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Ref Type Journal Article
PMID (30463996)
Authors Sanchez-Vega F, Hechtman JF, Castel P, Ku GY, Tuvy Y, Won H, Fong CJ, Bouvier N, Nanjangud GJ, Soong J, Vakiani E, Schattner M, Kelsen DP, Lefkowitz RA, Brown K, Lacouture ME, Capanu M, Mattar M, Qeriqi B, Cecchi F, Tian Y, Hembrough T, Nagy RJ, Lanman RB, Larson SM, Pandit-Taskar N, Schöder H, Iacobuzio-Donahue CA, Ilson DH, Weber WA, Berger MF, de Stanchina E, Taylor BS, Lewis JS, Solit DB, Carrasquillo JA, Scaltriti M, Schultz N, Janjigian YY
Title EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer.
Journal Cancer discovery
Vol 9
Issue 2
Date 2019 02
URL
Abstract Text The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.See related commentary by Klempner and Catenacci, p. 166.This article is highlighted in the In This Issue feature, p. 151.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
ERBB2 positive esophageal cancer predicted - sensitive Afatinib Phase II Actionable In a Phase II clinical trial, monotherapy with Gilotrif (afatinib) resulted in a moderate clinical benefit in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma, demonstrating a tumor reduction in 25% (5/20) according to RECIST, an objective partial response in 10% (2/20), a median progression-free survival of 2 months, and a median overall survival of 7 months (PMID: 30463996; NCT01522768). 30463996
ERBB2 positive gastric adenocarcinoma predicted - sensitive Afatinib Phase II Actionable In a Phase II clinical trial, monotherapy with Gilotrif (afatinib) resulted in a moderate clinical benefit in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma, demonstrating a tumor reduction in 25% (5/20) according to RECIST, an objective partial response in 10% (2/20), a median progression-free survival of 2 months, and a median overall survival of 7 months (PMID: 30463996; NCT01522768). 30463996
ERBB2 positive gastric adenocarcinoma predicted - sensitive Afatinib + Trastuzumab Phase II Actionable In a Phase II clinical trial, the combination therapy of Gilotrif (afatinib) and Herceptin (trastuzumab) in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma resulted in a partial response in 8% (1/12) and disease control for 4 months or more in 17% (2/12) (PMID: 30463996; NCT01522768). 30463996
ERBB2 positive gastroesophageal junction adenocarcinoma predicted - sensitive Afatinib + Trastuzumab Phase II Actionable In a Phase II clinical trial, the combination therapy of Gilotrif (afatinib) and Herceptin (trastuzumab) in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma resulted in a partial response in 8% (1/12) and disease control for 4 months or more in 17% (2/12) (PMID: 30463996; NCT01522768). 30463996
ERBB2 positive gastroesophageal junction adenocarcinoma predicted - sensitive Afatinib Phase II Actionable In a Phase II clinical trial, monotherapy with Gilotrif (afatinib) resulted in a moderate clinical benefit in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma, demonstrating a tumor reduction in 25% (5/20) according to RECIST, an objective partial response in 10% (2/20), a median progression-free survival of 2 months, and a median overall survival of 7 months (PMID: 30463996; NCT01522768). 30463996
ERBB2 positive esophageal cancer predicted - sensitive Afatinib + Trastuzumab Phase II Actionable In a Phase II clinical trial, the combination therapy of Gilotrif (afatinib) and Herceptin (trastuzumab) in ERBB2 (HER2)-positive patients with either gastroesophageal junction adenocarcinoma, metastatic esophageal cancer, or gastric adenocarcinoma resulted in a partial response in 8% (1/12) and disease control for 4 months or more in 17% (2/12) (PMID: 30463996; NCT01522768). 30463996
ERBB2 amp stomach cancer predicted - sensitive Fluorouracil + Oxaliplatin + Trastuzumab Case Reports/Case Series Actionable In a Phase II clinical trial, a gastric cancer patient with ERBB2 (HER2) amplification demonstrated a response for 24 months when treated with the combination of Adrucil (fluorouracil), Eloxatin (oxaliplatin), and Herceptin (trastuzumab) (PMID: 30463996; NCT01522768). 30463996
ERBB2 amp stomach cancer predicted - sensitive Afatinib + Trastuzumab Case Reports/Case Series Actionable In a Phase II clinical trial, a gastric cancer patient with ERBB2 (HER2) amplification who progressed on previous therapy demonstrated a 22% regression in a metastatic site when treated with a combination of Gilotrif (afatinib) and Herceptin (trastuzumab) (PMID: 30463996; NCT01522768). 30463996