Abstract 659P
Background
There is still a certain lack of preclinical and clinical understanding of NSCLC with EGFR exon 18 mutations. The present study aimed to elucidate the molecular characteristics of lung cancer with rare EGFR p.E709X point mutation (the second most prevalent exon 18 mutation behind EGFR p.G719X) and propose the optimal treatment strategies.
Methods
This study explored the “Burning Rock Medical Genome Database” (N=44,993) to reveal the genetic mutation characteristics of EGFR p.E709X. In addition, this study also included a real-world cohort of EGFR p.E709X mutant NSCLC patients (n=78) diagnosed in multi-centers in China to evaluate their clinical treatment response to different treatment regimens. A drug sensitivity experiment was also utilized to confirm the clinical finding.
Results
The EGFR p.E709X mutation occurs in approximately 1.5% of patients with EGFR mutations. Based on the mutational status of concurrent EGFR genetic alterations, EGFR p.E709X missense mutations could be divided into 3 categories: EGFR p.E709X/G719X; EGFR p.E709X/L858R and single EGFR p.E709X. For patients with EGFR p.E709X/G719X mutations or single EGFR p.E709X mutations, the therapeutic effect of afatinib is better than first-generation/third-generation EGFR-TKIs (first-generation EGFR-TKIs vs. afatinib vs. third-generation EGFR-TKIs vs. chemotherapy, ORR: 25.00% vs. 64.71% vs. 0.00% vs. 80.00%, median PFS: 7.59 vs. 11.50 vs. 4.56 vs. 5.93 months, P=0.12). However, for patients with EGFR p.E709X/L858R mutations, both afatinib or first-generation EGFR-TKIs showed favorable therapeutic effects (first-generation EGFR-TKIs vs. afatinib vs. third-generation EGFR-TKIs vs. chemotherapy, ORR: 75.00% vs.44.44% vs.16.67% vs.0.00%, median PFS: 12.98 vs.6.57 vs.5.03 vs.2.45 months, P=0.035). EGFR p.T790M mutation (16.7%) composed the most common resistance mechanism in patients with EGFR p.E709X mutation after progression on afatinib or first-generation EGFR-TKIs.
Conclusions
Incorporating the largest cohort of patients with NSCLC with EGFR p.E709X mutations, this study proposed the optimal treatment strategy based on molecular classification and first explored the resistance mechanism after EGFR-TKIs progression.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was financially supported by the Chinese National Natural Science Foundation Project (82173101, and 8237262), the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center, and the 308-Program for Clinical Research of Sun Yat-sen University Cancer Center.
Disclosure
All authors have declared no conflicts of interest.