**Zongertinib in Previously TreatedHER2-Mutant Non-Small-Cell Lung Cancer**

Heymach, John V. M.D., Ph.D.
Ruiter, Gerrina M.D., Ph.D.
Ahn, Myung-Ju M.D.
Girard, Nicolas M.D., Ph.D.
Smit, Egbert F. M.D., Ph.D.
Planchard, David M.D., Ph.D.
Wu, Yi-Long M.D.
Cho, Byoung Chul M.D., Ph.D.
Yamamoto, Noboru M.D., Ph.D.
Sabari, Joshua K. M.D.
Zhao, Yanqiu M.D.
Tu, Hai-Yan M.D.
Yoh, Kiyotaka M.D.
Nadal, Ernest M.D., Ph.D.
Sadrolhefazi, Behbood M.D.
Rohrbacher, Maren M.D., Ph.D.
von Wangenheim, Ute Ph.D.
Eigenbrod-Giese, Sabina M.D., Ph.D.
Zugazagoitia, Jon M.D., Ph.D.

^¹Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston
^²Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam
^³Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam
^⁴Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
^⁵Institut Curie, Institut du Thorax Curie-Montsouris, Paris
^⁶Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Versailles, France
^⁷Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, the Netherlands
^⁸Department of Medical Oncology, Institut Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, Villejuif, France
^⁹Faculty of Medicine, Paris-Saclay University, Paris
^¹⁰Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
^¹¹Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
^¹²Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo
^¹³Division of Medical Oncology, Perlmutter Cancer Center, New York University Langone Health, New York
^¹⁴Department of Medical Oncology, the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
^¹⁵Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
^¹⁶Thoracic Tumors Unit, Medical Oncology, Catalan Institute of Oncology, Bellvitge Biomedical Research institute, L'Hospitalet, Barcelona
^¹⁷Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT
^¹⁸Boehringer Ingelheim International, Ingelheim am Rhein, Germany
^¹⁹Boehringer Ingelheim Pharma, Biberach an der Riss, Germany
^²⁰Department of Medical Oncology, 12 de Octubre Hospital, Madrid

Dr. Heymach can be contacted at [email protected] or at the Department of Thoracic/Head and Neck Medical Oncology, Unit 432, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Blvd., Houston, TX 77030-4009.

^*The Beamion LUNG-1 investigators are listed in the Supplementary Appendix, available at NEJM.org.

This article was published on April 28, 2025, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Boehringer Ingelheim. The authors did not receive payment related to the development of the manuscript.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the patients and their families; the investigators and staff at the participating sites; Lukas Schröter, of Boehringer Ingelheim, for contributions to the data generation and analysis; Kristie Fernamberg, of Boehringer Ingelheim, for contributions toward the development of the manuscript; and Hannah Simmons, M.Sc., of Ashfield MedComms (an Inizio company) for providing medical writing support during the development of this manuscript under the direction of the authors.

New England Journal of Medicine 392(23):p 2321-2333, June 19, 2025. | DOI: 10.1056/NEJMoa2503704

Abstract

Background

Innovative oral targeted therapies are warranted for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study.

Methods

We evaluated zongertinib in a multicohort, phase 1a-1b trial involving patients with advanced or metastatic HER2-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5), and those with tumors harboring a non-tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival.

Results

In cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred.

Conclusions

Zongertinib showed clinical benefit with mainly low-grade adverse events in patients with previously treated HER2-mutant NSCLC. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.)