Resistance to third-generation EGFR TKIs - what can be expected from the fourth-generation?

Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations, and osimertinib is now established as first-line therapy for NSCLCs. Combination therapies (e.g., osimertininb plus chemotherapy; lazertinib plus amivantamab) have been shown to improve median progression-free survival (mPFS) and median overall survival (mOS) relative to monotherapy. However, due to several resistance mechanisms, patients experience disease progression following EGFR TKI treatment. On-target resistance mechanisms include additional mutations (e.g., C797S/G/N, L718Q, L844V, G724X). Within the heterogeneous group of off-target resistance mechanisms, human epidermal growth factor receptor 2 (HER2) amplifications, mesenchymal-epithelial transition factor (MET) alterations, oncogenic fusions (e.g., BRAF, FGFR, RET), histological changes, epithelial-mesenchymal transitions, and alterations of the RAS/MEK/ERK and the PI3K/AKT/mTOR signal transduction pathways are critical and can confer resistance to EGFR TKIs. Several drugs have been identified to inhibit these pathways, with some of them already approved for clinical use. Most fourth-generation EGFR TKIs are orally bioavailable and are mainly allosteric thiazole amide-based reversible inhibitors. Their activity results from selective binding to an allosteric site, which can alter the EGFR protein conformation, allowing them to bypass C797X. A recommendation for the optimal treatment strategy and sequence for NSCLC patients with acquired EGFR TKI-resistant tumours still cannot be given. An improved understanding of the underlying resistance mechanisms will help to pave the way for the development of innovative and highly specific drugs for the therapy of osimertinib-resistant NSCLCs. The putative clinical relevance of fourth-generation EGFR TKIs for NSCLC patients needs to be defined, and many development hurdles need to be cleared before victory can be declared.