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;

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.