Brain metastases is a common and challenging complication in HER2-mutant non−small cell lung cancer (NSCLC), making it critical to assess the intracranial efficacy of emerging HER2-targeted therapies. Despite this, patients with active brain metastases at baseline are often excluded from clinical trials, leaving a gap in treatment strategies. Zongertinib is an irreversible tyrosine kinase inhibitor that selectively targets HER2 while sparing EGFR, resulting in reduced risk of associated toxicities. Earlier data in previously treated HER2-mutant NSCLC patients showed that zongertinib provided sustained clinical benefit with manageable safety. The phase 1b Beamion LUNG-1 trial (NCT04886804) evaluates the efficacy and safety of zongertinib in patients with HER2-mutant advanced or metastatic NSCLC, including those with brain metastases at baseline. Patients with stable/asymptomatic brain metastases were enrolled in cohort 1; those with active brain metastases were in cohort 4.

In cohort 1, patients were randomized to receive zongertinib 120 or 240 mg once daily. Based on interim analysis, the 120-mg dose was selected for future use, and subsequently, all new patients in all cohorts received zongertinib 120 mg. As of March 26, 2025, in cohort 1, 75 patients received zongertinib 120 mg. Among 8 patients with stable/asymptomatic brain metastases at baseline, the systemic objective response rate (ORR) was 50%; 100% of patients achieved disease control rate (DCR) with a median duration of response of 12.5 months (95% confidence interval [CI], 11.1-Not Calculable). In a pooled analysis of 58 patients with stable, asymptomatic, or active brain metastases, treatment with zongertinib resulted in an ORR of 41%, which included a complete response in 9% and a partial response in 33% of patients. Additionally, the DCR was 83%, with 41% of patients achieving stable disease. Median progression-free survival (mPFS) was 8.2 months (95% CI, 4.5-12.3), demonstrating strong intracranial efficacy. Among the 41 patients in cohorts 1 and 4 who had not received prior brain radiotherapy, treatment with zongertinib resulted in an intracranial ORR of 44%. The DCR in this group was 83%. Of the evaluable patients, 95% experienced a reduction in brain lesion size from baseline; mPFS was 8.1 months (95% CI, 4.1-12.3).

In conclusion, zongertinib offers a promising option for patients with HER2-mutant NSCLC with stable, asymptomatic, or active brain metastases, including those who have not undergone prior brain radiotherapy. These findings highlight zongertinib’s potential as a meaningful therapeutic option for patients with limited treatment alternatives.

Source: G Ruiter, EF Smit, RA Soo, et al. Zongertinib in patients with previously treated HER2-mutant NSCLC and brain metastases at baseline: Beamion LUNG-1. Presented at: 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain.