2. Academic Validation
  3. Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma

Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma

  • Signal Transduct Target Ther. 2024 Jun 28;9(1):153. doi: 10.1038/s41392-024-01875-4.
Yanni Wang # 1,  Chang Liu # 1,  Huan Chen # 2,  Xi Jiao 1,  Yujiao Wang 1,  Yanshuo Cao 1,  Jian Li 3,  Xiaotian Zhang 3,  Yu Sun 4,  Na Zhuo 1,  Fengxiao Dong 1,  Mengting Gao 1,  Fengyuan Wang 1,  Liyuan Dong 1,  Jifang Gong 3,  Tianqi Sun 5,  Wei Zhu 6,  Henghui Zhang 7 8,  Lin Shen 9,  Zhihao Lu 10
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
  • 2 Genecast Biotechnology Co., Ltd, Wuxi, PR China.
  • 3 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China.
  • 5 Precision Scientific (Beijing) Co., Ltd., Beijing, China.
  • 6 Generulor Company Bio-X Lab, Zhuhai, Guangdong, China.
  • 7 Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. zhhbao@ccmu.edu.cn.
  • 8 Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. zhhbao@ccmu.edu.cn.
  • 9 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China. shenlin@bjmu.edu.cn.
  • 10 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China. zhihaolupku@bjmu.edu.cn.
  • # Contributed equally.
PMID: 38937446 DOI: 10.1038/s41392-024-01875-4
Abstract

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.

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