Dr. Janjigian reviews KEYNOTE-811, and how it led to the FDA approval of pembrolizumab for HER2-positive gastric cancers. Drs. Stephen Liu and Benjamin Weinberg continue their discussion on the safety of zenocutuzumab in NRG1 fusion+ PDAC. Drs. Stephen Liu and Benjamin Weinberg elaborate on the prevalence of NRG1 gene fusions in PDAC. Low-dose aspirin halved recurrence in resected PIK3CA-mutated colorectal cancer, per data from the ALASCCA trial. Dr. Michael Foote breaks down the CheckMate 8HW trial and supports dual immunotherapy as a first-line option in dMMR CRC. Dr. Foote discusses the BREAKWATER trial and the impact of BRAF-targeted therapy in metastatic colorectal cancer. Dr. Kim discusses how ctDNA compares to traditional imaging and how findings can affect adjuvant treatment decisions for BTC. Dr. Eng discusses the rising global incidence of early-onset CRC, as highlighted in a recent Lancet Oncology publication. Dr. Cytryn shares insights on the implications of recent data from the DESTINY-Gastric04 and MATTERHORN trials. Dr. Albiges shares her thoughts on the FDA approval of subcutaneous nivo in gastric cancer and how it will impact practice. Challenges in designing and conducting clinical trials for patients with metastatic pancreatic ductal cancer are discussed. The efficacy and safety of MEK inhibitors are compared to chemotherapy and other targeted therapies. The KRAS G12R mutation is analyzed against other alterations in pancreatic adenocarcinoma, and research findings are shared. Dr. Cytryn summarizes a trial in progress investigating a novel immunotherapy combination for gastroesophageal adenocarcinoma Drs. Finn and Yopp discuss the challenges of defining high-risk patient populations in adjuvant therapy trials for HCC. Nivolumab plus ipilimumab provided a higher OS and ORR rate, supporting the combination as a potential standard of care. The combination was shown to provide a 71% response rate, pointing to a new potential treatment for this patient population. With an OS rate of about 80%, encorafenib and cetuximab with FOLFOX may serve as a new FDA-approved frontline regimen. The panel discusses considerations around treating peritoneal gastric cancer, including the role of HIPEC. In part three of their discussion, the panel explores the role of ADCs in treating gastric and esophageal cancers.