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Co-occurring EGFR p.E709X Mutation Mediates Primary Resistance to the Third-Generation EGFR-TKIs in EGFR
Lanlan Pang1, Yihua Huang1, Weitao Zhuang1
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Purpose:
The current National Comprehensive Cancer Network (NCCN) guidelines recommend afatinib or osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC harboring EGFR p.G719X mutation. However, in the absence of head-to-head trials comparing afatinib with osimertinib in EGFR p.G719X-mutant patients, it is unclear which regimen is the preferred treatment option.
Experimental Design:
A large cohort of 4,228 treatment-naïve patients with lung cancer who underwent targeted next-generation sequencing (NGS) testing was screened for EGFR p.G719X mutation. A multicenter cohort involving 68 EGFR p.G719X-mutant patients with advanced NSCLC and NGS profiling was retrospectively enrolled to evaluate clinical responses to afatinib (n = 37) and the third-generation EGFR-TKIs (n = 31). Ba/F3 cells stably expressing the EGFR p.G719A mutation were created to investigate the response to EGFR-TKIs in vitro.
Results:
Concurrent EGFR p.E709X mutations, being the most frequent co-occurring EGFR mutation in EGFR p.G719X-mutant NSCLC (∼30%), exerted a detrimental effect on outcomes in patients treated with third-generation EGFR-TKI [G719X/E709X vs. G719X; objective response rate (ORR): 0.00% vs. 47.62%, P < 0.001; mPFS: 7.18 vs. 14.2 months, P = 0.04, respectively]. Conversely, no significant difference was found in the treatment efficacy of afatinib between EGFR p.G719X/E709X and EGFR p.G719X patients (G719X/E709X vs. G719X; ORR: 71.43% vs. 56.67%, P = 0.99; mPFS: 14.7 vs. 15.8 months, P = 0.69, respectively). In vitro experiments elucidated a resistant drug sensitivity and poor inhibition of EGFR phosphorylation in Ba/F3 cells expressing EGFR p.G719A/E709K mutation upon the third-generation EGFR-TKI treatment.
Conclusions:
Co-occurring EGFR p.E709X mutation mediated primary resistance to the third-generation EGFR-TKIs in EGFR p.G719X-mutant patients but remained sensitive to afatinib. A personalized treatment strategy should be undertaken based on the coexisting EGFR p.E709X mutation status.
Insights
Afatinib is effective for non-small cell lung cancer (NSCLC) with EGFR p.G719X mutations, even with co-occurring p.E709X mutations. Third-generation EGFR-TKIs are less effective when p.E709X mutations are present.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- National Comprehensive Cancer Network (NCCN) guidelines suggest afatinib or osimertinib for advanced non-small cell lung cancer (NSCLC) with EGFR p.G719X mutations.
- The optimal first-line treatment remains unclear due to a lack of head-to-head trials.
Purpose of the Study:
- To evaluate the clinical efficacy of afatinib versus third-generation EGFR-TKIs in NSCLC patients with EGFR p.G719X mutations.
- To investigate the impact of co-occurring EGFR p.E709X mutations on treatment outcomes.
Main Methods:
- Retrospective analysis of 68 advanced NSCLC patients with EGFR p.G719X mutations treated with afatinib (n=37) or third-generation EGFR-TKIs (n=31).
- In vitro experiments using Ba/F3 cells to assess drug sensitivity and EGFR phosphorylation inhibition.
Main Results:
- Afatinib demonstrated significant efficacy in patients with EGFR p.G719X/E709X mutations (ORR: 71.43%, mPFS: 14.7 months) and EGFR p.G719X mutations (ORR: 56.67%, mPFS: 15.8 months).
- Third-generation EGFR-TKIs showed significantly reduced efficacy in patients with co-occurring EGFR p.E709X mutations (ORR: 0.00%, mPFS: 7.18 months) compared to those with only EGFR p.G719X mutations (ORR: 47.62%, mPFS: 14.2 months).
- In vitro studies confirmed resistance to third-generation EGFR-TKIs with EGFR p.G719A/E709K mutations.
Conclusions:
- Co-occurring EGFR p.E709X mutations confer primary resistance to third-generation EGFR-TKIs in EGFR p.G719X-mutant NSCLC.
- Afatinib remains an effective treatment option for NSCLC patients with EGFR p.G719X mutations, irrespective of p.E709X co-mutation status.
- Personalized treatment strategies considering coexisting EGFR mutations are crucial for optimizing patient outcomes.
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