Targeted Therapies for EGFR Exon 20 Insertion Mutations in Non-Small Cell Lung Cancer

Lung cancer remains the leading cause of cancer-related death worldwide. Epidermal growth factor receptor (EGFR) mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with L858R point mutation or exon 19 deletions accounting for the majority of EGFR mutations. The development of EGFR-targeted therapies has significantly improved clinical outcomes and overall survival in patients harboring these classical activating mutations. However, EGFR exon 20 insertion mutations (Ex20ins) exhibit resistance to earlier-generation tyrosine kinase inhibitors (TKIs), including erlotinib, gefitinib, and afatinib, due to structural alterations that limit drug binding and reduce therapeutic efficacy. To address these challenges, novel EGFR-targeted TKIs and bispecific monoclonal antibodies have emerged as promising treatment strategies for patients with Ex20ins-mutated NSCLC. This review summarizes recent advances in targeted therapies for EGFR Ex20ins, highlighting treatments approved by the US Food and Drug Administration (FDA), including amivantamab and sunvozertinib, as well as emerging agents such as firmonertinib, zipalertinib, and becotarug.