Co-occurring EGFR p.E709X Mutation Mediates Primary Resistance to the Third-Generation EGFR-TKIs in EGFR p.G719X-Mutant Patients with Advanced NSCLC.
Clin Cancer Res
; 30(12): 2636-2646, 2024 Jun 14.
Article
em En
| MEDLINE
| ID: mdl-38578683
ABSTRACT
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. EXPERIMENTALDESIGN:
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 (â¼30%), 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteínas Quinases
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Receptores ErbB
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Neoplasias Pulmonares
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Mutação
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China