{"entity":{"id":"her2-mutant-nsclc","kind":"cancer","name":"HER2-mutant non-small-cell lung cancer","aka":["ERBB2-mutant lung cancer","HER2 exon 20 insertion NSCLC","HER2-positive lung adenocarcinoma"],"tldr":"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.\n\nTrastuzumab 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.\n\nBeamion 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HER2","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":[],"cancers":[],"sections":[],"technologies":["adc","her2-tyrosine-kinase-inhibitors","kinase-inhibitors","topoisomerase-inhibitors","cgp"],"targets":["her2","pd1"],"drugs":["trastuzumab-deruxtecan","zongertinib","sevabertinib","pembrolizumab","afatinib","neratinib"],"companies":["daiichi-sankyo","astrazeneca","boehringer-ingelheim","bayer"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation","pi3k-akt-mtor"],"terms":["driver-mutation","ild","hepatotoxicity","brain-metastases","her2-positive"],"trials":["destiny-lung02","beamion-lung-1","soho-01","nct06151574"],"people":["john-heymach","pasi-janne"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Pembrolizumab plus platinum-pemetrexed as for driver-negative disease; zongertinib or trastuzumab deruxtecan first line only in trials (Beamion LUNG-2, DESTINY-Lung04).","refs":["pembrolizumab","carboplatin","pemetrexed","keynote-024-189","nct06151574"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after platinum chemotherapy","approach":"Zongertinib (Beamion LUNG-1) or trastuzumab deruxtecan 5.4 mg/kg (DESTINY-Lung02); the other agent at further progression.","refs":["zongertinib","beamion-lung-1","trastuzumab-deruxtecan","destiny-lung02","sevabertinib","soho-01","ild"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain metastases","approach":"Zongertinib and trastuzumab deruxtecan both have intracranial activity; stereotactic radiosurgery for large or symptomatic lesions.","refs":["zongertinib","trastuzumab-deruxtecan","radiosurgery-srs","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["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."],"history":[{"year":2004,"title":"HER2 kinase domain mutations found in lung adenocarcinoma","refs":["her2"]},{"year":2022,"title":"DESTINY-Lung01: trastuzumab deruxtecan approved, the first HER2-directed lung cancer therapy","refs":["trastuzumab-deruxtecan","daiichi-sankyo"]},{"year":2023,"title":"DESTINY-Lung02 confirms the 5.4 mg/kg dose with less lung inflammation","refs":["destiny-lung02","trastuzumab-deruxtecan"]},{"year":2025,"title":"Beamion LUNG-1: zongertinib approved, the first oral HER2 inhibitor for lung cancer","refs":["beamion-lung-1","zongertinib","john-heymach","boehringer-ingelheim"]}],"pipeline":["nct06151574","sevabertinib","soho-01","zongertinib","trastuzumab-deruxtecan"],"openProblems":["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."],"parent":"nsclc"},"route":"/cancers/her2-mutant-nsclc/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"her2-tyrosine-kinase-inhibitors","kind":"technology","name":"HER2 tyrosine kinase inhibitors","route":"/technologies/her2-tyrosine-kinase-inhibitors/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"radiosurgery-srs","kind":"technology","name":"Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)","route":"/technologies/radiosurgery-srs/"},{"id":"topoisomerase-inhibitors","kind":"technology","name":"Topoisomerase-I inhibitors (and ADC payloads)","route":"/technologies/topoisomerase-inhibitors/"}],"target":[{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"afatinib","kind":"drug","name":"Afatinib","route":"/drugs/afatinib/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"neratinib","kind":"drug","name":"Neratinib","route":"/drugs/neratinib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"},{"id":"sevabertinib","kind":"drug","name":"Sevabertinib","route":"/drugs/sevabertinib/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"zongertinib","kind":"drug","name":"Zongertinib","route":"/drugs/zongertinib/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"bayer","kind":"company","name":"Bayer","route":"/companies/bayer/"},{"id":"boehringer-ingelheim","kind":"company","name":"Boehringer Ingelheim","route":"/companies/boehringer-ingelheim/"},{"id":"daiichi-sankyo","kind":"company","name":"Daiichi Sankyo","route":"/companies/daiichi-sankyo/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"brain-metastases","kind":"term","name":"Brain metastases (intracranial disease)","route":"/terms/brain-metastases/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"hepatotoxicity","kind":"term","name":"Hepatotoxicity (liver enzyme elevation)","route":"/terms/hepatotoxicity/"},{"id":"her2-positive","kind":"term","name":"HER2-positive (IHC 3+ or ISH-amplified)","route":"/terms/her2-positive/"},{"id":"ild","kind":"term","name":"Interstitial lung disease (ILD) / pneumonitis","route":"/terms/ild/"}],"trial":[{"id":"beamion-lung-1","kind":"trial","name":"Beamion LUNG-1","route":"/trials/beamion-lung-1/"},{"id":"nct06151574","kind":"trial","name":"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","route":"/trials/nct06151574/"},{"id":"destiny-lung02","kind":"trial","name":"DESTINY-Lung02","route":"/trials/destiny-lung02/"},{"id":"keynote-024-189","kind":"trial","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/"},{"id":"soho-01","kind":"trial","name":"SOHO-01","route":"/trials/soho-01/"}],"person":[{"id":"john-heymach","kind":"person","name":"John V. Heymach","route":"/people/john-heymach/"},{"id":"pasi-janne","kind":"person","name":"Pasi A. Jänne","route":"/people/pasi-janne/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}]}}