Co-occurrence of EGFR sensitising and resistance mutations at diagnosis in NSCLC

Background De novo epidermal growth factor receptor (EGFR) resistance mutations in tyrosine kinase inhibitor-naive patients are rare when assessed by standard genotyping methods. Methods Patients with EGFR mutations were identified using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. Results From 2008 to 2015, we observed de novo EGFR resistance mutations in 12.8 patients who received an EGFR TKI with an overall response rate of 25%, median PFS 24 months, and median OS 34 months. Five patients (63%) received erlotinib in the first-line setting with a 60% disease control rate (DCR) and a median duration of response of 6 months (range 4-45 months). Three (37%) received cytotoxic chemotherapy in the first-line setting with 67% DCR and a median duration of response of 11 months (range 10-12 months). In patients with de novo EGFR T790M mutations, 50% (2/4) had stable disease with one patient having an ongoing response to erlotinib of over 96 months. In patients with de novo EGFR S768I mutations who received erlotinib, 50% (2/4) have ongoing partial responses at 30 and 6 months. Conclusion This is the largest Irish review of de novo synchronous EGFR mutations. The incidence of co-occurring EGFR mutations in our cohort of non-small cell lung carcinoma (NSCLCA) is 1% on routine assays. Erlotinib appears to have activity in this cohort in both in the first-and second-line setting. De novo S768I and T790M represent distinct clinical entities. For de novo T790M mutations cytotoxic chemotherapy may still be considered first line. For de novo S768I mutations, erlotinib appears to be a reasonable therapeutic option.