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Preclinical studies assess its activity in lung cancer models carrying HER2 alterations, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. The work also evaluates sevabertinib in HER3 fusion-dependent cancer cell line systems. A phase 1/2 trial reports patient responses, suggesting potential benefit for HER2-mutant lung cancer.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/sevabertinib-a-reversible-her2-inhibitor-with-activity-in-lung-cancer/353516/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/sevabertinib-a-reversible-her2-inhibitor-with-activity-in-lung-cancer/353516.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-25","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are additional therapies needed for lung cancer with HER2 activating mutations?","Question",{"text":112,"@type":113},"Only limited therapeutic options exist for patients with HER2 activating mutations, including exon 20 insertions. The study highlights the need for improved treatments for HER2-mutant lung cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What HER2 alterations were evaluated in preclinical models?",{"text":117,"@type":113},"The research examines sevabertinib activity in models harboring HER2 exon 20 insertions, point mutations, and amplification of wild-type ERBB2.",{"name":119,"@type":110,"acceptedAnswer":120},"What do the phase 1/2 clinical trial results indicate?",{"text":121,"@type":113},"Patient responses in a phase 1/2 trial suggest potential benefit of sevabertinib for patients with HER2-mutant lung cancer.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},353516,1790324066,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","ReseaRch aRticle  \nSevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer   \nFranziska Siegel 1, Stephan Siegel 1, Kristýna Kotýnková2, Gizem Karsli Uzunbas2, Daniel Korr3,  \nHarunaTomono2, Sawyer Andersen2, Daniel Denney2, Markus Berger1, Volker K. Schulze1, Timothy A. Lewis4, Bethany Kaplan2, Sven Golfier3, Jérémie Mortier1, Roman C. Hillig3, Ulf Boemer3, Kirstin Petersen1, Knut Eis1, Sybil Williams5, Dominik Rüttinger1, Andrew D. Cherniack2,6, Herbert H. Loong7, Koichi Goto8, Paolo Grassi9, Matthew Meyerson2,6, and Heidi Greulich2,6  \nExon 20 insertions of HER2, encoded by erb-b2 receptor tyrosine kinase 2  \n(ERBB2), and other activating HER2 mutations occur in 2% to 4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR–HER2 inhibitor that is selective with respect to wild-type EGFR. In this study, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2 . We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of neuregulin-1, a ligand for the HER2 family member and heterodimerization partner, HER3 . Finally, we report patient responses to sevabertinib from a phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.  \nSIgnIfICAnCE: Additional therapeutic options are needed for patients with lung cancer with HER2 activating mutations, including exon 20 insertions. Sevabertinib shows activity against ERBB2-encoded HER2 exon 20 insertions in preclinical models of lung cancer, corroborated by early data from a phase 1/2 clinical trial.  \nintRoduction  \nThe erb-b2 receptor tyrosine kinase 2 (ERBB2), encoding the HER2 protein, is frequently altered in cancer. These alterations include ERBB2 amplifications in breast and other cancers (1), HER2 exon 20 insertions in lung cancer (2, 3), and activating point mutations of HER2 across cancers (4). ERBB2 amplifications in breast cancer are successfully targeted by a suite of mAbs and antibody-drug conjugates, including trastuzumab, pertuzumab, margetuximab, trastuzumab emtansine, and trastuzumab deruxtecan (T-DXd; refs. 5–9) . The small-molecule HER2 inhibitors, lapatinib, neratinib, and tucatinib, are additionally approved in the United States for the treatment of ERBB2-amplified breast cancer (10–12) . ERBB2 amplification is also found in gastroesophageal cancer, but HER2-targeted therapies are less effective in this tumor type due to tumor heterogeneity and co-occurring cancer gene mutations (13,14). Oncogenic fusions ofneuregulin-1 (NRG1),  \n1Bayer AG, Pharmaceuticals, Research & Early Development Oncology, Berlin, Germany. 2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 3Nuvisan ICB GmbH, Berlin, Germany. 4Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 5Bayer HealthCare Pharmaceuticals Inc. , Research & Early Development Oncology, Cambridge, Massachusetts.  \n6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 7The Chinese University of Hong Kong, Hong Kong SAR, China. 8National Cancer Center Hospital East, Kashiwa, Japan. 9Bayer S.p.A. , Milan, Italy.  \nCorresponding Authors: Heidi Greulich, Broad Institute, 415 Main Street, Cambridge, MA 02142. E-mail: [heidig@broadinstitute.org](heidig@broadinstitute.org); Franziska Siegel, Bayer AG, Research & Development, Pharmaceuticals, Muellerstrasse 178, 13342 Berlin, Germany. E-mail: [franziska.siegel@bayer.com](franziska.siegel@bayer.com); and Matthew Meyerson, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, [MA 02115. E-mail: matthew_meyerson@dfci.harvard.edu](MA 02115. E-mail: matthew_meyerson@dfci.harvard.edu)  \nCancer Discov 2026;16:81–94  \ndoi: 10. 1158/2159-8","cbCaii65gzzvF5fX","https://ap.wps.com/l/cbCaii65gzzvF5fX","pdf",7476003,14,"English","# Significance\n# Introduction","[{\"question\":\"Why are additional therapies needed for lung cancer with HER2 activating mutations?\",\"answer\":\"Only limited therapeutic options exist for patients with HER2 activating mutations, including exon 20 insertions. The study highlights the need for improved treatments for HER2-mutant lung cancer.\"},{\"question\":\"What HER2 alterations were evaluated in preclinical models?\",\"answer\":\"The research examines sevabertinib activity in models harboring HER2 exon 20 insertions, point mutations, and amplification of wild-type ERBB2.\"},{\"question\":\"What do the phase 1/2 clinical trial results indicate?\",\"answer\":\"Patient responses in a phase 1/2 trial suggest potential benefit of sevabertinib for patients with HER2-mutant lung cancer.\"}]","Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer | PDF",1790105880,35]