Afatinib is effective in the treatment of lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line standard treatment for advanced lung adenocarcinoma with mutant EGFR. Nevertheless, few studies have demonstrated the efficacy of first- and second-generation EGFR TKIs in patients harboring the uncommon p.L747P and p.L747S mutations in exon 19 of EGFR.From 2005-2018, we identified patients with lung adenocarcinoma with EGFR p.L747P or p.L747S mutations using DNA and cDNA sequencing or commercial kits and recorded their clinical data. Published data pertaining to these mutations were also reviewed.Twelve eligible patients were enrolled at National Taiwan University Hospital (NTUH), and ten additional patients were identified in published literature. In NTUH cohort, the direct DNA sequencing had a 60.0% (3 of 5 patients) false-negative rate, and use of commercial kits all caused misidentification of EGFR p.L747P or p.L747S. Of the 7 patients receiving EGFR TKI treatment, five stage-IV lung adenocarcinoma patients that received afatinib had a 80.0% objective response rate (ORR), while two patients administered gefitinib or erlotinib showed a 0% ORR. The median progression-free survival (PFS) rates were 11.97 and 0.92 months (P = 0.012) for afatinib and gefitinib/erlotinib, respectively. No patients (0%) acquired p.T790 M resistance after failure of afatinib (n = 3). Of 10 patients harboring EGFR p.L747P from published literature, six patients used first-generation EGFR TKIs as treatment also showed 0% ORR and 1.00 month median PFS.Patients with the uncommon EGFR mutations p.L747P and p.L747S could be incorrectly classified as having wild-type EGFR or a 19DEL when using direct DNA sequencing or commercial kits. Moreover, use of afatinib may provide significantly improved PFS in patients with advanced lung adenocarcinoma with one of these two EGFR mutations.