Variant cheat sheet · NSCLC
HER2 (ERBB2) activating mutations in NSCLC
Free clinical reference. Educational use only — not a substitute for professional medical advice.
TL;DR
HER2 (ERBB2) activating mutations in NSCLC — predominantly exon 20 insertions — are AMP/ASCO/CAP Tier I-A for trastuzumab deruxtecan (T-DXd) based on DESTINY-Lung01 and DESTINY-Lung02. Important to distinguish HER2 mutations (this page) from HER2 amplification — different biology, different drugs, sometimes both in the same tumor. Pneumonitis monitoring is mandatory.
Biology
HER2 (ERBB2) activating mutations in NSCLC are dominated by exon 20 in-frame insertions (e.g., Y772_A775dupYVMA). These produce a constitutively active receptor tyrosine kinase that drives MAPK + PI3K/AKT signaling. Unlike HER2 amplification in breast cancer, the mutations require an ADC strategy because classical anti-HER2 antibodies (trastuzumab alone) and small-molecule HER2 TKIs have shown limited efficacy.
Epidemiology
HER2 activating mutations occur in roughly 2-4% of NSCLC adenocarcinomas, enriched in never-smokers and younger patients, similar to other oncogenic-driver subsets. Exon 20 insertions are the dominant class.
Detection
- Comprehensive NGS panels (FoundationOne CDx, Tempus xT, Caris MI Profile) flag ERBB2 mutations and report variant class.
- Plasma circulating tumor DNA detection is feasible.
- IHC and FISH (which detect HER2 amplification) are not sufficient to detect HER2 mutations — NGS is required.
FDA-approved targeted therapies
| Drug | Indication | Line | Tier |
|---|---|---|---|
| Trastuzumab deruxtecan (T-DXd) | HER2-mutant unresectable/metastatic NSCLC (DESTINY-Lung02) | 2L+ (after platinum chemo) | I-A |
| Trastuzumab deruxtecan (T-DXd) | HER2-overexpressing NSCLC (broader DESTINY-Lung01 cohort) | 2L+ | I-A |
| Ado-trastuzumab emtansine (T-DM1) | HER2-mutant NSCLC, investigational | Off-label / trial | II-C |
Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.
Frequently asked questions
- What's the difference between HER2 mutation and HER2 amplification?
- HER2 amplification = extra copies of the ERBB2 gene, common in HER2-positive breast and gastric cancer. HER2 mutations = point mutations or insertions in the kinase domain (most commonly exon 20 insertions in NSCLC). Different biology, different testing modality, different drugs. Some tumors have both; comprehensive NGS catches the mutation, IHC/FISH catches the amplification.
- Why isn't trastuzumab effective against HER2 mutations?
- Trastuzumab binds the extracellular domain. HER2 exon 20 insertions activate the kinase intracellularly without changing the extracellular structure substantially, so antibody binding doesn't translate to effective signaling blockade. Antibody-drug conjugates like T-DXd work because they deliver a cytotoxic payload after internalization, bypassing the signaling-blockade limitation.
- What about small-molecule HER2 TKIs?
- Older HER2 TKIs (lapatinib, neratinib) have shown limited activity against HER2 exon 20 insertions. T-DXd is the current standard. Newer TKIs (poziotinib, mobocertinib) showed activity but pulled or restricted indications due to AE profiles and accelerated-approval issues.