Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers.
Birgit WildingLydia WoelflingsederAnke BaumKrzysztof ChylinskiGintautas VainoriusNeil GibsonIrene C WaizeneggerDaniel GerlachMartin AugstenFiona SpreitzerYukina ShiraiMasachika IkegamiSylvia TilandyovaDirk ScharnMark A PearsonJohannes PopowAnna C ObenaufNoboru YamamotoShunsuke KondoFrans L OpdamAnnemarie BruiningShinji KohsakaNorbert KrautJohn Victor HeymachFlavio SolcaRalph A NeumullerPublished in: Cancer discovery (2024)
Mutations in HER2 occur in 2-4% 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 anti-tumor 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.
Keyphrases
- small cell lung cancer
- poor prognosis
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- endothelial cells
- long non coding rna
- induced apoptosis
- small molecule
- oxidative stress
- high throughput
- transcription factor
- cell proliferation
- signaling pathway
- pluripotent stem cells
- young adults
- robot assisted
- minimally invasive