EGFR G719X + S768I co‑mutations in NSCLC: genomic landscape and differential responses to EGFR‑TKIs in a large real‑world cohort
Afatinib exhibited a significantly superior response compared with both first‑ and third‑generation EGFR‑TKIs in NSCLC patients harboring EGFR G719X + S768I co‑mutations, achieving an overall response rate of 76.8% versus 35.7% for first‑generation TKIs and 61.5% for third‑generation TKIs; median progression‑free survival was 23.4 months for afatinib versus 17.2 months for first‑generation and 17.4 months for third‑generation TKIs
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 harboring 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. 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. Afatinib showed a significantly better response compared to both first‑ and third‑generation EGFR‑TKIs. VAF and TP53 mutation status did not affect outcomes; 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.
These findings provide valuable insights to guide clinical decision‑making and facilitate the development of tailored therapeutic strategies for patients with this uncommon EGFR co‑mutation subtype.
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