Zongertinib Demonstrates Clinical Benefits for Non-Small Cell Lung Cancer

The HER2-targeted therapy zongertinib demonstrated clinical benefits for previously treated patients with advanced HER2-mutant non-small cell lung cancer – particularly those with specific HER2 mutations – with manageable side effects, according to results from the Phase Ia/Ib Beamion LUNG-1 trial led by researchers from The University of Texas MD Anderson Cancer Center.

Updated data from the trial were presented today by principal investigator John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology, at the American Association for Cancer Research (AACR) Annual Meeting 2025 and published simultaneously in The New England Journal of Medicine.

The trial previously reported a 71% objective response rate (ORR) – indicating tumor shrinkage – in 75 patients from the first cohort, but newly presented data include a median duration of response (DOR) of 14.1 months and progression free survival (PFS) of 12.4 months.

“A 71% response rate is unprecedented in this cancer subtype, and not only is the data strong in showing that this treatment works, but zongertinib has the added convenience of being a once-daily oral therapy,” Heymach said. “When you also consider the improved safety profile compared to less selective inhibitors, this suggests a promising approach for patients in need of new treatments. That’s exciting because just a few years ago these patients had no effective targeted therapies.”

The Beamion LUNG-1 trial is investigating zongertinib as a monotherapy in previously treated patients with advanced or metastatic non-small cell lung cancer harboring HER2 mutations. The only currently approved treatment for this patient population is the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which is delivered intravenously and has been linked to instances of interstitial lung disease.

Zongertinib is an oral inhibitor that, unlike previous tyrosine kinase inhibitors tested in this setting, selectively targets HER2 and spares EGFR, resulting in a significant reduction of adverse effects. Grade three or higher adverse events occurred in 17% of patients and mostly included diarrhea and rash, with no instances of interstitial lung disease.

The presentation included data from three cohorts. Cohort 1 included 75 patients with mutations in a specific region of HER2, known as tyrosine kinase domain (TKD) mutations; cohort 3 included 20 patients harboring non-TKD mutations; and cohort 5 included 31 patients with TKD mutations who previously were treated with a HER2-directed antibody-drug conjugate such as T-DXd. Outcomes are summarized below, although DOR and PFS data is not yet mature for cohort 3.

“This new data is particularly encouraging for patients who had disease progression after prior therapies, because it indicates that the resistance mechanisms to those therapies does not necessarily confer cross-resistance to zongertinib,” Heymach said.

Zongertinib was granted a breakthrough therapy designation and a priority review by the FDA earlier this year based on interim data from this study presented at the 2024 World Conference on Lung Cancer.

A clinical trial investigating zongertinib as a first-line treatment is underway (Beamion LUNG-2), and Heymach and colleagues are planning additional studies to investigate the drug’s potential in combination treatments in other tumor types harboring HER2 mutations.

Reference: Heymach John V., Ruiter Gerrina, Ahn Myung-Ju, et al. Zongertinib in previously treated HER2-mutant non–small-cell lung cancer. NEJM. 2025. doi: 10.1056/NEJMoa2503704

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