Overcoming triple mutant EGFR-tyrosine kinase barriers in the therapeutics of non-small cell lung cancer: a patent review on fourth-generation inhibitors (2017-2024)

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, with 'epidermal growth factor receptor (EGFR)' mutations being a primary driver of tumor progression. This review highlights the significance of fourth-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) in addressing acquired resistance mechanisms, such as the C797S mutation, which compromises the efficacy of third-generation inhibitors like Osimertinib and explores their potential to revolutionize NSCLC treatment through enhanced molecular specificity. This review covers the latest progress in the patented Fourth-Generation EGFR-Tyrosine Kinase inhibitors and their clinical trial status for the treatment of Non-Small Cell Lung Cancer (NSCLC) from 2017 to the present. Osimertinib, a third-generation EGFR inhibitor, revolutionized treatment for T790M mutations but is limited by resistance from C797S mutations. Fourth-generation EGFR inhibitors, incorporating scaffolds like aminopyrimidine and quinazoline, are designed to selectively target resistant EGFR variants, including L858R/T790M/C797S. Preclinical trials highlight the potential of sulfonyl and phosphine oxide-based compounds for their potency, selectivity, and favorable pharmacokinetics. Promising clinical trials with inhibitors like BDTX-1535, JIN-A02, and HS-10504 could redefine NSCLC treatment, with future success likely relying on innovative strategies, such as combination therapies, to combat resistance and enhance efficacy.