Beamion Lung-1: Zongertinib Emerges as a Promising Option in HER2 NSCLC

Sawyer Bawek, DO University at Buffalo

The current treatment landscape for HER2-mutant non–small cell lung cancer (NSCLC) is rapidly evolving, with Beamion LUNG-1—a promising new study—showing exciting results. Key findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 and published in The New England Journal of Medicine on April 28. The multicohort, phase 1a-1b study evaluated the potential of zongertinib, an oral HER2-targeted tyrosine kinase inhibitor, in patients with previously treated advanced or metastatic HER2-mutant NSCLC. 

Key Takeaways from Beamion Lung-1

• High response rate in HER2-mutant NSCLC: Zongertinib demonstrated a 71% objective response rate in cohort 1 (HER2 tyrosine kinase domain mutations), with a median duration of response of 14.1 months and progression-free survival of 12.4 months.
• Favorable safety profile versus trastuzumab deruxtecan (T-DXd): Just 17% of participants experienced grade 3 or higher treatment-related adverse events (AEs). No interstitial lung disease was reported, in contrast to T-DXd’s 26% incidence.
• Encouraging brain metastases activity: Zongertinib showed a 65% intracranial response rate, nearly matching the overall response rate—critical for treating patients with NSCLC who have central nervous system involvement.
• Potential post–T-DXd option: In previously treated patients (cohort 5), zongertinib showed a 48% response rate, indicating benefit even after antibody–drug conjugate failure.
• Oral, once-daily dosing: Practical for real-world community use, zongertinib’s oral administration could enhance patient adherence and quality of life.

Favorable Safety Profile

• Common AEs: diarrhea (51%) and rash (27%)
• Grade 3 or greater AEs: only 17% overall (mainly elevated liver enzymes)
• No interstitial lung disease, which is a serious concern with trastuzumab deruxtecan

HER2 Mutations in NSCLC

HER2, also known as ERBB2, is present in approximately 2%-4% of individuals with NSCLC. Until now, the only FDA–approved targeted option (current standard of care) has been T-DXd, based on results from the DESTINY-Lung01 trial. 

DESTINY-Lung01 analyzed T-DXd, an antibody–drug conjugate (ADC) that delivers a cytotoxic drug directly to cells expressing HER2, for metastatic HER2-mutant NSCLC patients who were refractory to standard treatment. The study showed an objective response rate (ORR) of 55% (95% CI, 44-65), median duration of response (DOR) of 9.3 months (95% CI, 5.7-14.7), median overall survival (OS) of 17.8 months (95% CI, 13.8-22.1), and median progression-free survival (PFS) of 8.2 months (95% CI, 6.0-11.9). 

However, even though the safety profile was similar to that of previous studies, serious associated AEs, such as interstitial lung disease occurred in 26% of patients and resulted in two deaths. Concerns about T-DXd’s safety profile underscored the need for safer alternatives.

Beamion LUNG-1: Key Findings

The promising results of Beamion LUNG-1 reveal zongertinib’s potential as a new standard of care in patients with HER2-mutant NSCLC. The study assessed 3 cohorts based on the type of HER2 mutation and previous treatments. Cohort 1 included patients with tyrosine kinase domain mutations, cohort 3 focused on patients with non–tyrosine kinase domain mutations, and cohort 5 involved patients with previously treated HER2-directed ADCs. Participants were initially randomly assigned either 120 milligram (mg) or 240 mg once daily. Following a dose-selection analysis, the 120-mg dose was selected based on similar efficacy. However, the 240-mg dose had an increased incidence of serious AEs. 

The results for patients who received the 120-mg dose of zongertinib are striking: 

Cohort 1 (75 patients)

• ORR: 71% (95% CI, 60-80; P < .001)
• Median DOR: 14.1 months 
• Median PFS: 12.4 months

Cohort 3 (20 patients)

• Confirmed ORR: 30% 
• DOR and PFS: not mature at time of analysis
• Grade 3 or higher AEs: 25% 

Cohort 5 (31 patients)

• Confirmed ORR: 48% 
• Median DOR: 5.3 months
• Median PFS: 6.8 months
• Grade 3 or higher AEs: 3% 

The study also analyzed brain metastases response rate, which was 65%—nearly identical to the overall cohort of 71%. Even more compelling: Zongertinib’s favorable safety profile outshone T-DXd’s. Just 17% of patients had grade 3 or higher drug-related AEs—primarily, elevated liver enzymes—with no cases of interstitial lung disease. The most common AEs were diarrhea (51%) and rash (27%). 

Future Role of Zongertinib in HER2-NSCLC

The FDA has already granted priority review to zongertinib for HER2-mutant NSCLC, recognizing its promise, including for previously treated patients with brain metastases. From a practical standpoint, the once-daily oral administration could significantly improve patient adherence and quality of life. The results show that zongertinib may also benefit patients who did not respond or relapsed following treatment with T-DXd. 

Bottom Line for Community Oncologists
The Beamion LUNG-1 trial signals a meaningful shift in treating HER-2 mutant NSCLC. Compared with T-DXd, zongertinib had a higher response rate and a better safety profile, with encouraging results for patients who have brain metastases. The findings point to a compelling option for patients who have progressed on standard therapies, potentially improving both clinical outcomes and quality of life for the patients of community oncologists.