Zongertinib is being evaluated in Phase I, II and III clinical trials across a range of patient populations.^3–11

zongertinib clinical trials

zongertinib mechanism of action

Zongertinib is an irreversible TKI that selectively inhibits HER2 while sparing wild-type EGFR, thereby limiting associated toxicities. Zongertinib targets wild-type HER2 and a broad range of oncogenic HER2 mutations outside and inside the tyrosine kinase domain (TKD), including HER2 exon 20 insertion mutations.¹

Zongertinib irreversibly inhibits the kinase activity of HER2, downstream signaling, and blocks the growth and survival of cultured HER2-driven cancer cells.¹

zongertinib mechanism of action^1,3,12

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In Ba/F3 cells, zongertinib demonstrated a large difference in binding affinity to wild-type EGFR compared with HER2^YVMA. Zongertinib binds the adenosine triphosphate (ATP)-binding site of HER2 and forms a covalent bond with cysteine 805. The covalent binding of HER2 is critical for the high potency of zongertinib in inhibiting cell proliferation.^1,3

Zongertinib has shown potent antiproliferative activity against tumor cell lines dependent on HER2. Anti-tumor activity including tumor regressions were demonstrated at clinically achievable exposures in different HER2-driven murine tumor xenograft models derived from human tumors.¹

HER2 (ErbB2) is a member of the ErbB family of receptor tyrosine kinases, which also includes epidermal growth factor receptor (EGFR), ErbB3, and HER4.^13,14 HER2 is the preferred dimerization partner for ErbB family receptors, despite being the only member that lacks a ligand-binding domain.^13–15 Ligand binding and dimerization of these receptors activate signaling pathways that promote cell proliferation and survival.^15,16

The most common HER2 alterations include protein overexpression, gene amplification and genomic mutations, all of which can result in uncontrolled cell proliferations.¹² 

HER2 mutations are most common within the active site of the tyrosine kinase domain (approximately 53% occur in exons 18 to 21), particularly exon 20, and are mostly insertion mutations.^4,17 Mutations in HER2 can result in uncontrolled cell proliferation, inhibition of apoptosis, and promotion of tumor growth and spread.^14,15,18,19 This was confirmed in preclinical models with documented tumor shrinkage associated with the withdrawal of HER2 expression.¹⁴ HER2 insertions are seen across a number of different cancer types, with a high prevalence in non-small cell lung cancer (NSCLC), where more than 90% of HER2 mutations may be exon 20 insertions.^20,21

*Zongertinib was recently approved in the United States (accelerated), China (conditional), and Japan for patients with previously treated advanced HER2-mutant NSCLC.^22–24

ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; ex, exon; HER2, human epidermal growth factor receptor 2; NSCLC, non-small cell lung cancer; TKD, tyrosine kinase domain; TKI, tyrosine kinase inhibitor.