# HER2-mutant non-small-cell lung cancer

Source: https://onco.cc/cancers/her2-mutant-nsclc/  
OnCo record `her2-mutant-nsclc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

HER2-mutant lung cancer carries a mutation in the same receptor that drives HER2-positive breast cancer, but the breast cancer antibodies alone did little here. The antibody-drug conjugate trastuzumab deruxtecan shrinks about half of tumours after chemotherapy, and the pill zongertinib about seven in ten, and both are approved.

## Summary

HER2 mutations in lung cancer were recognised in 2004, but for fifteen years the drugs borrowed from breast cancer disappointed: trastuzumab and the pan-HER inhibitors afatinib, neratinib and dacomitinib gave response rates below 20 percent, and poziotinib and pyrotinib were limited by EGFR-driven diarrhoea and rash. First-line treatment is still pembrolizumab plus platinum-pemetrexed as for driver-negative disease, although checkpoint inhibitors alone work poorly and the mutation is one of the few that is usually found by DNA panel rather than RNA testing.

Trastuzumab deruxtecan, a HER2 antibody carrying a topoisomerase I payload, changed the picture: DESTINY-Lung01 (2022) reported a 55 percent response rate in previously treated patients, the FDA granted accelerated approval in August 2022, the first HER2-directed therapy in lung cancer, and DESTINY-Lung02 (2023) confirmed a 49 percent response rate at the 5.4 mg/kg dose with interstitial lung disease in 13 percent, half the rate of the higher dose. Zongertinib, an oral inhibitor selective for mutant HER2 over EGFR, produced a 71 percent confirmed response rate in 75 previously treated patients in Beamion LUNG-1 and 48 percent in patients who had already received a HER2 antibody-drug conjugate, with mostly low-grade diarrhoea and rash, and was approved in August 2025, the first oral HER2 drug for lung cancer. Sevabertinib, a second HER2-selective inhibitor tested in SOHO-01, followed.

Beamion LUNG-2 is comparing zongertinib with chemoimmunotherapy first line, and DESTINY-Lung04 is doing the same for trastuzumab deruxtecan. Open questions are whether an oral inhibitor or an antibody-drug conjugate should come first, how to manage interstitial lung disease, and whether HER2-amplified and HER2-overexpressing tumours without a mutation benefit from the same drugs.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: ERBB2-mutant lung cancer; HER2 exon 20 insertion NSCLC; HER2-positive lung adenocarcinoma
- Tags: subtype-page; lung
- Group: lung
- Burden: HER2 (ERBB2) activating mutations, mostly exon 20 insertions such as A775_G776insYVMA, occur in 2 to 3 percent of lung adenocarcinomas, more often in women and never-smokers; brain metastases develop in about half. HER2 amplification and protein overexpression without mutation are separate and less well defined groups.
- Subtypes: HER2 exon 20 insertion adenocarcinoma (A775_G776insYVMA and others; zongertinib, trastuzumab deruxtecan); HER2 point mutations outside exon 20 (tyrosine kinase domain and extracellular); HER2-amplified or HER2-overexpressing adenocarcinoma without a mutation (trastuzumab deruxtecan under study); HER2-mutant disease with brain metastases
- Biomarkers: HER2 (ERBB2) mutation by DNA sequencing (tyrosine kinase domain, exon 20); HER2 amplification by sequencing or fluorescence in situ hybridisation; HER2 immunohistochemistry (expression, not mutation; separate indication); Brain MRI at diagnosis; Lung imaging and symptoms for interstitial lung disease on trastuzumab deruxtecan; liver enzymes on zongertinib

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/her2-mutant-nsclc/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/her2-mutant-nsclc/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/her2-mutant-nsclc/#what-it-is [4 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/her2-mutant-nsclc/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/her2-mutant-nsclc/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/her2-mutant-nsclc/#evidence [28 trials, 3 key papers, 4 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/her2-mutant-nsclc/#science [3 targets, 3 pathways]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/her2-mutant-nsclc/where-you-are/ [34 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/her2-mutant-nsclc/#living-with-it [17 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/her2-mutant-nsclc/coming/ [9 medicines, 27 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/her2-mutant-nsclc/data/ [71 connected records]

