Hernexeos (zongertinib)

The following ten drugs received FDA approval in 2025 - avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant ROS1 in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant HER2 in NSCLC). This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.

P3, N=400, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

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.

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.

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

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.

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.

P3, N=400, Not yet recruiting, Boehringer Ingelheim | Trial completion date: May 2034 --> Sep 2036

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.

Zongertinib demonstrated good bioavailability in healthy participants. A small dose-dependent food effect was observed.

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.

P3, N=400, Not yet recruiting, Boehringer Ingelheim