First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments

Naifu Nie; Jianghua Li; Jian Zhang; Jie Dai; Zhulin Liu; Zhenyu Ding; Yubo Wang; Mengxiao Zhu; Chen Hu; Rui Han; Huan Tang; Li Li; Yong He

doi:10.1177/11795549221134735

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments

Clin Med Insights Oncol. 2022 Nov 11:16:11795549221134735. doi: 10.1177/11795549221134735. eCollection 2022.

Authors

Naifu Nie¹, Jianghua Li¹, Jian Zhang¹, Jie Dai¹, Zhulin Liu¹, Zhenyu Ding², Yubo Wang¹, Mengxiao Zhu¹, Chen Hu¹, Rui Han¹, Huan Tang¹, Li Li¹, Yong He¹

Affiliations

¹ Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China.
² Department of Thoracic Oncology, West China Hospital of Sichuan University, Sichuan, P.R. China.

Abstract

Background: Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established.

Methods: Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened. The samples of pre-osimertinib and osimertinib-resistance were all detected by next-generation sequencing (NGS) panels. Statistical analyses were carried out using SPSS 23.0 software. Survival analyses were performed using the Kaplan-Meier method and compared using a log-rank test between groups.

Results: Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA). A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%). A total of 15 patients received subsequent treatments, with mPFS of 7.3 months (95% CI 5.0 months -NA). Among them, 7 patients with EGFR C797 S or/and MET amplification received subsequent second-line targeted therapy, achieving mPFS of 7.3 months (95% CI 4.5 months -NA). Of note, 3 patients received immunotherapy as second- or third-line treatment after osimertinib resistance, achieving median clinical benefit of 37.3 months.

Conclusions: MET amplification and C797S mutation are main resistance mechanisms, which could be targeted by crizotinib and gefitinib, respectively. More than 50% patients could receive subsequent anticancer targetable therapies after first-line osimertinib resistance. Immunotherapy may also be an acceptable choice after osimertinib resistance.

Keywords: NSCLC; first-line treatment; osimertinib; resistance; subsequent treatments.