EGFR Exon 20 Insertion–Mutated Non-Small Cell Lung Cancer: Current Treatment Landscape and Future Directions

Epidermal growth factor receptor (EGFR) exon 20 insertions are the third most common EGFR mutation subtype in non-small cell lung cancer, occurring in up to ~4% of cases. Although the clinical profile overlaps with classical sensitizing EGFR mutations, most exon 20 insertions confer primary resistance to earlier generation epidermal growth factor receptor tyrosine kinase inhibitors, reflecting position- and variant-dependent steric constraints within the adenosine triphosphate-binding pocket. More than 100 distinct variants have been described, motivating structure- and variant-informed frameworks for diagnosis and treatment selection. Accurate detection is therefore essential: fixed-content polymerase chain reaction assays may miss clinically actionable variants, whereas next-generation sequencing improves variant capture and supports standardized reporting, including identification of co-alterations. Plasma cell-free DNA testing can complement tissue profiling when biopsy is not feasible, but low circulating tumour DNA shedding can yield false-negative results, supporting reflex tissue testing after negative plasma findings when clinical suspicion remains high. Therapeutically, the landscape has shifted rapidly since 2021, with the introduction of exon 20 insertion-directed strategies including bispecific antibodies and next-generation tyrosine kinase inhibitors, alongside an expanding pipeline of mutant-selective agents and rational combinations. Despite these advances, response durability remains limited for many patients, and both intrinsic and acquired resistance via on-target changes, bypass signalling and tumour evolution continues to drive unmet need. Future progress will likely depend on central nervous system-active strategies, adaptive sequencing guided by longitudinal molecular profiling and combination approaches that address pathway bypass and tumour heterogeneity.