Neratinib In Combination With Chemotherapy/Trastuzumab/Pembrolizumab In HER2 Gastroesophageal Cancer

This study tests whether adding neratinib (a targeted oral drug) to the standard treatment of chemotherapy, trastuzumab (Herceptin), and pembrolizumab (an immunotherapy) improves outcomes in patients with HER2-positive esophageal, stomach, or gastroesophageal junction cancer. **You may be eligible if...** - You have confirmed HER2-positive esophageal, gastric, or gastroesophageal junction cancer - You have not received chemotherapy for metastatic (stage IV) disease, or you received prior adjuvant therapy more than 6 months ago - You have measurable cancer visible on scans - Your heart function (ejection fraction) is normal - Your ECOG performance status is 0 or 1 (fully active or restricted only in strenuous activity) **You may NOT be eligible if...** - You have active cancer spread to the brain - You have an active autoimmune disease that required systemic treatment in the past 2 years - You have significant chronic diarrhea or serious gastrointestinal disease - You have had a COVID-19 infection in the last 90 days - You have significant heart disease (heart failure, arrhythmia, or heart attack in the last 6 months) - You are pregnant or breastfeeding Talk to your doctor to see if this trial is right for you.