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Ref Type Journal Article
PMID (29449271)
Authors Maron SB, Alpert L, Kwak HA, Lomnicki S, Chase L, Xu D, O'Day E, Nagy RJ, Lanman RB, Cecchi F, Hembrough T, Schrock A, Hart J, Xiao SY, Setia N, Catenacci DVT
Title Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ABT-806 ABT-806 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ABT-806 Depatuxizumab EGFR Antibody 55 Depatuxizumab (ABT-806) is a monoclonal antibody that binds to the epitope of EGFR vIII and amplified EGFR, but not wild-type EGFR, and may result in anti-tumor activity (PMID: 25731184, PMID: 29449271).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References