Oral Zongertinib Shows Impressive Results in HER2-Mutant Lung Cancer

Approximately 2-4% of patients with advanced non-small cell lung cancer (NSCLC) have mutations in human epidermal growth factor receptor 2 (HER2). Until now, HER2-targeted treatment options have been extremely limited, and the only FDA-approved option was an antibody-drug conjugate such as trastuzumab deruxtecan (T-DXd; Enhertu) . These treatments, however, do not work for every patient and carry risks of serious adverse effects, particularly complications such as interstitial lung disease.

In this context, developing an effective, tolerable HER2-targeted treatment with the convenience of oral administration has become an important need for patients and oncologists alike. Presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting and published simultaneously on 28 April 2025 in New England Journal of Medicine, the Beamion LUNG-1 study introduced a strong candidate to address this need: Zongertinib.

What Is Zongertinib? An Oral TKI Specific to HER2 Mutations

Zongertinib is a next-generation oral tyrosine kinase inhibitor (TKI) that targets HER2 mutations with high selectivity. Unlike existing HER2 inhibitors, it does not inhibit epidermal growth factor receptor (EGFR), resulting in fewer common side effects such as rash and diarrhea.

Study Design: The Beamion LUNG-1 Phase Ia/Ib Clinical Trial

• The study enrolled previously treated patients with advanced NSCLC.

• Three cohorts were examined:

  • Cohort 1: 75 patients with HER2 mutations in the tyrosine kinase domain (TKD)

  • Cohort 3: 20 patients with HER2 mutations outside the TKD

  • Cohort 5: 31 patients with TKD mutations who had previously received a HER2-targeted ADC, such as T-DXd

• Patients received zongertinib 120 mg once daily. Some initially received 240 mg, after which the dose was standardized.

Key Results: Clinical Efficacy

1. Objective Response Rate (ORR)

• Cohort 1: 71% response rate (95% CI: 60-80%). This was significantly higher than the historical reference threshold of 30% (p<0.001).

• Cohort 3: 30% response rate (95% CI: 15-52%)

• Cohort 5: 48% response rate (95% CI: 32-65%)

2. Disease Control Rate (DCR)

• Cohort 1: 96%

• Cohort 3: 65%

• Cohort 5: 97%

3. Duration of Response (DOR) and Progression-Free Survival (PFS)

• Cohort 1:

  • Median duration of response: 14.1 months (95% CI: 6.9 – not estimable)

  • Median progression-free survival (PFS): 12.4 months (95% CI: 8.2 – not estimable)

• Cohort 5:

  • Median duration of response: 5.3 months

  • Median progression-free survival: 6.8 months

Data in cohort 3 were not yet mature.

Safety Profile: Zongertinib Side Effects

Zongertinib was generally well tolerated:

• Rates of grade 3 or higher adverse events:

  • Cohort 1: 17%

  • Cohort 3: 25%

  • Cohort 5: 3%

• Interstitial lung disease was not reported.

• Severe toxicities such as rash, diarrhea or pneumonitis were very uncommon.

These results suggest that zongertinib could be both more effective and less toxic than other HER2 inhibitors.

Commentary

• The First Oral HER2-Selective TKI: Zongertinib has the potential to become the first oral tyrosine kinase inhibitor developed for HER2-mutant NSCLC.

• Activity Even in Patients Who Do Not Respond to ADCs: It also showed strong activity in patients who had not responded to prior ADC treatment such as T-DXd.

• It is being reviewed under FDA Fast Track and Breakthrough Therapy designations .

• Patient Convenience: Its oral formulation would allow patients to receive treatment without intravenous infusions in a hospital setting.

If approved, zongertinib would offer a treatment option that could transform care for HER2-mutant NSCLC . For this population, which has lacked an effective oral targeted treatment, zongertinib could fill an important gap through high efficacy and a manageable safety profile.