Targeting EGFR Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer: Changes in Treatment Strategies are Coming

Epidermal growth factor receptor ( EGFR) exon 20 insertion (ex20ins) mutations are the third most frequent EGFR mutation type, following only exon 19 deletions and exon 21 L858R point mutations. EGFR ex20ins mutations are found in approximately 4%-12% of all EGFR-positive non-small cell lung cancers (NSCLCs). Unlike classical EGFR mutations, EGFR ex20ins mutations display remarkable subtype diversity and heterogeneity. Patients harboring these mutations generally have an inferior prognosis because of insensitivity to conventional treatment approaches such as immunotherapy, chemotherapy, and targeted therapy. Consequently, there remains a significant unmet medical need for efficacious treatments. Recently, amivantamab and sunvozertinib have demonstrated notable efficacy as first-line treatments, and several other promising novel targeted drugs are also challenging the status quo of traditional first-line platinum-based chemotherapy regimens. These developments are anticipated to further improve survival outcomes for NSCLC patients with EGFR ex20ins mutations. Hence, this review summarizes the epidemiology, molecular attributes, detection methodologies, and therapeutic advancements for EGFR ex20ins mutations in NSCLC, and briefly discusses the mechanisms of drug resistance.