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    DRUG:

    Hernexeos (zongertinib)

    i
    Other names: BI 1810631, BI1810631, BI-1810631
    Company:
    Boehringer Ingelheim, Sino Biopharm
    Drug class:
    HER2 exon 20 mutation inhibitor
    Related drugs:
    1d
    Zongertinib: First Approval. (PubMed, Drugs)
    It received its first approval under accelerated approval in August 2025 in the USA following positive results from the Beamion LUNG-1 phase Ia/Ib trial in patients with previously treated HER2-mutant non-small cell lung cancer (NSCLC). This article summarizes the milestones in the development of zongertinib leading to this first approval for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have HER2 tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.
    Journal
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • HER-2 mutation • HER-2 expression • EGFR expression • EGFR wild-type
    |
    Hernexeos (zongertinib)
    1d
    Loss of payload sensitivity and other mechanisms of resistance to T-DXd in HER2-mutant NSCLC: implications for subsequent responsiveness to HER2 TKIs. (PubMed, J Thorac Oncol)
    In HER2 mutant NSCLC patients, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • ABCC1 (ATP Binding Cassette Subfamily C Member 1)
    |
    HER-2 mutation
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki) • Pozenveo (poziotinib) • Hernexeos (zongertinib)
    1m
    Beamion BCGC-1: A Study to Find a Suitable Dose of Zongertinib Used Alone and in Combination With Other Treatments to Test Whether it Helps People With Different Types of HER2+ Cancer That Has Spread (clinicaltrials.gov)
    P1/2, N=768, Recruiting, Boehringer Ingelheim | N=582 --> 768 | Trial completion date: Sep 2029 --> Jan 2029 | Trial primary completion date: Sep 2029 --> Jan 2029
    Enrollment change • Trial completion date • Trial primary completion date
    |
    5-fluorouracil • Kadcyla (ado-trastuzumab emtansine) • Enhertu (fam-trastuzumab deruxtecan-nxki) • capecitabine • oxaliplatin • leucovorin calcium • Ziihera (zanidatamab-hrii) • Hernexeos (zongertinib)
    2ms
    Zongertinib, a Novel HER2 Tyrosine Kinase Inhibitor, Maintains an Anticancer Activity for Trastuzumab Deruxtecan-Resistant Cancers Harboring HER2-Overexpression. (PubMed, Int J Mol Sci)
    Meanwhile, both DSR32 and DSR4 cells maintained HER2 activation; thus, zongertinib, a HER2-selective tyrosine kinase inhibitor, blocked the HER2 pathway, induced apoptosis, and inhibited colony formation. Overall, zongertinib can provide therapeutic relief to patients with HER2-overexpressing cancer who have developed resistance to T-DXd.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 overexpression • HER-2 amplification
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki) • Hernexeos (zongertinib)
    3ms
    Synthesis of BI 1584142 and BI 1810631 (Zongertinib), Two Potent HER2 Inhibitors, Labeled With Carbon-14 and With Deuterium. (PubMed, J Labelled Comp Radiopharm)
    Therefore, a common carbon-14-labeled intermediate like the sulfoxide [14C]-8 was prepared in four radioactive steps and used to provide [14C]-1 and [14C]-2 in two and three extra steps, respectively. Deuterium-labeled 1 and 2 were also synthesized as internal standards, using piperazine-d8 and 4-aminopiperidine-d9 for bioanalytical studies and other studies.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    Hernexeos (zongertinib)
    3ms
    Beamion LUNG-3: A Study to Test Whether Zongertinib Helps People With Surgically Removed, Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment (clinicaltrials.gov)
    P3, N=400, Not yet recruiting, Boehringer Ingelheim | Trial completion date: May 2034 --> Sep 2036
    Trial completion date
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab) • Hernexeos (zongertinib)
    3ms
    Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers. (PubMed, Future Oncol)
    Phase Ib (dose escalation) will determine the maximum tolerated dose of zongertinib plus trastuzumab emtansine (T-DM1), T-DXd, or trastuzumab ± capecitabine, in patients with HER2-positive mBC, and plus T-DXd in patients with HER2-positive mGEAC. The trial is actively recruiting in six countries globally. www.clinicaltrials.gov identifier is NCT06324357.
    P1/2 data • Journal
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 positive • HER-2 amplification
    |
    Kadcyla (ado-trastuzumab emtansine) • Enhertu (fam-trastuzumab deruxtecan-nxki) • capecitabine • Hernexeos (zongertinib)
    3ms
    Relative Bioavailability of Zongertinib, an Orally Administered HER2-Selective Tyrosine Kinase Inhibitor, under Fed and Fasted Conditions in Healthy Male Participants: Results from Two Randomized, Open-Label, Crossover Studies. (PubMed, Mol Pharm)
    Zongertinib demonstrated good bioavailability in healthy participants. A small dose-dependent food effect was observed.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 mutation
    |
    Hernexeos (zongertinib)
    3ms
    Nonclinical and Clinical Assessments of an Optimized Tablet Formulation of the Novel HER2-Selective Tyrosine Kinase Inhibitor Zongertinib: Focus on Relative Bioavailability and Impact of Variation of Gastric pH. (PubMed, Mol Pharm)
    Geometric mean Cmax and AUC0-tz were similar after treatment with zongertinib SDD with and without rabeprazole. Zongertinib SDD formulation showed good bioavailability irrespective of pH, supporting further clinical development.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    Hernexeos (zongertinib)
    4ms
    Beamion LUNG-3: A Study to Test Whether Zongertinib Helps People With Surgically Removed, Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment (clinicaltrials.gov)
    P3, N=400, Not yet recruiting, Boehringer Ingelheim
    New P3 trial
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab) • Hernexeos (zongertinib)
    5ms
    Beamion PANTUMOR-1: A Study to Test Whether Zongertinib Helps People With Advanced Cancers With HER2 Alterations (clinicaltrials.gov)
    P2, N=430, Recruiting, Boehringer Ingelheim | Trial primary completion date: Dec 2028 --> Dec 2027
    Trial primary completion date • Pan tumor
    |
    Hernexeos (zongertinib)
    5ms
    Beamion PANTUMOR-1: A Study to Test Whether Zongertinib Helps People With Advanced Cancers With HER2 Alterations (clinicaltrials.gov)
    P2, N=430, Recruiting, Boehringer Ingelheim | N=200 --> 430 | Trial primary completion date: Sep 2027 --> Dec 2028
    Enrollment change • Trial primary completion date • Pan tumor
    |
    Hernexeos (zongertinib)