Yubo Wang1, Li Li1, Rui Han1, Lin Jiao1, Jie Zheng1, Yong He2. 1. Department of Respiratory Medicine, Daping Hospital, Third Military Medical University, Chongqing, PR China. 2. Department of Respiratory Medicine, Daping Hospital, Third Military Medical University, Chongqing, PR China. Electronic address: heyong8998@126.com.
Abstract
INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated. OBJECTIVES: This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification. METHODS: We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis. RESULTS: Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically. CONCLUSIONS: We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS/OS after osimertinib treatment. Moreover, we reported the first clinical evidence of efficacy generated by combination of first-generation EGFR-TKI icotinib and crizotinib after the resistance to osimertinib.
INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated. OBJECTIVES: This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification. METHODS: We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis. RESULTS: Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically. CONCLUSIONS: We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS/OS after osimertinib treatment. Moreover, we reported the first clinical evidence of efficacy generated by combination of first-generation EGFR-TKI icotinib and crizotinib after the resistance to osimertinib.
Authors: Zhen Chen; Karin A Vallega; Haiying Chen; Jia Zhou; Suresh S Ramalingam; Shi-Yong Sun Journal: Pharmacol Res Date: 2021-11-24 Impact factor: 7.658
Authors: Caroline E McCoach; Aiming Yu; David R Gandara; Jonathan W Riess; Daniel P Vang; Tiahong Li; Primo N Lara; Matthew Gubens; Frances Lara; Philip C Mack; Laurel A Beckett; Karen Kelly Journal: JCO Precis Oncol Date: 2021-01-14