Zongertinib

Zongertinib is an inhibitor of mutant HER2 containing an activating exon 20 insertion (HER2^YVMA; IC₅₀ = 13 nM in a cellular phosphorylation assay using HEK cells).¹ It is selective for the inhibition of HER2^YVMA over wild-type EGFR (IC₅₀ = 576 nM in a cellular phosphorylation assay using HEK cells). It is also selective for HER2 over 394 kinases in a kinase inhibition assay at 1 µM but does inhibit HER4 and BMX by >80% in the same assay at the same concentration. Zongertinib selectively inhibits the proliferation of Ba/F3 cells engineered to be dependent on HER2^YVMA over those dependent on wild-type EGFR (IC₅₀s = 16 and 1,549 nM, respectively). It also inhibits the proliferation of NCI H2170 non-small cell lung cancer (NSCLC) cells expressing wild-type HER2 or HER2^YVMA (IC₅₀s = 6.3 and 20 nM, respectively) but not A431 epidermal cancer cells dependent on EGFR (IC₅₀ = >5,000 nM). Zongertinib (2.5-20 mg/kg twice per day) reduces tumor growth in an NCI N87 HER2-amplified gastric cancer mouse xenograft model. Formulations containing zongertinib have been used in the treatment of NSCLC in which tumor cells express HER2 activating mutations.

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1. Wilding, B., Woelflingseder, L., Baum, A., et al. Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers. Cancer Discov. 15(1), 119-138 (2025).