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Review Girard Wild-type EGFR Intrinsic mutant EGFR ERBB heterodimers e.g., HER2: ERBB3 Acquired T790M EGFR Erlotinib Gefitinib Afatinib Dacomitinib Osimertinib Preclinical activity 1st-generation TKI Activity range Irreversible covalent binding to mutant EGFR Specificity for EGFR T790M mutant; EGFR wild-type sparing Activity Activity range Broader activity to overcome EGFR TKI-resistant mutations Irreversible covalent binding to EGFR, ERBB2 and ERBB4 to inhibit all ERBB family signalling Inactive on T790M mutant Reversible binding to wild-type and mutant EGFR 2nd-generation TKI 3rd-generation TKI EGFR inhibition EGFR mutant-specific inhibitor ERBB family blockade Kinase domain K K K K K K K K range Figure 1. Overview of activity range of first-, second- and third-generation EGFR tyrosine kinase inhibitors. TKI: Tyrosine kinase inhibitor. agents to provide the best chance of long-term survival, while also considering the impact on quality of life, which is of particular importance to patients with advanced cancer. Based on the molecular evolution of lung tumors, sequencing of EGFR TKIs may be key to obtaining the best outcome. In this review, we consider the data supporting the use of the available EGFR TKIs and key considerations for selection of first-line treatment. First- & second-generation EGFR TKIs The first-generation EGFR TKIs, erlotinib and gefitinib, demonstrated superior efficacy to platinum-based chemotherapy in several Phase III trials (OPTIMAL [11] , EURTAC [12] and ENSURE [13] for erlotinib, and IPASS [subgroup of EGFR mutation-positive NSCLC] [14] , WJTOG3405 [15] and NEJ002 [16] for gefitinib [ Ta- ble 1 ]). In these trials, erlotinib and gefitinib were associated with median PFS of 9.2–13.1 months compared with 4.6–6.3 months among patients receiving platinum-based chemotherapy. However, none of the trials were able to show an overall survival (OS) improvement with the first-generation TKIs, which was thought to be related to crossover from chemotherapy to an EGFR TKI upon progression [13 , 17–20] . Overall, the EGFR TKIs were tolerable, with key adverse events (AEs) including class-related gastrointestinal and skin toxicities (discussed in further detail later). The second-generation ERBB family blocker, afatinib, has also demonstrated significantly improved PFS versus platinum-based chemotherapy in patients with EGFR mutation-positive NSCLC in two large, randomized Phase III trials ( Table 1 ). In LUX-Lung 3, in patients with common mutations (Del19 / L858R), median PFS was 13.6 months for afatinib versus 6.9 months with cisplatin–pemetrexed [25] . These results were confirmed in the LUX-Lung 6 trial, which was conducted in Asia [27] . Subgroup analysis showed that the results were consistent irrespective of age, gender and race. While PFS generally favored afatinib irrespective of mutation type, benefit was most pronounced among those with Del19-positive disease ( Table 1 ) [25 , 27] . This has also been observed for the first-generation EGFR TKIs [31 , 32] . LUX-Lung 3 and 6 both also included prespecified analyses of patient-reported outcomes, whereby afatinib was associated with longer time to deterioration and improvements in lung cancer-related symptoms, such as cough, dyspnea and pain [25 , 27 , 33] . Moreover, in contrast with the first-generation EGFR TKIs, afatinib was associated with an OS benefit in both of these trials. Among patients with Del19-positive NSCLC, median OS was significantly longer in patients receiving afatinib than those receiving chemotherapy (LUX-Lung 3: median, 33.3 vs 10.2217/fon-2017-0636 Future Oncol. (Epub ahead of print) future science group

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