Human epidermal growth factor receptor 2 (HER2) exon 20 mutant forms (HER2 (ERBB2))

Human epidermal growth factor receptor 2 (HER2), encoded by the ERBB2 gene, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (NIH, 2020). While HER2 is well-known for its role in breast and gastric cancers through gene amplification, specific mutations in exon 20—primarily in-frame insertions—have emerged as critical oncogenic drivers in approximately 1-4% of non-small cell lung cancers (NSCLC) (NIH, 2025). These mutations induce a conformational change that locks the kinase domain into an active state, leading to constitutive, ligand-independent signaling through the PI3K/AKT and MAPK/ERK pathways (ASCO, 2022). This aberrant signaling promotes uncontrolled cell proliferation, survival, and metastasis, often presenting a more aggressive clinical course with a high incidence of brain metastases (BioWorld, 2022). Historically, HER2 exon 20 mutations were resistant to conventional tyrosine kinase inhibitors (TKIs) due to steric hindrance in the drug-binding pocket (ResearchGate, 2020). However, the therapeutic landscape has shifted with the approval of antibody-drug conjugates like trastuzumab deruxtecan and next-generation, mutation-selective TKIs such as zongertinib and sevabertinib, which provide targeted efficacy while minimizing off-target inhibition of wild-type EGFR (ASCO Post, 2025).

Other names

ERBB2 exon 20 mutationsHER2 exon 20 insertionsHER2-YVMANeu exon 20 mutationsERBB2 tyrosine kinase domain (TKD) activating mutations

Inhibition of the intracellular tyrosine kinase domain or targeted delivery of cytotoxic agents via antibody-drug conjugates to cells expressing the mutated receptor (NIH, 2020; ASCO Post, 2025).