## Standard of care

- Advanced, first line: Pembrolizumab plus platinum-pemetrexed as for driver-negative disease; zongertinib or trastuzumab deruxtecan first line only in trials (Beamion LUNG-2, DESTINY-Lung04). ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [KEYNOTE-024 & KEYNOTE-189](https://onco.cc/trials/keynote-024-189/), [Beamion LUNG-2: A Study to Test Whether Zongertinib (BI 1810631) Helps People With Advanced Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment](https://onco.cc/trials/nct06151574/))
- Advanced, after platinum chemotherapy: Zongertinib (Beamion LUNG-1) or trastuzumab deruxtecan 5.4 mg/kg (DESTINY-Lung02); the other agent at further progression. ([Zongertinib](https://onco.cc/drugs/zongertinib/), [Beamion LUNG-1](https://onco.cc/trials/beamion-lung-1/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Lung02](https://onco.cc/trials/destiny-lung02/), [Sevabertinib](https://onco.cc/drugs/sevabertinib/), [SOHO-01](https://onco.cc/trials/soho-01/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/))
- Brain metastases: Zongertinib and trastuzumab deruxtecan both have intracranial activity; stereotactic radiosurgery for large or symptomatic lesions. ([Zongertinib](https://onco.cc/drugs/zongertinib/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))

## State of the art

- Trastuzumab deruxtecan (2022) and zongertinib (2025) approved after platinum chemotherapy, the first HER2-directed therapies in lung cancer.
- HER2-selective inhibitors that spare EGFR remove the diarrhoea and rash that sank earlier pan-HER drugs.
- First-line phase 3 trials of both drugs against chemoimmunotherapy under way.

