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Review
. 2018 Feb 19;17(1):29.
doi: 10.1186/s12943-018-0778-0.

Third generation EGFR TKIs: current data and future directions

Chee-Seng Tan  1 , Nesaretnam Barr Kumarakulasinghe  1 , Yi-Qing Huang  1 , Yvonne Li En Ang  1 , Joan Rou-En Choo  1 , Boon-Cher Goh  1   2   3 , Ross A Soo  4   5   6
Affiliations
Review

Third generation EGFR TKIs: current data and future directions

Chee-Seng Tan et al. Mol Cancer. .

Abstract

Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

Keywords: FLAURA; Osimertinib; Resistance mechanism; Sequencing; T790 M; Third generation EGFR TKI.

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Conflict of interest statement

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Figures

Fig. 1
Fig. 1
Pre -clinical efficacy based on IC50 (nM) comparing between first, second and selected third generation EGFR TKIs. EGFR WT = epidermal growth factor wild-type. EGFR WT is based on H2073 cell line for gefitinib, erlotinib, afatinib, dacomitinib, osimertinib; HaCaT cell line for nazartinib; A549 cell line for PF-06747775, A431 cell line for avitinib. L858R is based on H3255 cell line for all compounds. del19 is based on PC9 cell line for all compounds except HCC 827 cell line for nazartinib. del19/T790 M is based on PC9VanR cell line for all compounds. L858R/T790 M is based on H1975 cell line for all compounds
Fig. 2
Fig. 2
Potential Sequencing of EGFR Tyrosine Kinase Inhibitors and its Estimated Overall Survival (OS). @ Estimated based on First Line EGFR TKI studies IPASS, WJTOG3405. *Estimated based on Pooled analysis AURA Extension & AURA2 as well as AURA3 Study. P Estimated based on OS reported from the Pooled analysis AURA. Extension & AURA2 Reported OS: 26.8 months + 10–12 months expected PFS from 1st Gen TKI. μ updated OS from Lux Lung 7. #Currently limited data. Only ~ 10% of patients received osimertinib post progression on Afatinib in Lux Lung 7. OS for these 10% patients is not available. ^ Estimated based on AURA3
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