Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers
Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation), thus supporting the ongoing clinical development of zongertinib. Significance: HER2-mutant NSCLC poses a challenge in the clinic due to limited options for targeted therapies. Pan-ERBB blockers are limited by wild-type EGFR-mediated toxicity. Zongertinib is a highly potent and wild-type EGFR-sparing HER2 inhibitor that is active in HER2-driven tumors in the preclinical and clinical settings.
Authors
- Johannes Popow (ORCID: https://orcid.org/0000-0002-1093-0936)
- Daniel Gerlach (ORCID: https://orcid.org/0000-0001-9338-3765)
- Anke Baum (ORCID: https://orcid.org/0000-0001-8083-4416)
- Gintautas Vainorius (ORCID: https://orcid.org/0000-0001-6552-4743)
- Fiona Spreitzer (ORCID: https://orcid.org/0000-0001-6142-549X)
- Frans L. Opdam (ORCID: https://orcid.org/0000-0002-9489-6535)
- Masachika Ikegami (ORCID: https://orcid.org/0000-0003-0491-7142)
- Yukina Shirai (ORCID: https://orcid.org/0009-0001-9196-9794)
- Irene C. Waizenegger (ORCID: https://orcid.org/0000-0002-3911-6970)
- Noboru Yamamoto (ORCID: https://orcid.org/0000-0002-0787-2851)
- Lydia Woelflingseder (ORCID: https://orcid.org/0000-0002-8068-5323)
- Ralph A. Neumüller (ORCID: https://orcid.org/0000-0002-1514-6278)
- Annemarie Bruining (ORCID: https://orcid.org/0000-0003-4327-1655)
- John Victor Heymach (ORCID: https://orcid.org/0000-0001-9068-8942)
- Birgit Wilding (ORCID: https://orcid.org/0000-0002-1896-3708)
- Shinji Kohsaka (ORCID: https://orcid.org/0000-0001-8651-6136)
- Norbert Kraut (ORCID: https://orcid.org/0000-0003-3941-7105)
- Krzysztof Chylinski (ORCID: https://orcid.org/0000-0001-7029-8090)
- Flavio Solca (ORCID: https://orcid.org/0000-0001-8756-2046)
- Dirk Scharn
- Anna C. Obenauf (ORCID: https://orcid.org/0000-0002-9556-5914)
- Shunsuke Kondo (ORCID: https://orcid.org/0000-0001-9565-117X)
- Mark Pearson
- Sylvia Tilandyová (ORCID: https://orcid.org/0009-0007-3900-7807)
- Martin Augsten (ORCID: https://orcid.org/0009-0007-8712-1786)
- Neil Gibson
Institutions
- Boehringer Ingelheim (Germany) (DE)
- The University of Texas MD Anderson Cancer Center (US)
- Research Institute of Molecular Pathology (AT)
- Dutch Cancer Society (NL)
- The Netherlands Cancer Institute (NL)
- National Cancer Centre Japan (JP)
- Boehringer Ingelheim (Austria) (AT)
- Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NL)
- National Cancer Center Hospital East (JP)
- Tokyo National Hospital (JP)
- National Cancer Research Institute (GB)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-0306
- Citations
- 34
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 9.61
Funders
- Broad Institute
- Österreichische Forschungsförderungsgesellschaft