AZ14289671 is a highly selective and blood-brain barrier penetrant irreversible TKI that targets EGFRExon20 insertions.

Current clinical therapeutics against non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (EGFRExon20Ins) mutations yield limited responses particularly against brain metastases; therefore, there is a need for an effective tyrosine kinase inhibitor (TKI). AZ14289671 is an oral, potent, irreversible, selective, and blood-brain barrier penetrant TKI targeting EGFRExon20Ins mutations while sparing wild-type (WT) EGFR. Preclinical assessments using cell lines, cell line-derived xenograft, and patient-derived xenograft models harboring EGFRExon20Ins demonstrate that AZ14289671 exhibits strong signaling pathway inhibition and highly sustained tumor regression against multiple EGFRExon20Ins, whereas its activity against WT is minimal. Additionally, AZ14289671 can cross the blood-brain barrier. This has the potential to improve outcomes of NSCLC patients with EGFRExon20Ins.