Neratinib and Fam-Trastuzumab Deruxtecan in Advanced Gastro-esophageal Cancer Patients

This study tests combining neratinib and fam-trastuzumab deruxtecan (two HER2-targeted drugs) for people with advanced HER2-overexpressing gastrointestinal cancers (including esophageal, stomach, colon, bile duct, or pancreatic cancers). **You may be eligible if...** - You have confirmed advanced or metastatic gastrointestinal cancer with HER2 overexpression (a protein overabundance on tumor cells) - For gastroesophageal cancers: you have already received at least one prior HER2-targeted treatment - Your cancer can be measured by imaging - You are well enough to participate (adequate organ function) **You may NOT be eligible if...** - Your tumor does not overexpress HER2 - You have not yet tried required prior treatments (for GE junction cancer) - You have uncontrolled heart disease, significant lung problems, or severe liver dysfunction - You are pregnant or breastfeeding Talk to your doctor to see if this trial is right for you.