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 KRAS^G12C 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.