Lung Cancer: Targets and Therapy (Oct 2023)
Co-Occurring EGFR S645C and EGFR L858R in a Patient with Lung Adenocarcinoma Induced Primary Resistance to Osimertinib
Abstract
Li Wang,1,* Fei Quan,2,* Zhen Guo,3 Zhongyu Lu,2 Duoxia Yang,2 Meiqi Shi1 1Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The Medical Department, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, People’s Republic of China; 3Radiology Department, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meiqi Shi, Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, No. 42, Baiziting, Xuanwu District, Nanjing, Jiangsu, 210009, People’s Republic of China, Tel/Fax +86 25 83283568, Email [email protected]: Approximately 10– 20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.Keywords: EGFR S645C, osimertinib, primary resistance, NSCLC, subclone
