HER2-mutant mNSCLC

Identify patients for treatment with ENHERTU based on the presence of an activating HER2 (ERBB2) mutation

Activating HER2 mutations are an actionable biomarker in mNSCLC1

  • An activating HER2 mutation is any mutation identified within the HER2 (ERBB2) gene that is known to play a role in the oncogenic process2

There are important differences between HER2 mutations and other HER2 alterations in NSCLC3,4

  • HER2 mutations occur in the HER2 (ERBB2) gene and are synonymous with ERBB2 mutations5

    Other HER2 alterations4

    • HER2 amplification is distinct from HER2 mutations, in that they result in abnormally high HER2 (ERBB2) gene copies
    • HER2 overexpression is characterized by an overabundance of HER2 receptors on the surface of cancer cells

HER2 mutations have been observed in 2-4% of patients with NSCLC4

  • HER2 mutations occur at a similar frequency to many other actionable biomarkers in NSCLC4

    Other actionable biomarkers6:

    • ALK fusion ≈ 3.8%
    • MET splice (MET exon 14) ≈ 3%
    • ROS1 fusion ≈ 2.6%
    • BRAF V600E ≈ 2.1%
    • EGFR exon 20 ≈ 2.1%
Patients with HER2 mutations are unlikely to have high PD-L1 expression or another
oncogenic driver mutation3,7-12
ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer;
PD-L1, programmed death ligand 1; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.


Testing eligible patients with mNSCLC for HER2 (ERBB2) mutations is recommended in the NCCN Guidelines®13

Testing for HER2 (ERBB2)

  • HER2 mutations can be detected through broad molecular profiling, typically via NGS, which is recommended for the identification of biomarkers like HER2 mutations in mNSCLC1,3,4,13
  • Most NGS panels include HER2 (ERBB2) mutations14
  • Tissue or plasma specimens can be used to identify patients with activating HER2 (ERBB2) mutations1
  • If no mutation is detected with plasma, tumor tissue should be tested1

Reporting HER2 (ERBB2)
mutation status

  • HER2 mutations are synonymous with and are often reported as mutations in the ERBB2 gene5
  • HER2 mutation results should be listed alongside other actionable biomarkers1,15,16
  • With the approval of ENHERTU in NSCLC, HER2 mutations can be classified as Tier 1A variants based on the criteria outlined in the joint consensus recommendation of the AMP, ASCO, and CAP1,15,16
  • Diagnostic labs may be able to run a report that can identify whether you have patients in your practice with a HER2 mutation
For patients with mNSCLC, refer back to their NGS results to confirm the presence of an activating HER2 (ERBB2) mutation
Information on FDA-approved tests for the detection of activating HER2 mutations is
available at http://www.fda.gov/CompanionDiagnostics.
AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; FDA, Food and Drug Administration; NGS, next-generation sequencing; NCCN, National Comprehensive Cancer Network® (NCCN®).