Rare EGFR E709-T710delinsX: Molecular characteristics and superior response to afatinib treatment in NSCLC patients.

Objectives: Currently, whether patients with rare epidermal growth factor receptor (EGFR) mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs) demands further studies. Limited clinical data are available regarding the molecular characteristics and clinical response in non-small-cell lung cancer (NSCLC) patients harboring EGFR E709-T710delinsX mutations, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR E709-T710delinsX mutated Chinese patients.

Methods: Next-generation sequencing (NGS) tests were performed in 15,078 NSCLC patients. A multicenter retrospective cohort involving 17 advanced lung cancer patients with EGFR E709-T710delinsX was collected to evaluate clinical responses to diverse therapies. In silico protein structure modeling was conducted to predict drug response.

Results: 5905 EGFR mutant patients (39.2%, 5905/15078) were identified, with 26 cases (0.44%, 26/5905) harbored EGFR E709-T710delinsD. Afatinib showed a better overall objective response rate (ORR) compared with the first-generation (1G) EGFR TKIs and chemotherapy with significant difference. Superior progression free survival (PFS) was also observed in patients treated with afatinib (afatinib 10.85 m vs 1G EGFR TKIs 4.0 m vs chemotherapy 2.8 m, p = 0.0007). In silico protein structure modeling predicts better binding of afatinib with EGFR E709-T710delinsD compared with other EGFR TKIs.

Conclusions: This is the largest studies for EGFR E709-T710delinsX, with 26 cases with EGFR E709-T710delinsX being identified (0.44% in EGFR mutant NSCLC, 0.17% in NSCLC patients). This study also firstly revealed that afatinib might exert superior antitumor activity to the 1G EGFR TKIs and chemotherapy in EGFR E709-T710delinsX mutant patients.