EGFR exon 18 DelE709_T710insD as an Acquired Resistance Mechanism to Afatinib in an Advanced EGFR exon 18 E709H Lung Adenocarcinoma
Authors: Liang Zeng, Yongchang Zhang, Nong Yang
Journal: Journal of Thoracic Oncology (2018)

EGFR exon 18 mutations, including 18E709H and DelE709_T710insD, are extremely rare.1Shi Y. Au J.S. Thongprasert S. et al.A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER).J Thorac Oncol. 2014; 9: 154-162Google Scholar, 2Kobayashi Y. Togashi Y. Yatabe Y. et al.EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs.Clin Cancer Res. 2015; 21: 5305-5313Google Scholar Until now, we have had no powerful data to show their sensitivity to EGFR tyrosine kinase inhibitors. A 58-year-old man presented to the hospital with complaints of headache and unstable walking for 1 month. The patient smoked for 20 years. A chest computed tomography (CT) scan and brain magnetic resonance imaging (MRI) showed a right lung nodule, innumerable bilateral solid pulmonary nodules, and numerous lesions in the brain with significant edema (Fig. 1D). A CT-guided biopsy of the right lung nodule was performed and showed lung adenocarcinoma. The patient tested positive for EGFR exon 18 E709H mutation (Fig. 1B) by next-generation sequencing(Borning Rock, Guangzhou, China), and he began undergoing whole brain radiotherapy and taking icotinib, 125 mg orally three times daily. Two months later, the patient experienced significant deterioration and shortness of breath. CT showed a significant increase in the size of the right lung nodule and the innumerable diffuse bilateral pulmonary nodules (Fig. 1E). After being assessed as having progressive disease, the patient was given afatinib, 40 mg orally daily. CT and brain MRI showed a significant decrease in the size of the right lung nodule and innumerable diffuse bilateral pulmonary nodules 2 months later (Fig. 1F). There were no serious adverse effects related to afatinib except for grade 2 rash. After the patient had received afatinib for 8 months, CT showed an increase in size of the right lung nodule and brain MRI showed new lesions (Fig. 1G). He was assessed as having progressive disease. After rebiopsy of the right lung nodule, adenocarcinoma was identified. Next-generation sequencing established a change in mutation type to EGFR exon 18DelE709_T710insD (Fig. 1C). The patient's treatment was shifted to chemotherapy with pemetrexed combined with carboplatin, and total tumor evolution was also assessed (Fig. 1 H). This case showed that an advanced EGFR exon 18 E709H lung adenocarcinoma was resistant to icotinib. In the LUX-LUNG studies, the data show that afatinib provided a lot of improvement in patients harboring an uncommon EGFR mutation, but exon 18 E709H was unknown.3Yang J.C. Sequist L.V. Geater S.L. et al.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Lancet Oncol. 2015; 16: 830-838Google Scholar Our data showed that the EGFR exon 18 E709H advanced lung adenocarcinoma was sensitive to afatinib, with progression-free survival of 8 months. Otherwise, unlike DelE709_T710insD was sensitive to afatinib,4Ibrahim U. Saqib A. Atallah J.P. EGFR exon 18 delE709_T710insD mutated stage IV lung adenocarcinoma with response to afatinib.Lung Cancer. 2017; 108: 45-47Google Scholar this case presents as an acquired drug resistant mechanism to afatinib after receiving EGFR exon 18DelE709_T710insD. This work was partially supported by the National Natural Science Foundation (grants No. 81401902 and No. 81501992) and Hunan Natural Science Foundation (grant No. 2017SK2134). Dr. Zhang prepared the manuscript and Mr. Zeng collected the data. Mr. Yang reviewed the manuscript.