Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma

Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR 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 EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS 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. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged. (c) 2018 AACR.