Abstract
The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is common in East Asia, and approximately 50% of adenocarcinomas harbor EGFR mutations. Undoubtedly, EGFR-TKIs, with their promising efficacy, are the mainstay of primary therapy. However, even if tumor shrinkage is achieved, most patients become resistant to EGFR-TKIs and relapse; hence, EGFR-TKIs do not achieve a radical cure. The problem of the development of resistance to targeted drugs has been a persistent challenge. After the role of EGFR T790M mutation in acquired drug resistance was reported, osimertinib, a third-generation irreversible EGFR-TKI, was designed to overcome the resistance conferred by T790M mutation. In addition, some studies have reported the mechanism of drug resistance caused by mutations other than the T790M mutation and strategies to overcome them. Elucidating the mechanism underlying drug resistance development and combining therapeutic approaches are expected to further improve NSCLC prognosis.
Highlights
The role of activating mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) was reported in 2004 [1]
This review focuses on the latest treatments for EGFR mutation-positive lung cancer and the strategies aimed at overcoming drug resistance; we discuss the prospects for their use in clinical settings
Phase III clinical trials comparing the use of EGFR-tyrosine kinase inhibitors (TKIs) with platinum in NSCLC harboring a deletion mutation in exon 19 and the L858R mutation in exon 21 [2,3,13,14] showed that EGFR-TKI monotherapy significantly improved the response rate and progression-free survival (PFS) compared to platinum combination therapy, establishing it as the standard of care (Table 1)
Summary
The role of activating mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) was reported in 2004 [1]. Genes whose mutations and alterations are directly responsible for the increased growth and progression of cancer are collectively referred to as driver genes Kinase inhibitors targeting these mutations/alternations are the primary therapeutic choices for patients harboring driver gene mutations. This review focuses on the latest treatments for EGFR mutation-positive lung cancer and the strategies aimed at overcoming drug resistance; we discuss the prospects for their use in clinical settings. Phase III clinical trials comparing the use of EGFR-TKIs (gefitinib and erlotinib) with platinum in NSCLC harboring a deletion mutation in exon 19 and the L858R mutation in exon 21 [2,3,13,14] showed that EGFR-TKI monotherapy significantly improved the response rate and progression-free survival (PFS) compared to platinum combination therapy, establishing it as the standard of care (Table 1). Based on the results of these pivotal clinical trials, both first- and second-generation EGFR-TKIs are being used in clinical settings worldwide
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