Zongertinib

Shows activity

Also known as:

BI-1810631 NSC-854531

Cancer types include:

breast cancer esophageal cancer non-small cell lung cancer small cell lung cancer stomach cancer

HealthScout AI Analysis

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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)

Active trials using Zongertinib

Found 3 active trials using this drug:

Beamion BCGC-1: A Phase Ib Dose Escalation and Phase II Dose Optimization, Randomized, Open-label, Multicenter Trial of Oral Zongertinib (BI 1810631) Alone or in Combination With Other Agents for the Treatment of Patients With Advanced HER2+ Metastatic Breast Cancer (mBC) and Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma (mGEAC)

Sponsor: Boehringer Ingelheim (industry) Phase: 1/2 Start date: June 28, 2024

HealthScout AI summary: This trial enrolls adults with HER2-positive metastatic breast, gastric, gastroesophageal junction, or esophageal adenocarcinoma who have progressed after standard therapy, testing the selective HER2 tyrosine kinase inhibitor zongertinib (BI 1810631) alone or in combination with HER2-targeted agents (T-DXd, T-DM1, trastuzumab, capecitabine). Eligible patients must have measurable disease and good performance status (ECOG 0-1).

ClinicalTrials.gov ID: NCT06324357

Beamion LUNG 2: A Phase III, Open-label, Randomized, Active-controlled, Multi-centre Trial Evaluating Orally Administered Zongertinib (BI 1810631) Compared With Standard of Care as First-line Treatment in Patients With Unresectable, Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Harbouring HER2 Tyrosine Kinase Domain Mutations

Sponsor: Boehringer Ingelheim (industry) Phase: 3 Start date: Feb. 9, 2024

HealthScout AI summary: This trial enrolls adults with unresectable, locally advanced or metastatic non-squamous NSCLC harboring HER2 kinase domain mutations, randomizing them to first-line treatment with either zongertinib, an oral selective inhibitor of HER2, or standard of care with pembrolizumab plus platinum-pemetrexed chemotherapy. Eligible patients must be previously untreated for advanced disease and have at least one measurable lesion.

ClinicalTrials.gov ID: NCT06151574

Beamion LUNG-1: An Open Label, Phase I Dose Escalation Trial, With Dose Confirmation and Expansion, of Zongertinib (BI 1810631) as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations

Sponsor: Boehringer Ingelheim (industry) Phase: 1 Start date: July 2, 2021

HealthScout AI summary: This trial enrolls adults with advanced or metastatic solid tumors harboring HER2 aberrations, with a focus on NSCLC patients with HER2 mutations, including those previously treated, treatment-naïve, or with brain metastases. Patients receive zongertinib, an oral, selective covalent tyrosine kinase inhibitor targeting both wild-type and mutant HER2 while sparing EGFR.

ClinicalTrials.gov ID: NCT04886804