zongertinib

Overview

Zongertinib (BI-1810631; NSC-854531) is an oral, irreversible tyrosine kinase inhibitor (TKI) that selectively targets HER2 (ERBB2). In August 2025, the US FDA granted accelerated approval for zongertinib (brand name Hernexeos) for adults with unresectable or metastatic, nonsquamous NSCLC with HER2 tyrosine kinase domain (TKD) activating mutations who have received prior systemic therapy. The approval was based on objective response rate and duration of response from the Beamion LUNG-1 trial, with continued approval contingent on confirmatory evidence. (fda.gov)

Mechanism of action

Zongertinib is a covalent, HER2-selective TKI designed to inhibit HER2 signaling while sparing EGFR, aiming to reduce EGFR-related toxicities seen with less selective pan-ERBB inhibitors. Preclinical studies showed potent anti-tumor activity in HER2-driven models (including HER2 exon 20 insertions) and synergy with other agents; early clinical cases outside NSCLC also suggested activity. (aacrjournals.org)

Efficacy

Key data come from the phase Ia/Ib, multi-cohort Beamion LUNG-1 trial (NCT04886804):

• Phase Ia dose-escalation (various HER2-altered solid tumors, including NSCLC; data cutoff May 23, 2024): confirmed ORR 30% overall and 35% in NSCLC; median duration of response (DoR) 12.7 months. Recommended once-daily doses for expansion were 120 mg and 240 mg. Activity was observed across common HER2 TKD variants (e.g., A775_G776insYVMA) and in patients previously treated with HER2-directed therapy. (ascopubs.org)

• Phase Ib (HER2-mutant NSCLC): at the AACR Annual Meeting 2025, updated cohort results reported ORR 71% (95% CI 60–80), including 7% complete responses; median DoR 14.1 months and median PFS 12.4 months; disease control rate 96%. Intracranial activity was reported in patients with measurable brain metastases. These data were presented as Abstract CT050 and highlighted by AACR and institutional releases. (aacrjournals.org)

The FDA’s approval summary described ORR 75% in a subset previously treated with platinum-based chemotherapy but no HER2-targeted ADC/TKI, and ORR 44% in those previously treated with a HER2-targeted ADC, both assessed by blinded independent central review. (ons.org)

Safety

In early-phase studies, zongertinib showed a generally manageable tolerability profile:

• Phase Ia: treatment-related adverse events (TRAEs) occurred in 82% of patients; grade ≥3 TRAEs in 10%. Most common TRAEs included diarrhea (50%; grade ≥3, 1%), rash (16%; grade ≥3, 2%), anemia (10%), decreased appetite (10%), and elevated ALT (10%; grade ≥3, 4%). MTD was not reached. (ascopubs.org)

• Phase Ib (interim/updated): low incidence of grade ≥3 drug-related AEs was reported; diarrhea was typically grade 1–2. (ascopubs.org)

The FDA label includes warnings/precautions for hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity. (fda.gov)

Further reading

• Cancer Discovery preclinical/early clinical translational report describing HER2 selectivity and EGFR sparing: Zongertinib (BI-1810631), an Irreversible HER2 TKI. (aacrjournals.org)
• Journal of Clinical Oncology: Phase Ia dose-escalation study in HER2-altered solid tumors. (ascopubs.org)
• AACR 2025 Abstract CT050 and news release summarizing Phase Ib HER2-mutant NSCLC results. (aacrjournals.org)
• FDA approval announcement and indication details (August 8, 2025). (fda.gov)

Last updated: Oct 2025