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

Cancer Discov. 2018 Jun;8(6):696-713. doi: 10.1158/2159-8290.CD-17-1260. Epub 2018 Feb 15.


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.Significance: This paper highlights the role of EGFR inhibitors in EGFR-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. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Cell Line, Tumor
  • Cetuximab / administration & dosage*
  • Cetuximab / therapeutic use
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Disease-Free Survival
  • ErbB Receptors / genetics
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / therapeutic use
  • Gene Amplification*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intention to Treat Analysis
  • Leucovorin / administration & dosage
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / therapeutic use
  • Prospective Studies
  • Response Evaluation Criteria in Solid Tumors
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • Organoplatinum Compounds
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab
  • Leucovorin
  • Fluorouracil
  • depatuxizumab
  • Camptothecin

Supplementary concepts

  • Folfox protocol
  • IFL protocol