Incidence of T790M in Patients With NSCLC Progressed to Gefitinib, Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are characterized by different pharmacologic profiles, potentially affecting the development of resistance mutations, which were investigated in the present study. We retrospectively included patients with EGFR-mutant non small-cell lung cancer who had received EGFR TKIs as first-line therapy. Circulating cell-free DNA was analyzed at disease progression to investigate the incidence of T790M. We found a greater occurrence of T790M in patients with progression during gefitinib or erlotinib versus afatinib therapy, although the time to progression was comparable. We found that EGFR TKIs behave differently with respect to the development of the T790M resistance mutation, and this finding could have implications in the choice of second-line treatment. Background: Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib. Patients and Methods: The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay. Results: A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001). Conclusions: Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment. (C) 2019 Elsevier Inc. All rights reserved.