HER2-mutant non-small-cell lung cancer
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowSkin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
- Call the 24-hour line nowInterstitial lung disease or pneumonitis
Any new or worsening cough, breathlessness or fever. The label says to interrupt treatment for any suspected ILD and to permanently discontinue for grade 2 or higher.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
See all on the product pages:CarboplatinPembrolizumabPemetrexedSevabertinibTrastuzumab deruxtecanZongertinib·Printable cards in the navigator
Anatomy and lymph node drainage
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)
- Nodes: hilar (N1)
- Nodes: mediastinal (N2)
- Nodes: supraclavicular (N3)
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)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
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)HER2 exon 20 insertion adenocarcinoma (A775_G776insYVMA and others; zongertinib, trastuzumab deruxtecan) · HER2-amplified or HER2-overexpressing adenocarcinoma without a mutation (trastuzumab deruxtecan under study)
- hilar (N1)
- mediastinal (N2)
- supraclavicular (N3)
Same organ: Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, KRAS G12C-mutant non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid)
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Pembrolizumab plus platinum-pemetrexed as for driver-negative disease; zongertinib or trastuzumab deruxtecan first line only in trials (Beamion LUNG-2, DESTINY-Lung04).
Zongertinib (Beamion LUNG-1) or trastuzumab deruxtecan 5.4 mg/kg (DESTINY-Lung02); the other agent at further progression.
Zongertinib and trastuzumab deruxtecan both have intracranial activity; stereotactic radiosurgery for large or symptomatic lesions.
Subtypes & biomarkers
top- 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
- 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
How often this target appears
- 2004HER2 kinase domain mutations found in lung adenocarcinoma
- 2022DESTINY-Lung01: trastuzumab deruxtecan approved, the first HER2-directed lung cancer therapy
- 2023DESTINY-Lung02 confirms the 5.4 mg/kg dose with less lung inflammation
- 2025Beamion LUNG-1: zongertinib approved, the first oral HER2 inhibitor for lung cancer
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 9 changes by month →- 2026-09-17This recordHER2-mutant non-small-cell lung cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2025Trial resultBeamion LUNG-1Beamion LUNG-1 reported
Confirmed response rate 71% in 75 previously treated patients naive to HER2-directed therapy; 48% after a HER2 antibody-drug conjugate; FDA accelerated approval August 2025.
- 2025Trial resultSOHO-01SOHO-01 reported
ORR ~64%; accelerated approval Nov 2025.
- 2025MilestoneBeamion LUNG-1Beamion LUNG-1: zongertinib approved, the first oral HER2 inhibitor for lung cancer
A milestone in how this cancer is treated.
- 2023Trial resultDESTINY-Lung02DESTINY-Lung02 reported
Confirmed response rate 49.
- 2023MilestoneDESTINY-Lung02DESTINY-Lung02 confirms the 5.4 mg/kg dose with less lung inflammation
A milestone in how this cancer is treated.
What is in development for HER2-mutant non-small-cell lung cancer, drawn from the whole corpus: 4 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 1
Trials reported · 3
- SOHO-01 · phase 1/2 · 2025 · positive
- Beamion LUNG-1 · phase 1/2 · 2025 · positive
- DESTINY-Lung02 · phase 2 · 2023 · positive
Open problems and what is being done
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.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Houston · cancer center | United States | 0 | 6,724 | 95,007 | #2 | ||
| South Korea | none recorded | 0 | 1,312 | 17,172 | #3 | ||
Rochester, MN · hospital | United States | 0 | 4,511 | 44,748 | #5 | ||
Villejuif · cancer center | France | none recorded | 0 | 1,855 | 31,182 | #6 | |
| South Korea | none recorded | 0 | 1,607 | 24,676 | #8 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Berlin · university | Germany | none recorded | 0 | 1,563 | 17,749 | #12 | |
Tokyo · government | Japan | none recorded | 0 | 1,599 | 21,937 | none recorded | #13 |
| United States | 0 | 3,582 | 54,857 | #16 | |||
Cleveland · hospital | United States | 0 | 2,264 | 29,412 | #20 | ||
Seoul · hospital | South Korea | none recorded | 0 | 464 | 3,248 | #22 | |
Stanford · university | United States | 0 | 3,000 | 50,162 | #30 | ||
San Francisco · cancer center | United States | 0 | 2,800 | 46,704 | #33 | ||
Stockholm · university | Sweden | none recorded | 0 | 987 | 12,440 | #39 | |
London · hospital | United Kingdom | none recorded | 0 | 2,376 | 28,940 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with HER2-mutant non-small-cell lung cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about HER2-mutant non-small-cell lung cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example HER2mutation by DNA sequencing, HER2 amplification by sequencing or fluorescence in situ hybridisation, HER2 immunohistochemistry, Brain MRI at diagnosis, Lung imaging and symptoms for interstitial lung disease on trastuzumab deruxtecan; liver enzymes on zongertinib), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include HER2 exon 20 insertion adenocarcinoma, HER2 point mutations outside exon 20, HER2-amplified or HER2-overexpressing adenocarcinoma without a mutation.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Advanced, first line
- For my situation (advanced, first line), which of the standard options do you recommend and why?Why: Guideline options include: Pembrolizumab plus platinum-pemetrexed as for driver-negative disease; zongertinib or trastuzumab deruxtecan first line only in trials (Beamion LUNG-2, DESTINY-Lung04).
- Am I a candidate for Pembrolizumab, Carboplatin, Pemetrexed, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-024 & KEYNOTE-189 and 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 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced, after platinum chemotherapy
- For my situation (advanced, after platinum chemotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Zongertinib (Beamion LUNG-1) or trastuzumab deruxtecan 5.4 mg/kg (DESTINY-Lung02); the other agent at further progression.
- Am I a candidate for Zongertinib, Trastuzumab deruxtecan, Sevabertinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Beamion LUNG-1 and DESTINY-Lung02 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Brain metastases
- For my situation (brain metastases), which of the standard options do you recommend and why?Why: Guideline options include: Zongertinib and trastuzumab deruxtecan both have intracranial activity; stereotactic radiosurgery for large or symptomatic lesions.
- Am I a candidate for Zongertinib, Trastuzumab deruxtecan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of 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, Sevabertinib, SOHO-01, Zongertinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No trial yet compares an oral HER2 inhibitor with an antibody-drug conjugate or settles the sequence”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Interstitial lung disease from trastuzumab deruxtecan is unpredictable and occasionally fatal”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with HER2-mutant non-small-cell lung cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
9targets
3drugs
8companies
6pathways
3terms
5trials
5people
2Latest papers
topQuery for this cancer: (TITLE:"HER2-mutant non-small-cell lung cancer" OR ABSTRACT:"HER2-mutant non-small-cell lung cancer" OR TITLE:"ERBB2-mutant lung cancer" OR ABSTRACT:"ERBB2-mutant lung cancer" OR TITLE:"HER2 exon 20 insertion NSCLC" OR ABSTRACT:"HER2 exon 20 insertion NSCLC" OR TITLE:"HER2-positive lung adenocarcinoma" OR ABSTRACT:"HER2-positive lung adenocarcinoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HER2-mutant non-small-cell lung cancer, not a curated reading list.
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