HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib - Phase Ia Dose-Escalation Study in Advanced/Metastatic Solid Tumors With HER2 Alterations

Sep 24, 2026

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Human epidermal growth factor receptor 2 (HER2) alterations drive many solid cancers, yet durable options in non–small cell lung cancer remain limited. Beamion LUNG-1 evaluates zongertinib (BI 1810631), a HER2-selective tyrosine kinase inhibitor that spares EGFR, using a multicenter phase Ia dose-escalation design. Phase Ia assesses safety, maximum tolerated dose, and dose-limiting toxicities, with tumor response as a secondary endpoint. Results describe treated patients, recommended expansion doses, treatment-related adverse events, and preliminary confirmed antitumor activity across HER2-altered tumors.

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CategoryHealthcare

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Pages12

Reading Time30 min

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Background on HER2 in cancer

Current HER2-targeted therapies in NSCLC

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Original Reports | Thoracic Oncology HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study John V. Heymach, MD, PhD1 ; Frans Opdam, MD, PhD2; Minal Barve, MD3 ; Hai-Yan Tu, MD4 ; Yi-Long Wu, MD, PhD4 ; David Berz, MD, PhD5; Lukas Schrter, MSc6; Yanick Botilde, PhD7; Behbood Sadrolhefazi, MD8; Josep Serra, BSc9; Kiyotaka Yoh, MD10 ; and Noboru Yamamoto, MD, PhD11 DOI [https://doi.org/10.1200/JCO-24-01727](https://doi.org/10.1200/JCO-24-01727) | ABSTRACT | | | --- | --- | | PURPOSE | Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non–small cell lung cancer (NSCLC) . Beamion LUNG-1 (ClinicalTrials.gov identiﬁer: NCT04886804) is assessing the safety/efﬁcacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors. | | MATERIALS
AND METHODS | Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); tumor response was a secondary end point. | | RESULTS | As of May 23, 2024, 105 patients were treated. Two DLTs occurred during the MTDevaluation period; MTD was not reached (NR). The recommended doses for expansion were 120 mg once daily and 240 mg once daily. Treatment-related adverse events (TRAEs; any/grade ≥3) occurred in 82%/10% of patients. The most common TRAEs (any/grade ≥3) included diarrhea (50%/1%), rash (16%/ 2%), anemia (10%/0%), decreased appetite (10%/1%), and increased alanine transaminase (10%/4%). The conﬁrmed investigator-assessed overall response rate (ORR) across all doses/tumors was 30%(95% CI, 23 to 40); median duration of response was 12.7 months (95% CI, 6.9 to NR) . In 54 patients with NSCLC, conﬁrmed ORR was 35%(95% CI, 24 to 49) . Activity was observed in patients with A775_G776insYVMA (ORR, 38%) and those who had received previous HER2-directed therapy (ORR, 28%) . In patients with NSCLC receiving zongertinib once daily, median progression-free survival was 17.2 months (95% CI, 8.3 to NR) . | | CONCLUSION | Zongertinib had a manageable safety proﬁle and demonstrated preliminary antitumor activity in patients with HER2-altered tumors, including those with HER2-mutant NSCLC. | ACCOMPANYING CONTENT Data Sharing Statement Data Supplement Protocol Accepted January 24, 2025 Published March 3, 2025 J Clin Oncol 43:1337-1347 © 2025 by American Society of Clinical Oncology View Online Article Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION The human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptors, plays a critical role in the regulation of cell proliferation and survival.1 HER2 alterations, including protein overexpression, gene ampliﬁcation, and genetic mutations, occur frequently across many human malignancies including breast, gastric, and lung cancers.1 HER2-targeted agents have transformed care for patients with breast and gastric cancers. Nevertheless, primary and acquired resistance to therapy remains a challenge in these settings.2 To date, HER2-targeted agents have had less of an impact in non–small cell lung cancer (NSCLC) than in breast and gastric cancers. Only one HER2-targeted therapy, the antibody-drug conjugate trastuzumab deruxtecan, is approved for the treatment of NSCLC after previous systemic therapy in patients with HER2 mutations and, after a recent pan-tumor approval, patients with HER2-overexpressing tumors (immunohistochemistry of 31) .3 HER2-mutant NSCLC accounts for 2%-5% of all cases of [ascopubs.org/journal/jco](ascopubs.org/journa

FAQs

What is the main purpose of the Beamion LUNG-1 study?

To assess the safety and efficacy of zongertinib (BI 1810631) in patients with HER2-altered solid tumors, including HER2-mutant NSCLC.

How was the phase Ia part of the trial designed?

It is an ongoing multicenter, multicohort phase Ia/Ib trial where phase Ia evaluated zongertinib given twice daily (15–150 mg) or once daily (60–360 mg) in pretreated patients. Primary endpoints were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).

What did the study report for recommended expansion doses and overall response?

Recommended doses for expansion were 120 mg once daily and 240 mg once daily. Confirmed overall response rate (ORR) across all doses and tumors was 30%, with a median duration of response of 12.7 months.

Sep 24, 2026

Uploaded by Angel