What question did this study set out to answer?

The aim was to explore the genomic landscape and treatment response of NSCLC patients with EGFR G719X and S768I co-mutations.

March 25, 2026BMC Cancer0 citationsOpen Access

EGFR G719X + S768I co-mutations in NSCLC: genomic landscape and differential responses to EGFR-TKIs in a large real-world cohort

CZChao ZhangBeijing Institute of Technology RDRuoyu DengKunming Medical University WZWen ZhangKunming Medical University

Key Points

The aim was to explore the genomic landscape and treatment response of NSCLC patients with EGFR G719X and S768I co-mutations.
Retrospective screening of 645 EGFR-mutant NSCLC patients.
Next-generation sequencing performed on 126 patients.
Evaluation of first-line EGFR-TKI efficacy in 96 patients with stage IV disease.
Analysis of variant allele frequency and TP53 mutations.
G719C was the most prevalent variant at 69.8%.
Overall objective response rate (ORR) for first-line EGFR-TKIs was 68.8%.
Median progression-free survival (mPFS) was 21.4 months.
Afatinib showed a better response compared to other generations of EGFR-TKIs (P = 0.01).
Patients with brain and liver metastases had shorter mPFS.

Abstract

Comprehensive genomic analysis and optimal treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) G719X + S768I co-mutations remain limited. This study aimed to elucidate the genetic landscape and the clinical effectiveness of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in this subset. A total of 645 EGFR-mutant NSCLC patients were retrospectively screened, with 142 patients harbored EGFR G719X + S768I co-mutations. Among these patients, next-generation sequencing was performed in 126 patients, and the efficacy of first-line EGFR-TKIs was evaluated in 96 patients with stage IV disease. Impacts of variant allele frequency (VAF) and concurrent TP53 mutations were also analyzed. Among G719X variants, G719C was most prevalent (69.8%), followed by G719A (19.0%) and G719S (8.7%). The most common co-existing mutation was TP53 (38.0%), followed by ALK and PIK3CA (6.3% each). For first-line EGFR-TKIs, the overall objective response rate (ORR) reached 68.8%, with a median progression-free survival (mPFS) of 21.4 months (95% CI: 18.2–24.6). Afatinib showed a significantly better response compared to both first- and third-generation EGFR-TKIs (1st vs. 2nd vs. 3rd generations, ORR: 35.7% vs. 76.8% vs. 61.5%, P = 0.01; mPFS: 17.2 vs. 23.4 vs. 17.4 months, P = 0.008). VAF and TP53 mutation status did not affect outcomes (P > 0.05), but patients with metastases in the brain and liver experienced notably shorter mPFS. Brain metastases patients had an ORR of 70.5% without additional benefit from third-generation TKIs. This study delineates the genomic profile of EGFR G719X + S768I co-mutated NSCLC and highlights the superior effectiveness of second-generation EGFR-TKIs, particularly afatinib. These findings provided valuable insights to guide clinical decision-making and facilitate the development of tailored therapeutic strategies for this subset.

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