Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including -negative clones, deletion, amplification/mutation, , and amplification, and mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3 infiltrate, including one who demonstrated increased NKp46 , and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged. This paper highlights the role of EGFR inhibitors in -amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. .