Human epidermal growth factor receptor 2 (HER2)

Human epidermal growth factor receptor 2 (HER2) mutations have emerged as important oncogenic drivers in non-small cell lung cancer (NSCLC), leading to uncontrolled cell growth and survival. Zongertinib is an irreversible tyrosine kinase inhibitor of HER2. Its acrylamide moiety forms a covalent bond with the cysteine 805 residue of the HER2 receptor, thereby inhibiting HER2 phosphorylation and the activation of downstream signaling pathways, including extracellular signal-regulated kinase (ERK), mitogen-activated protein kinases (MAPK), and PI3K/Akt. The inhibition of these pathways leads to a reduction in the proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations.

In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC with HER2 tyrosine kinase domain activating mutations. A key characteristic of zongertinib is its selectivity for HER2 - including exon 20 insertion mutations - while sparing wild-type epidermal growth factor receptor (EGFR), which is believed to limit EGFR-associated toxicities. In a preclinical proliferation assay, zongertinib showed 100-fold greater sparing activity for wild-type EGFR compared to its activity against the HER2 YVMA mutation. It is effective against various HER2 tyrosine kinase domain mutations, including A775-G776YVMA and P780-Y781insGSP. Zongertinib has also demonstrated intracranial activity, with an intracranial objective response rate of 37% and a disease control rate of 83% observed in patients with baseline brain metastases in a subanalysis of the Beamion LUNG-1 trial.

Absorption
The absolute oral bioavailability of zogatinib is 76.2%. In patients with solid tumors, the median time to reach maximum plasma concentration (Tmax) after oral administration is approximately 2 hours. The recommended dose is 120 mg once daily, with a steady-state geometric mean maximum concentration (Cmax, ss) of 3.0 µmol/L and a total systemic exposure (AUC) of 34 µmol·h/L. Within the dose range of 60 mg to 360 mg, zogatinib exposure increases approximately dose-proportional. The cumulative AUC is approximately 1.5-fold, and the cumulative Cmax is approximately 1.3-fold, reaching steady state within 2.5 days.
Elimination Routes
Zogatinib and its metabolites are primarily excreted in feces. In healthy subjects, approximately 93% of the total dose is recovered in feces and 1.3% in urine after a single oral administration of the radiolabeled drug. Of the administered dose, 31% is excreted unchanged in feces, while only 0.2% is excreted unchanged in urine.
Volume of Distribution
The apparent oral volume of distribution of zongertinib in patients is 118 L. In a study of healthy volunteers, the steady-state volume of distribution was 138 L after intravenous administration of a microtracer.
Clearance
The apparent oral clearance of zongertinib in patients is 115 mL/min. A study of healthy volunteers using an intravenous microtracer determined the total plasma clearance to be 106 mL/min.
Protein Binding
Zongertinib is >99% bound to proteins in plasma. The specific proteins it binds to are not yet known.
Metabolism/Metabolites
Zongatinib is primarily metabolized in the liver via three main pathways: CYP-mediated oxidation (48% to 62%), glucuronidation (13% to 25%), and glutathione conjugation (13% to 26%). The main enzymes involved are CYP3A4 and CYP3A5 (for oxidation) and UGT1A4 (for glucuronidation). In a human ADME study, 14 metabolites were identified—the two most abundant circulating metabolites being M551(1) (monooxidation) and M656(1) (cysteine conjugate), accounting for 5.7% and 2.5% of total plasma radioactivity, respectively.
Biological Half-Life
The effective half-life of zongatinib at steady state in patients is 12 hours. A single-dose study in healthy volunteers reported a terminal half-life of 42.7 hours after intravenous injection and 45.2 hours after oral administration.

