Review Girard Executive summary First- & second-generation EGFR tyrosine kinase inhibitors The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib and afatinib, have demonstrated robust efficacy for the first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), and are approved in this indication. Recent data suggest that second-generation ERBB family blockers, afatinib and dacomitinib, have improved efficacy compared with first-generation EGFR TKIs, erlotinib and gefitinib. Third-generation EGFR TKIs in patients with acquired resistance Despite the evidence observed in the first-line setting with first- and second-generation TKIs, resistance develops, predominantly due to acquisition of the EGFR T790M mutation. The third-generation EGFR TKIs show high potency for T790M mutations. Osimertinib significantly prolonged progression-free survival versus chemotherapy in patients with T790M-positive NSCLC who had disease progression after first-line EGFR TKI therapy, and is approved in this setting. Third-generation EGFR TKIs as first-line treatment Recently, osimertinib has demonstrated improved progression-free survival versus the first-generation EGFR TKIs in the first-line setting. Factors influencing first-line treatment choice: mechanisms of resistance & subsequent therapy For patients who receive a first- or second-generation EGFR TKI and experience resistance due to a T790M mutation (around 50–70% of cases), osimertinib is a clear treatment of choice. For patients who receive a first- or second-generation EGFR TKI and experience resistance due to another mechanism, chemotherapy is the principal treatment; options, including afatinib in combination with cetuximab or immuno-oncology agents in combination with novel targeted agents, are under investigation. Resistance mechanisms for osimertinib appear heterogeneous, with MET amplification, small-cell transformation and EGFR C797S mutation identified as the main mechanisms. The likely current second-line treatment option post-osimertinib will be chemotherapy, although investigational agents within clinical trials may be suitable for particular mutations. Further information on the overall sequence of first- or second-generation TKIs followed by osimertinib versus osimertinib in first-line are required. Factors influencing first-line treatment choice: brain metastases Osimertinib and afatinib have both demonstrated activity in patients with brain metastases in prospective randomized trials, while evidence for erlotinib and gefitinib is more limited. Further information on long-term outcomes of patients with brain metastases is required to determine the best first-line treatment option. Factors influencing first-line treatment choice: tolerability profile EGFR TKIs have a predictable, class-related adverse event (AE) profile, although there are some differences between different EGFR TKIs. Afatinib has a well-defined dose adjustment protocol for management of treatment-related AEs, which does not impact on efficacy. Osimertinib, which is EGFR wild-type sparing, has a favorable safety profile, with a lower incidence of grade ≥ 3 treatment-related AEs than gefitinib. The tolerability of the overall treatment sequence should also be considered. Conclusion Erlotinib, gefitinib and afatinib are approved for the first-line treatment of EGFR mutation-positive NSCLC, and recent data have also positioned osimertinib as a potential first-line treatment option. Selecting the optimal first-line treatment requires consideration of patient factors, subsequent therapy options for long-term treatment and the tolerability profile of the overall treatment sequence. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by C Allinson of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this article. Open access This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit 10.2217/fon-2017-0636 Future Oncol. (Epub ahead of print) future science group