{"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":["egfr-mutant-nsclc","kras-g12c-nsclc","braf-v600e-nsclc","met-altered-nsclc","alk-positive-nsclc","ntrk-fusion-nsclc"],"cancers":[],"sections":[],"technologies":["adc","her2-tyrosine-kinase-inhibitors","kinase-inhibitors","topoisomerase-inhibitors","cgp"],"targets":["her2","pd1"],"drugs":["trastuzumab-deruxtecan","zongertinib","sevabertinib","pembrolizumab","afatinib","neratinib","poziotinib"],"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","destiny-lung01","nct05048797"],"people":["john-heymach","pasi-janne"],"bottlenecks":[],"keyPapers":["paper-destiny-lung01-nejm-2022","paper-destiny-lung02-goto-jco-2023","paper-beamion-lung-1-zongertinib-nejm-2025"],"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":{"cancer":[{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"braf-v600e-nsclc","kind":"cancer","name":"BRAF V600E-mutant non-small-cell lung cancer","route":"/cancers/braf-v600e-nsclc/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"met-altered-nsclc","kind":"cancer","name":"MET exon 14 and MET-amplified non-small-cell lung cancer","route":"/cancers/met-altered-nsclc/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"ntrk-fusion-nsclc","kind":"cancer","name":"NTRK fusion-positive non-small-cell lung cancer","route":"/cancers/ntrk-fusion-nsclc/"}],"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":"poziotinib","kind":"drug","name":"Poziotinib","route":"/drugs/poziotinib/"},{"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":"nct06496490","kind":"trial","name":"A Clinical Trial of TQB2102 for Injection in Non-small Cell Lung Cancer With HER2 Gene Abnormality","route":"/trials/nct06496490/"},{"id":"nct06616766","kind":"trial","name":"A Phase 1/2, Open-label, Multicenter, FIH Study to Evaluate Safety, Tolerability, PK and Anti-tumor Activity of YH42946","route":"/trials/nct06616766/"},{"id":"nct06695845","kind":"trial","name":"A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors","route":"/trials/nct06695845/"},{"id":"nct05246514","kind":"trial","name":"A Single Arm Phase 2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan for Patients With HER2 Mutant NSCLC","route":"/trials/nct05246514/"},{"id":"nct06706076","kind":"trial","name":"A Study of BH-30643 in Subjects With Locally Advanced or Metastatic NSCLC Harboring EGFR and/or HER2 Mutations","route":"/trials/nct06706076/"},{"id":"nct07264816","kind":"trial","name":"A Study of BL-M07D1 in Combination With Pembrolizumab in Patients With Unresectable Locally Advanced or Metastatic HER2-Overexpressing Non-Squamous NS","route":"/trials/nct07264816/"},{"id":"nct06114511","kind":"trial","name":"A Study of BL-M07D1 in Patients With HER2-mutated, Locally Advanced or Metastatic Non-small-cell Lung Cancer","route":"/trials/nct06114511/"},{"id":"nct07178795","kind":"trial","name":"A Study of BL-M07D1 vs Pembrolizumab-platinum Chemotherapy in First-line Treatment of HER2-mutant Advanced or Metastatic Non-squamous NSCLC","route":"/trials/nct07178795/"},{"id":"nct06003231","kind":"trial","name":"A Study of Disitamab Vedotin in Previously Treated Solid Tumors That Express HER2","route":"/trials/nct06003231/"},{"id":"nct05745740","kind":"trial","name":"A Study of RC48-ADC Combined With Pyrotinib For Treatment of Local Advanced or Metastasis NSCLC With HER2 Mutation","route":"/trials/nct05745740/"},{"id":"nct06430437","kind":"trial","name":"A Study of SHR-A1811 in First-line Treatment of Patients With Advanced or Metastatic Non-small Cell Lung Cancer With HER2 Mutations","route":"/trials/nct06430437/"},{"id":"nct02716116","kind":"trial","name":"A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer","route":"/trials/nct02716116/"},{"id":"nct07428044","kind":"trial","name":"A Study of Trastuzumab Deruxtecan in People With Non-Small Cell Lung Cancer","route":"/trials/nct07428044/"},{"id":"nct05048797","kind":"trial","name":"A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/Metastatic N","route":"/trials/nct05048797/"},{"id":"nct06452277","kind":"trial","name":"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","route":"/trials/nct06452277/"},{"id":"nct05482568","kind":"trial","name":"A Trial of Injectable SHR-A1811 in Combination With Pyrotinib or SHR-1316 in Subjects With Advanced Non-small Cell Lung Cancer","route":"/trials/nct05482568/"},{"id":"nct03974022","kind":"trial","name":"Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR or HER2 Mutation (WU-KONG1)","route":"/trials/nct03974022/"},{"id":"nct04579380","kind":"trial","name":"Basket Study of Tucatinib and Trastuzumab in Solid Tumors With HER2 Alterations","route":"/trials/nct04579380/"},{"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":"nct07195695","kind":"trial","name":"Beamion LUNG-3: Adjuvant Zongertinib vs Standard Treatment in People With Completely Resected Stage II-IIIB NSCLC Harboring Activating HER2 TKD Mutati","route":"/trials/nct07195695/"},{"id":"destiny-lung01","kind":"trial","name":"DESTINY-Lung01","route":"/trials/destiny-lung01/"},{"id":"destiny-lung02","kind":"trial","name":"DESTINY-Lung02","route":"/trials/destiny-lung02/"},{"id":"nct06043817","kind":"trial","name":"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","route":"/trials/nct06043817/"},{"id":"keynote-024-189","kind":"trial","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/"},{"id":"nct05532696","kind":"trial","name":"Phase 1b/2 Study to Evaluate ABT-101 in Solid Tumor and NSCLC Patients","route":"/trials/nct05532696/"},{"id":"soho-01","kind":"trial","name":"SOHO-01","route":"/trials/soho-01/"},{"id":"nct06899126","kind":"trial","name":"Study of Trastuzumab Deruxtecan, Pembrolizumab, and Platinum-based Chemotherapy in First-line HER2 Overexpressing Non-small Cell Lung Cancer","route":"/trials/nct06899126/"}],"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/"}],"paper":[{"id":"paper-beamion-lung-1-zongertinib-nejm-2025","kind":"paper","name":"Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer","route":"/key-papers/paper-beamion-lung-1-zongertinib-nejm-2025/"},{"id":"paper-destiny-lung01-nejm-2022","kind":"paper","name":"DESTINY-Lung01: trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer","route":"/key-papers/paper-destiny-lung01-nejm-2022/"},{"id":"paper-destiny-lung02-goto-jco-2023","kind":"paper","name":"DESTINY-Lung02: two doses of trastuzumab deruxtecan in HER2-mutant metastatic non-small-cell lung cancer","route":"/key-papers/paper-destiny-lung02-goto-jco-2023/"}]}}