564P - Co-occurring EGFR p.E709X mutation affects the treatment response to the third-generation EGFR-TKIs in EGFR p.G719X-mutant patients with advanced NSCLC

Background

The current National Comprehensive Cancer Network guideline recommends Afatinib and/or Osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC carrying EGFR p.G719X mutation. 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.

Methods

A large cohort of 4228 treatment-naïve patients with lung cancer who underwent targeted next-generation sequencing (NGS) testing was screened in terms of the EGFR p.G719X mutation. Ba/F3 cells stably expressing the EGFR p.G719A mutation with either the p.E709K mutation or not were created to investigate the response to EGFR-TKIs. The patient-derived lung cancer organoid (LCO) cultures were created, and the corresponding drug treatments and sensitivity (DTS) test was performed.

Results

EGFR p.G719X mutation occurs with a prevalence of 2.56%. EGFR p.E709X(30.4%) composed the most frequent co-occurring EGFR mutation. Co-occurring EGFR p.E709X mutations exerted a detrimental effect on outcomes in Osimertinib-treated patients (G719X/E709X VS. G719X; ORR: 0.00% VS. 47.62%, P<0.001; mPFS:7.18 VS. 14.2 months, P=0.042; respectively). In contrast, no significant difference was found in the treatment efficacy between EGFR p.G719X/E709X and EGFR p.G719X patients upon Afatinib treatment (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 treated with the third-generation EGFR-TKIs. The DTS result of LCO revealed that the second-generation EGFR-TKIs may be superior to first or third-generation EGFR-TKIs for patients with EGFR p.G719X/E709X mutation.

Conclusions

We enrolled the largest available dataset of EGFR p.G719X-mutant patients with NSCLC. The variable sensitivity of EGFR p.G719X mutation to different EGFR TKIs indicates that a personalized treatment strategy should be undertaken in patients depending on the status of underlying co-existing EGFR p.E709X mutation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.