Boehringer Ingelheim’s drug candidate for human epidermal growth factor receptor 2 (HER2)-mutated non-small cell lung cancer (NSCLC) has demonstrated a durable response of more than 14 months while maintaining a manageable safety profile.
In the Phase Ib Beamion LUNG-1 trial (NCT04886804), Boehringer investigated dose escalation, dose confirmation and expansion of its daily oral candidate zongertinib as a monotherapy in patients with advanced or metastatic solid tumours and NSCLC with activating HER2 alterations.
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While patients have been split across five cohorts, the primary cohort enrolled 75 previously treated patients with advanced NSCLC who have HER2 mutations within the tyrosine kinase domain (TKD).
Presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 and published in The New England Journal of Medicine, new data from the primary cohort showed a median duration of response (DoR) of 14.1 months and median progression-free survival (PFS) of 12.4 months after treatment with Boehringer’s zongertinib.
Boehringer previously presented data for its lung cancer drug showing an objective response rate (ORR) of 71%. Updated data also shows a 7% complete response (CR) rate, 64% partial response and 96% disease control in previously treated patients.
Updated intracranial activity data from 27 previously treated patients who had brain metastases showed that 41% achieved response and 81% achieved disease control.
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By GlobalDataPatients with advanced NSCLC with HER2 mutations in the TKD, who were previously treated with platinum-based chemotherapy and HER2-directed antibody-drug conjugates (ADCs), demonstrated an ORR of 48%, with 97% of patients achieving disease control.
Zongertinib, an investigational HER2-specific tyrosine kinase inhibitor (TKI), was granted US Food and Drug Administration (FDA) fast track designation in 2023 and breakthrough therapy designation last year. In February 2025, Boehringer filed a drug application for zongertinib after being granted FDA Priority Review designation. The Prescription Drug User Fee Act (PDUFA) action date is set for Q3 2025.
Safety profile also promising
HER2 mutations in NSCLC are relatively rare, affecting between 2% and 4% of patients. It was only three years ago that the first drug for this patient population was approved – AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) received FDA approval in August 2022 for the patient population, with the drug later obtaining approval from Europe in October 2023.
A potential benefit above Enhertu, however, is that zongertinib targets HER2 while sparing EGFR [epidermal growth factor receptor], which can lead to events such as interstitial lung disease (ILD), an adverse event (AE) associated with Enhertu.
Meanwhile, there were no drug-related deaths, cases of ILD or cardiotoxicity reported with zongertinib. The most reported AE was Grade 1 diarrhoea, with a low incidence (17%) of Grade ≥3 drug-related events in patients with TKD mutations.
The University of Texas MD Anderson Cancer Center’s chair of thoracic/head and neck medical oncology Dr John Heymach said: “Notably, more than 70% of patients experienced a tumour response, which is highly meaningful for those with this subtype of lung cancer. If approved by the FDA, zongertinib would be the first oral, targeted treatment option that addresses an unmet need for these patients.”
The drug is also being investigated in the Phase III Beamion LUNG-2 trial (NCT06151574), an open-label, randomised, active-controlled study in patients with unresectable, locally advanced or metastatic non-squamous NSCLC with HER2 TKD mutations. The trial is pitting zongertinib against the standard of care (SOC).
