Hernexeos (zongertinib)

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

P2, N=430, Recruiting, Boehringer Ingelheim | Trial primary completion date: Dec 2028 --> Dec 2027

P2, N=430, Recruiting, Boehringer Ingelheim | N=200 --> 430 | Trial primary completion date: Sep 2027 --> Dec 2028

Human epidermal growth factor receptor 2 (HER2) mutations are rare in NSCLC and the only FDA approved agent until recently, was trastuzumab deruxtecan in the second line setting. Zongertinib is a HER2 selective tyrosine kinase inhibitor that covalently binds to HER2 receptors, including exon20ins mutations. Zongertinib is safe and effective for patients with HER2-mutated NSCLC based on initial results from preclinical studies and the phase I Beamion LUNG-1 trial showing promising response rates and safety profile ultimately leading to the FDA accelerated approval on August 8, 2025.

In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, treatment was initiated with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations.

Upregulation of HER2 phosphorylation promotes internalization of mutant HER2 mediated by clathrin-dependent endocytosis, likely contributing to the efficacy of HER2-targeted ADCs in NSCLC positive for HER2 mutations.