Jianchun Duan1, JiaChen Xu1, Zhijie Wang1, Hua Bai1, Ying Cheng2, Tongtong An3, Hongjun Gao4, Kai Wang5, Qing Zhou6, Yanping Hu7, Yong Song8, Cuimin Ding9, Feng Peng10, Li Liang11, Yi Hu12, Cheng Huang13, Caicun Zhou14, Yuankai Shi1, Jiefei Han1, Di Wang1, Yanhua Tian1, Zhenlin Yang15, Li Zhang16, Shaokun Chuai17, Junyi Ye17, Guanshan Zhu18, Junhui Zhao19, Yi-Long Wu6, Jie Wang20. 1. State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. 2. Division of Thoracic Oncology, Jilin Cancer Hospital, Jilin Province Cancer Hospital, Changchun, People's Republic of China. 3. Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China. 4. The 307th Hospital of Chinese People's Liberation Army, Beijing, People's Republic of China. 5. Department of Respiratory Medicine, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China. 6. Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. 7. Department of Oncology, Hubei Cancer Hospital, Hubei, People's Republic of China. 8. Nanjing General Hospital of Nanjing Military Command and PLA Bayi Hospital, Nanjing, People's Republic of China. 9. Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Hebei, People's Republic of China. 10. Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, People's Republic of China. 11. Peking University Third Hospital, Beijing, People's Republic of China. 12. Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China. 13. Department of Medical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian University of Traditional Chinese Medicine, Teaching Hospital of Fujian Medical University, Fuzhou, People's Republic of China. 14. Shanghai Pulmonary Hospital, Tongji University, Shanghai, People's Republic of China. 15. Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. 16. Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. 17. Burning Rock Biotech, Guangdong, People's Republic of China. 18. Amoy Diagnostics, Xiamen, People's Republic of China. 19. Department of Medical Oncology, Affiliated Hospital of Qinghai University, Qinghai, People's Republic of China. 20. State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. Electronic address: zlhuxi@163.com.
Abstract
INTRODUCTION: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. METHODS: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. RESULTS: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment. CONCLUSIONS: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.
INTRODUCTION: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. METHODS: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. RESULTS: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment. CONCLUSIONS: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.