Beamion LUNG-1 Study: Zongertinib’s Novel Brain Activity in HER2-Mutant NSCLC

Human epidermal growth factor receptor 2 (HER2)-mutant non–small cell lung cancer (NSCLC) is a rare subtype of NSCLC associated with higher rates of brain metastases.¹ Despite advances in treatment for NSCLC, there is a paucity of treatment options for patients harboring this mutation.

Recently, positive data from the phase 1 Beamion LUNG-1 study (NCT04886804) evaluating the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (Hernexeos) in advanced or metastatic HER2-mutant NSCLC^2,3 were presented at the IASLC 2025 World Conference on Lung Cancer (WCLC). In August 2025, the FDA granted accelerated approval to zongertinib in this intent-to-treat population for patients who have received prior systemic therapy.⁴

In an interview with Targeted Oncology, Gerrina Ruiter, MD, PhD, Netherlands Cancer Institute and study investigator, explains the rationale and design of the Beamion LUNG-1 study, highlights the significance of the study’s findings, and outlines next steps in this line of research.

Targeted Oncology: What are the unmet needs in this population that prompted this research?

Gerrina Ruiter, MD, PhD: HER2-mutated lung cancer is rare, but brain metastasis is highly prevalent in these patients. Fifty percent of patients who have HER2-mutant [NSCLC] develop brain metastases during their lifetime. This means that despite new treatments developing [for NSCLC], one [being] zongertinib, it is also important to see that these drugs work for brain metastases.

What was the study’s design?

The Beamion LUNG-1 trial is a classical phase 1 trial, which consisted of a dose-escalation phase for all solid tumors with HER2 alterations and a dose-expansion phase. In th[e] dose-expansion [phase], only [patients with] NSCLC were included, consisting of 5 different cohorts. Four of these cohorts were previously treated patients, and 1 cohort was for patients who were previously untreated.

There were 2 cohorts within this expansion phase in which patients with either treated or active untreated brain metastases were included. In cohort 1, previously treated patients with stable, asymptomatic brain metastases were included; in cohort 4, treatment-naive patients with active brain metastases at baseline were included. We presented th[e first results from these cohorts] for the first time at the WCLC in Barcelona recently—the first data of patients with brain metastases.

What were the findings of the study regarding efficacy and safety?

There were no new safety signals. The safety data has been published this year in The New England Journal of Medicine, and we did not see a difference regarding safety in these new cohorts that we presented.

So, there's not much news there, but the main result was that … 41% of patients showed an objective response within the brain according to the Response Assessment in Neuro-Oncology Brain Metastases [RANO-BM]. And if you look at the disease control rate, that was even higher, [at] 83%. The median progression-free survival was 8.2 months.

Of the findings in this study, did any stand out as an important clinical implication?

I think the fact that zongertinib works in the brain is the major finding, because we did not know that, and we do not have any HER2 TKI so far that has demonstrated [an] effect in the brain. So, this is really important to show—that this drug not [only] has a high systemic response rate but also induces responses in the brain.

What are the next steps for this research? What questions do you still have unanswered?

The next step would be [to investigate], what is the optimal timing of giving this TKI to patients? For now, we have the Beamion LUNG-2 study [NCT06151574], a phase 3 [study] in which untreated patients receive either standard chemotherapy in first line or zongertinib. So, that will give us a better idea of the optimal sequencing of this treatment. And of course, the data is not mature yet for the intracranial responses, so we have to wait [for] that further.

REFERENCES:

1. Zhang Q, Yang Y, Xie M, et al. Survival and prognostic factors of HER2-mutant advanced non-small cell lung cancer with brain metastases. Lung Cancer. 2025;205:108616-108616. doi:https://doi.org/10.1016/j.lungcan.2025.108616

2. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in Previously Treated HER2 -Mutant Non–Small-Cell Lung Cancer. N Engl J Med. Published online April 28, 2025. doi:10.1056/nejmoa2503704

3. Beamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene). ClinicalTrials.gov. Updated September 19, 2025. https://clinicaltrials.gov/study/NCT04886804

4. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. US FDA. August 8, 2025. Accessed October 1, 2025. https://tinyurl.com/fbakh64s