuzumab deruxtecan as superior second-line therapy for HER2-positive gastric cancer, mandating re-biopsy. Given the great interest in circulating tumor DNA, we integrate the ESMO 2025 DYNAMIC-III trial, demonstrating ctDNA-guided de-escalation reduces toxicity with outcomes approaching standard care. These advances mandate comprehensive biomarker testing while highlighting persistent evidence gaps.