The Beamion LUNG-1 (NCT04886804) was an open-label, multicenter, multicohort trial evaluating the efficacy of zongertinib in patients with unresectable or metastatic HER2 (ERBB2) TKD-mutant non-squamous non-small cell lung cancer (NSCLC) who had previously received systemic therapy. The primary efficacy endpoints were objective response rate (ORR) and duration of response (DOR), assessed independently by a center-blinded method and determined according to RECIST v1.1 criteria. In 71 patients who had previously received platinum-based chemotherapy but had not received HER2-targeted tyrosine kinase inhibitors or antibody-drug conjugates (ADCs), the ORR was 75% (95% CI: 63, 83), with 58% of patients having a DOR ≥ 6 months. In 34 patients who had previously received platinum-based chemotherapy and HER2-targeting antibody-drug conjugates (ADCs), the objective response rate (ORR) was 44% (95% CI: 29, 61), with 27% of patients having a duration of response (DOR) ≥ 6 months. Prescribing information includes warnings and precautions regarding hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonia, and embryo-fetal toxicity. The recommended dose of zogatinib is based on body weight. For patients weighing <90 kg, the dose is 120 mg orally daily. For patients weighing ≥90 kg, the dose is 180 mg orally daily. Zogatinib can be taken with or without food and should continue until disease progression or intolerable toxicity. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations

[1]. WHO Drug Informat ion - World Health Organization (WHO).

[2]. Synthesis of diazino-pyrimidines as anticancer agents: World Intellectual Property Organization, WO2021213800. 2021-10-28.

[3]. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel). 2023 May 24;15(11):2899.

Zongertinib is a selective, irreversible tyrosine kinase inhibitor that targets human epidermal growth factor receptor 2 (HER2). It covalently binds to the HER2 receptor (including exon 20 insertion mutations), inhibiting downstream signaling pathways without affecting wild-type epidermal growth factor receptor (EGFR), thereby reducing related toxicities. On August 8, 2025, the US FDA granted accelerated approval to Zongertinib for the treatment of advanced non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain activating mutations. Zongertinib is a kinase inhibitor. Its mechanism of action is as a HER2/Neu/cerbB2 antagonist and an inhibitor of breast cancer resistance proteins. Zongertinib is an orally bioavailable receptor tyrosine kinase inhibitor that inhibits human epidermal growth factor receptor 2 (HER2; ErbB2; HER-2) and has potential antitumor activity. After oral administration, Zongertinib covalently binds to and inhibits the activity of wild-type and mutant HER2 (including HER2 mutants with exon 20 insertion mutations). This can block HER2-mediated signaling and may lead to the death of HER2-expressing tumor cells. HER2 is a receptor tyrosine kinase that is overexpressed in a variety of tumor cell types and plays an important role in tumor cell proliferation and tumor angiogenesis. Zongertinib is a small molecule drug currently in Phase III clinical trials and has one investigational indication. Zongertinib is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations and who have previously received systemic therapy.

C29H29N9O2

535.599664449692

535.244

C, 65.03; H, 5.46; N, 23.54; O, 5.97

2728667-27-2

160283094

Light yellow to green yellow solid powder

4.1

2

9

7

40

870

0

C(NC1CCN(C2=NC=C3N=CN=C(NC4=CC=C(OC5=CC=C6N(C)C=NC6=C5)C(C)=C4)C3=N2)CC1)(=O)C=C

YSGNGFPNTLERCR-UHFFFAOYSA-N

InChI=1S/C29H29N9O2/c1-4-26(39)34-19-9-11-38(12-10-19)29-30-15-23-27(36-29)28(32-16-31-23)35-20-5-8-25(18(2)13-20)40-21-6-7-24-22(14-21)33-17-37(24)3/h4-8,13-17,19H,1,9-12H2,2-3H3,(H,34,39)(H,31,32,35)

N-[1-[4-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidin-6-yl]piperidin-4-yl]prop-2-enamide

2728667-27-2; N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide; N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo(d)imidazol-5-yl)oxy)phenyl)amino)pyrimido(5,4-d)pyrimidin-2-yl)piperidin-4-yl)acrylamide; RefChem:823502; ...; Zongertinib;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 31.25 mg/mL (58.35 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)