Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival benefits.Our preclinical data showed the promi...Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival benefits.Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC.This proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity profile.Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR expression.Notably,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment.Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.展开更多
基金supported by the National Natural Science Foundation of China(No.92159106,82073230)the National Youth Top-Level Talent Support Program(“Ten Thousand Talents Scheme”)(12Y4962).
文摘Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival benefits.Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC.This proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity profile.Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR expression.Notably,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment.Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.
