Review For reprint orders, please contact: Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Nicolas Girard* ,1,2 1 Thoracic Oncology, Universit´e de Lyon, Universit´e Claude Bernard Lyon 1, Lyon, 69622, France 2 Thoracic Surgery, Institut Curie, Institut du Thorax Curie-Montsouris, Paris, 75248, France * Author for correspondence: Despite the efficacy of standard-of-care EGFR tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib and afatinib, in EGFR mutation-positive non-small-cell lung cancer, resistance develops, most commonly due to the T790M mutation. Osimertinib showed clinical activity in the treatment of T790M-positive disease following progression on a first-line TKI, and is approved in this setting. Recently, osimertinib improved efficacy versus first-generation TKIs (erlotinib and gefitinib) in the first-line setting. Multiple factors can influence first-line treatment decisions, including subsequent therapy options, presence of brain metas- tases and tolerability, all of which should be considered in the long-term treatment plan. Further research into treatment sequencing is also needed, to optimize outcomes in EGFR mutation-positive non-small-cell lung cancer. First draft submitted: 17 November 2017; Accepted for publication: 15 December 2017; Published online: 16 January 2018 Keywords: afatinib • dacomitinib • EGFR • erlotinib • gefitinib • non-small-cell lung cancer • osimertinib • resistance • treatment sequencing • T790M Somatic mutations of the EGFR gene are found in up to 50% of Asian patients and 10–15% of Caucasian patients with lung adenocarcinoma [1] . Tumors with these mutations become dependent on EGFR signaling, enabling molecularly targeted inhibition of this pathway with tyrosine kinase inhibitors (TKIs) to be used as treatment [2] . Erlotinib and gefitinib were the first EGFR TKIs developed; they reversibly and competitively inhibit the tyrosine kinase domain of EGFR ( Figure 1 ) [3] . Known as the first-generation EGFR TKIs, they rapidly became standard of care first-line treatment for EGFR mutation-positive non-small-cell lung cancer (NSCLC), and molecular testing for EGFR mutations in patients with lung adenocarcinoma is now recommended as part of baseline workup [4] . The hypothesis that broader inhibition of the EGFR family could improve outcomes led to the development of second-generation ERBB family blockers, afatinib and dacomitinib. These agents irreversibly bind to EGFR, ERBB2 and ERBB4 and block transphosphorylation of ERBB3 to inhibit all ERBB family signaling ( Figure 1 ) [5] . Currently, erlotinib, gefitinib and afatinib are standard of care for the first-line treatment of EGFR mutation-positive NSCLC [4] . Despite their proven efficacy, resistance to these treatments inevitably develops. The most common mechanism of resistance is acquisition of another EGFR mutation, EGFR T790M (around 50–70% of cases) [6 , 7] . The most recent additions to the EGFR TKI family – the third-generation EGFR TKIs – add to the targeting of EGFR -activating mutations, with specific activity on EGFR T790M ( Figure 1 ). One such agent, osimertinib, demonstrated striking efficacy in patients with EGFR T790M-positive disease that had progressed on a first- or second-generation EGFR TKI and is approved in this setting [7–9] . These data highlight the importance of molecular testing throughout treatment to understand tumor evolution and enable the use of targeted therapies. Most recently, osimertinib has been assessed as a first-line treatment for EGFR mutation-positive NSCLC compared with a first-generation EGFR TKI (erlotinib or gefitinib), demonstrating a significant improvement in median progression-free survival (PFS), and thus positioning it as another potential first-line treatment option [10] . Consequently, physicians now have a number of options available and need to consider how best to use these Future Oncol. (Epub ahead of print) ISSN 1479-6694 10.2217/fon-2017-0636 C 2018 Nicolas Girard