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First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance
Naifu Nie1, Jianghua Li1, Jian Zhang1
1Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, P.R. China.
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.
Insights
Osimertinib resistance in non-small cell lung cancer is often driven by MET amplification or C797S mutations. Subsequent targeted therapies and immunotherapy offer viable treatment options for patients progressing on first-line osimertinib.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- First-line osimertinib (a third-generation EGFR-TKI) has improved non-small cell lung cancer (NSCLC) treatment.
- However, acquired resistance to osimertinib presents a significant clinical challenge.
- Understanding resistance mechanisms and subsequent treatments is crucial for optimizing patient outcomes.
Purpose of the Study:
- To investigate the primary mechanisms of resistance to first-line osimertinib in EGFR-mutant NSCLC.
- To evaluate the efficacy of subsequent treatment strategies following osimertinib resistance.
- To identify potential therapeutic targets and approaches for patients who progress on osimertinib.
Main Methods:
- Retrospective analysis of 56 EGFR-mutant NSCLC patients treated with first-line osimertinib.
- Next-generation sequencing (NGS) of pre-osimertinib and resistance samples.
- Survival analysis using Kaplan-Meier method and log-rank test.
Main Results:
- Median progression-free survival (mPFS) on first-line osimertinib was 15.4 months.
- MET amplification (28.6%) and C797S mutation (23.8%) were the most frequent resistance mechanisms.
- Subsequent treatments yielded a mPFS of 7.3 months, with targeted therapies and immunotherapy showing clinical benefit.
Conclusions:
- MET amplification and C797S mutations are key resistance mechanisms to first-line osimertinib.
- Targeted therapies (e.g., crizotinib, gefitinib) and immunotherapy represent effective subsequent treatment options.
- Over 50% of patients can receive further anticancer therapies after osimertinib resistance.
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