Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going

- Treatment of EGFR mutated NSCLC is an evolving therapeutic paradigm.
- EGFR mutated patients treated with 1st/2nd generation EGFR TKIs develop AR after 9-13 months.
- T790M mutation is the major mechanism of AR to these agents.
- 3rd generation EGFR TKIs are emerging as a novel promising therapeutic strategy after AR.
- Osimertinib is the first mutant-selective EGFR TKI approved by FDA and EMA.

The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.