Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers

Authors

Birgit Wilding
Lydia Woelflingseder
Anke Baum
Krzysztof Chylinski
Gintautas Vainorius
Neil Gibson
Irene C Waizenegger
Daniel Gerlach
Martin Augsten
Fiona Spreitzer
Yukina Shirai
Masachika Ikegami
Sylvia Tilandyová
Dirk Scharn
Mark A Pearson
Johannes Popow
Anna C Obenauf
Noboru Yamamoto
Shunsuke Kondo
Frans L Opdam
Annemarie Bruining
Shinji Kohsaka
Norbert Kraut
John V Heymach
Flavio Solca
Ralph A Neumüller

Publication Date

1-13-2025

Journal

Cancer Discovery

Abstract

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.

Keywords

Humans, Receptor, ErbB-2, Animals, Mice, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, ErbB Receptors, Female, Cell Line, Tumor, Signal Transduction, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Pyrazoles, Antineoplastic Agents

DOI

10.1158/2159-8290.CD-24-0306

PMID

39248702

PMCID

PMC11726021

PubMedCentral® Posted Date

9-5-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes