biomarkersBiomarker

HER2 (ERBB2) activating mutation

aka HER2 mutation, ERBB2 mutation, HER2-mutant NSCLC, ERBB2 exon 20 insertion, HER2 tyrosine kinase domain mutation, HER2 YVMA insertion, HER2 TKD mutation

A HER2 mutation is a change in the gene's kinase domain, most often an exon 20 insertion, found in about 2 to 3 percent of lung adenocarcinomas. It is a different thing from HER2 amplification or overexpression, and it selects trastuzumab deruxtecan and, since 2025, zongertinib in lung cancer.

Activating ERBB2 mutations cluster in the tyrosine kinase domain (exons 18 to 21), the commonest being the exon 20 insertion A775_G776insYVMA; they are detected by sequencing of tumour tissue or plasma. Trastuzumab deruxtecan's label covers unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations in tumour or plasma specimens after prior systemic therapy (DESTINY-Lung02). Zongertinib (Hernexeos), approved in 2025, is labelled for non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain activating mutations detected by an FDA-authorised test, testing plasma first and tissue if plasma is negative. The FDA list carries the Oncomine Dx Target Test and Guardant360 CDx for both drugs.

Part ofHER2· ERBB2Other readoutsHER2 IHC 0 HER2 IHC 1+HER2 IHC 2+HER2 IHC 3+HER2 ISH amplified HER2-low HER2-ultralow All readouts

HER2: what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers.

Sequencing 2 approval thresholds

What it means for a patient

A HER2 mutation in lung cancer is found by a gene sequencing test, not by the HER2 stain used in breast cancer. If your report shows one, zongertinib is an on-label first treatment and trastuzumab deruxtecan is on label after prior treatment. If only a blood test was done and it was negative, the label asks for the tumour tissue to be tested too.

Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.

Scoring rule

Presence of an activating ERBB2 mutation (single nucleotide variants in exons 18 to 21 of the tyrosine kinase domain or exon 20 insertions) by sequencing of tumour tissue or plasma; a negative plasma result should be followed by tissue testing.

“ERBB2/HER2 activating mutations (SNVs in exons 18-21 within the tyrosine kinase domain and exon 20 insertions)”
FDA: List of FDA-Authorized Companion Diagnostic Devices

Thresholds used in approvals

Threshold	Drug	Cancer	Regulator	Source
Activating HER2 (ERBB2) mutation, tumour or plasma	Trastuzumab deruxtecan	Non-small-cell lung cancer	FDA	label
HER2 (ERBB2) tyrosine kinase domain activating mutation	Zongertinib	Non-small-cell lung cancer	FDA	label

Drugs whose label names it

Trastuzumab deruxtecan Zongertinib

Companion diagnostics (FDA list)

Device	Maker	Indication and sample	Drug	PMA / 510(k)
Oncomine Dx Target Test	Life Technologies (Thermo Fisher Scientific)	Non-Small Cell Lung Cancer (NSCLC) - Tissue	Trastuzumab deruxtecan	P160045/S035 (08/11/2022)
Guardant360 CDx	Guardant Health	Non-Small Cell Lung Cancer (NSCLC) - Plasma	Trastuzumab deruxtecan	P200010/S008 (08/11/2022)
Oncomine Dx Target Test	Life Technologies (Thermo Fisher Scientific)	Non-Small Cell Lung cancer (NSCLC) - Tissue	Zongertinib	P160045/S049 (08/08/2025)
Guardant360 CDx	Guardant Health	Non-small cell lung cancer (NSCLC) - Plasma	Zongertinib	P200010/S027 (06/10/2026)

Tests that measure it

Guardant360 CDx Oncomine Dx Target Test Tempus xT and xT CDx FoundationOne CDx Guardant360 CDx Illumina TruSight Oncology Comprehensive

Trials that name this readout

Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.