In the realm of advanced non–small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKI), addressing optimal treatment for uncommon EGFR mutations like G719X in exon 18, S768I in exon 20, and L861Q in exon 21 remains a pivotal yet challenging frontier. Contrary to the well-established efficacy of EGFR-TKIs in common EGFR mutations, these uncommon alterations pose unmet medical needs due to a lack of comprehensive evidence. While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. Recent developments include multiple clinical trials investigating the efficacy of both second- and third-generation EGFR-TKIs in patients with uncommon EGFR mutations. A noteworthy example is a prospective phase II trial of osimertinib including the landmark UNICORN study, which has shown promising results in treating uncommon EGFR mutations. Despite various reports on the efficacy of afatinib and osimertinib in treating uncommon EGFR mutations, the appropriate use of these TKIs remains unclear. This review aims to consolidate the findings from the latest clinical trials focused on uncommon EGFR mutations, outlining variations in the therapeutic efficacy of these TKIs based on the specific genetic mutation. By synthesizing these findings, we aim to guide oncologists toward more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.

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