EGFR / HER2 exon 20 mutations

Class

Mutant-selective, irreversible small-molecule tyrosine kinase inhibitor

Pathway

Selectively inhibits EGFR/HER2 exon 20 mutant kinase signaling, with reported superior selectivity against HER2 exon 20 mutations in NSCLC

EGFR and HER2 are cell-surface receptor tyrosine kinases that, upon activation, trigger intracellular signaling cascades controlling cell growth, survival, and division. In a subset of non-small cell lung cancers, insertion mutations occur in exon 20 of either gene's kinase domain, locking the receptor into a constitutively active state that drives uncontrolled proliferation independent of the normal external signals that would otherwise regulate it. These exon 20 insertions differ structurally from the more common EGFR activating mutations (such as exon 19 deletions or L858R), and this structural difference makes exon 20 mutant tumors poorly responsive to earlier-generation EGFR-targeted therapies. Mutant-selective, irreversible tyrosine kinase inhibitors are designed to bind covalently within the kinase domain of the mutant receptor, blocking its enzymatic activity while sparing the wild-type receptor found in normal tissues such as skin and gastrointestinal epithelium. Because exon 20 insertions arise in both EGFR and HER2 and produce biologically similar oncogenic signaling, an inhibitor with activity against both broadens the population of tumors that can be addressed by a single mechanism. This class of mechanism is relevant wherever exon 20-driven signaling underlies tumor growth, particularly in lung cancer subtypes historically difficult to treat with existing targeted agents.