Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor & when? Review Evidence #1 TKIs are standard up front Evidence #2 Not all TKIs are equal Evidence #5 Sequence makes survival Evidence #4 Biological monitoring is key Evidence #3 Biology drives sequence Figure 5. Evidence to evaluate when choosing the sequence in patients with EGFR mutation-positive non-small-cell lung cancer. TKI: Tyrosine kinase inhibitor. as another first-line choice. While, given the results from FLAURA, it may seem intuitive to use osimertinib in the first-line, it is important to consider the long-term treatment plan. Currently, subsequent treatment options for osimertinib are not clearly defined, and mature OS data are not available. Extent of OS from FLAURA will be of great interest, as we cannot extrapolate from the sum of median PFS in individual trials. In LUX-Lung 3, 6 and 7, afatinib was associated with median OS of around 30 months in patients with NSCLC and common (Del19 / L858R) mutations, despite few patients receiving a subsequent T790M inhibitor (due to availability) [26 , 82] . In some cases, it may also be appropriate for patients to receive treatment beyond progression (as seen in LUX-Lung 7 and AURA3). In addition, use of local therapies with continued EGFR TKI treatment, for oligoprogression or focal progression, may provide long-term disease control for some patients [83] . Although there is a lack of data-assessing sequential treatment with EGFR TKIs, initial hypothesis-generating data show that sequential afatinib followed by osimertinib confers encouraging survival outcomes in post hoc analysis (median OS not yet reached after a median follow-up of > 4 years) for the subset of patients treated with the sequence. Overall, further research is needed to determine the most appropriate sequential therapy to optimize clinical benefit in patients with EGFR mutation-positive NSCLC. An illustrated summary of this section can be found in Figure 5 . Future perspective Over the next 5–10 years, it is likely that research will focus on outcomes and tolerability of different sequences, for example, first- or second-generation TKIs followed by a third-generation TKI, or a third-generation TKI followed by appropriate treatment. This will enable us to determine the optimal treatment sequence to prolong patient survival, while maintaining quality of life. Additional research on mechanisms of resistance and suitable post- treatment options for the third-generation TKI, osimertinib, will be of great interest, particularly if it is possible to target specific mutations and thus enable personalized medicine. There is rationale for novel combination regimens in the post-osimertinib setting and the results of ongoing early phase trials are eagerly awaited. Treatment options for patients with T790M-negative disease following progression on an EGFR TKI are also likely to evolve, given the unmet medical need in this patient population. Further assessment of currently available EGFR TKIs for patients with brain metastases could help to define the optimal treatment for these patients, along with novel agents that can effectively penetrate the blood–brain barrier. Supplementary data A video abstract and transcript are available as an accompaniment to this paper. To view the supplementary transcript for this please visit the journal website at: Financial & competing interests disclosure N Girard has acted as a consultant and received financial assistance for travel from AstraZeneca, Hoffman LaRoche, Boehringer Ingelheim and Pfizer. The author has also received academic grants from AstraZeneca, Hoffman LaRoche, Boehringer Ingelheim and Pfizer. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. future science group 10.2217/fon-2017-0636