Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer

Author(s): John V. Heymach, M.D., Ph.D.¹; Gerrina Ruiter, M.D., Ph.D.^2,3; Myung-Ju Ahn, M.D.⁴; Nicolas Girard, M.D., Ph.D.^5,6; Egbert F. Smit, M.D., Ph.D.^3,7; David Planchard, M.D., Ph.D.^8,9; Yi-Long Wu, M.D.¹⁰; Byoung Chul Cho, M.D., Ph.D.¹¹; Noboru Yamamoto, M.D., Ph.D.¹²; Joshua K. Sabari, M.D.¹³; Yanqiu Zhao, M.D.¹⁴; Hai-Yan Tu, M.D.¹⁰; Kiyotaka Yoh, M.D.¹⁵; Ernest Nadal, M.D., Ph.D.¹⁶; Behbood Sadrolhefazi, M.D.¹⁷; Maren Rohrbacher, M.D., Ph.D.¹⁸; Ute von Wangenheim, Ph.D.¹⁹; Sabina Eigenbrod-Giese, M.D., Ph.D.¹⁸; Jon Zugazagoitia, M.D., Ph.D.²⁰; for the Beamion LUNG-1 Investigators;

Source: N Engl J Med 2025;392:2321-2333

Dr. Maen Hussein's Thoughts

Another option for HER-2 lung cancer patients. 71% had an objective response with a duration of 14.1 months and progression-free survival (PFS) of 12.4 months. Grade 3 adverse events were observed in 17% of patients. Some patients had been previously treated with HER-2 ADC therapy.

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.)

Author Affiliations

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;

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