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.

P1/2, N=370, Active, not recruiting, Bayer | Trial primary completion date: Dec 2025 --> Nov 2026

Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity...In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient with harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to meet the unmet need for brain-penetrant therapies for NSCLC with EGFR exon 20 insertions or other atypical mutations.

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

Sevabertinib showed antitumor activity in patients with locally advanced or metastatic HER2-mutant NSCLC. Diarrhea was the most common adverse event. (Funded by Bayer; SOHO-01 ClinicalTrials.gov number, NCT05099172.).

We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.

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