## Open problems

- No trial yet compares an oral HER2 inhibitor with an antibody-drug conjugate or settles the sequence.
- Interstitial lung disease from trastuzumab deruxtecan is unpredictable and occasionally fatal.
- HER2-amplified and HER2-overexpressing lung cancers without a mutation lack a defined standard.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/HER2
- Wikipedia: https://en.wikipedia.org/wiki/HER2
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [BRAF V600E-mutant non-small-cell lung cancer](https://onco.cc/cancers/braf-v600e-nsclc/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/), [MET exon 14 and MET-amplified non-small-cell lung cancer](https://onco.cc/cancers/met-altered-nsclc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [NTRK fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ntrk-fusion-nsclc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [HER2 tyrosine kinase inhibitors](https://onco.cc/technologies/her2-tyrosine-kinase-inhibitors/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/)
- targets: [HER2](https://onco.cc/targets/her2/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Afatinib](https://onco.cc/drugs/afatinib/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Neratinib](https://onco.cc/drugs/neratinib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Poziotinib](https://onco.cc/drugs/poziotinib/), [Sevabertinib](https://onco.cc/drugs/sevabertinib/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Zongertinib](https://onco.cc/drugs/zongertinib/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Bayer](https://onco.cc/companies/bayer/), [Boehringer Ingelheim](https://onco.cc/companies/boehringer-ingelheim/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Hepatotoxicity (liver enzyme elevation)](https://onco.cc/terms/hepatotoxicity/), [HER2-positive (IHC 3+ or ISH-amplified)](https://onco.cc/terms/her2-positive/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/)
- trials: [A Clinical Trial of TQB2102 for Injection in Non-small Cell Lung Cancer With HER2 Gene Abnormality](https://onco.cc/trials/nct06496490/), [A Phase 1/2, Open-label, Multicenter, FIH Study to Evaluate Safety, Tolerability, PK and Anti-tumor Activity of YH42946](https://onco.cc/trials/nct06616766/), [A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors](https://onco.cc/trials/nct06695845/), [A Single Arm Phase 2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan for Patients With HER2 Mutant NSCLC](https://onco.cc/trials/nct05246514/), [A Study of BH-30643 in Subjects With Locally Advanced or Metastatic NSCLC Harboring EGFR and/or HER2 Mutations](https://onco.cc/trials/nct06706076/), [A Study of BL-M07D1 in Combination With Pembrolizumab in Patients With Unresectable Locally Advanced or Metastatic HER2-Overexpressing Non-Squamous NS](https://onco.cc/trials/nct07264816/), [A Study of BL-M07D1 in Patients With HER2-mutated, Locally Advanced or Metastatic Non-small-cell Lung Cancer](https://onco.cc/trials/nct06114511/), [A Study of BL-M07D1 vs Pembrolizumab-platinum Chemotherapy in First-line Treatment of HER2-mutant Advanced or Metastatic Non-squamous NSCLC](https://onco.cc/trials/nct07178795/), [A Study of Disitamab Vedotin in Previously Treated Solid Tumors That Express HER2](https://onco.cc/trials/nct06003231/), [A Study of RC48-ADC Combined With Pyrotinib For Treatment of Local Advanced or Metastasis NSCLC With HER2 Mutation](https://onco.cc/trials/nct05745740/), [A Study of SHR-A1811 in First-line Treatment of Patients With Advanced or Metastatic Non-small Cell Lung Cancer With HER2 Mutations](https://onco.cc/trials/nct06430437/), [A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer](https://onco.cc/trials/nct02716116/), [A Study of Trastuzumab Deruxtecan in People With Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07428044/), [A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/Metastatic N](https://onco.cc/trials/nct05048797/), [A Study to Learn More About How Well Sevabertinib Works and How Safe it is Compared With Standard Treatment, in Participants Who Have Advanced Non-sma](https://onco.cc/trials/nct06452277/), [A Trial of Injectable SHR-A1811 in Combination With Pyrotinib or SHR-1316 in Subjects With Advanced Non-small Cell Lung Cancer](https://onco.cc/trials/nct05482568/), [Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR or HER2 Mutation (WU-KONG1)](https://onco.cc/trials/nct03974022/), [Basket Study of Tucatinib and Trastuzumab in Solid Tumors With HER2 Alterations](https://onco.cc/trials/nct04579380/), [Beamion LUNG-1](https://onco.cc/trials/beamion-lung-1/), [Beamion LUNG-2: A Study to Test Whether Zongertinib (BI 1810631) Helps People With Advanced Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment](https://onco.cc/trials/nct06151574/), [Beamion LUNG-3: Adjuvant Zongertinib vs Standard Treatment in People With Completely Resected Stage II-IIIB NSCLC Harboring Activating HER2 TKD Mutati](https://onco.cc/trials/nct07195695/), [DESTINY-Lung01](https://onco.cc/trials/destiny-lung01/), [DESTINY-Lung02](https://onco.cc/trials/destiny-lung02/), [First-In-Human Study of STX-721/PFL-721 in Participants With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR or HER2 Exon 20 Insertion Mutations](https://onco.cc/trials/nct06043817/), [KEYNOTE-024 & KEYNOTE-189](https://onco.cc/trials/keynote-024-189/), [Phase 1b/2 Study to Evaluate ABT-101 in Solid Tumor and NSCLC Patients](https://onco.cc/trials/nct05532696/), [SOHO-01](https://onco.cc/trials/soho-01/), [Study of Trastuzumab Deruxtecan, Pembrolizumab, and Platinum-based Chemotherapy in First-line HER2 Overexpressing Non-small Cell Lung Cancer](https://onco.cc/trials/nct06899126/)
- people: [John V. Heymach](https://onco.cc/people/john-heymach/), [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- key papers: [Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer](https://onco.cc/key-papers/paper-beamion-lung-1-zongertinib-nejm-2025/), [DESTINY-Lung01: trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer](https://onco.cc/key-papers/paper-destiny-lung01-nejm-2022/), [DESTINY-Lung02: two doses of trastuzumab deruxtecan in HER2-mutant metastatic non-small-cell lung cancer](https://onco.cc/key-papers/paper-destiny-lung02-goto-jco-2023/)

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JSON: https://onco.cc/api/v1/entities/her2-mutant-nsclc.json