Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future

Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Although the first through third generations of EGFR tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy, the emergence of drug resistance continues to pose a challenge. Current research is now focused on fourth-generation EGFR-TKIs, which specifically target the EGFR harbouring the C797S mutation. This review examines the design strategies, antitumor activity both in vivo and in vitro, binding modes, pharmacokinetics, as well as the advantages and disadvantages of each inhibitor, alongside the progress of clinical stage research related to fourth-generation inhibitors. Additionally, the review discusses future development directions for fourth-generation EGFR-TKIs, aiming to provide insights for successful research and development in this field.