In an ongoing multicentre, multicohort phase Ia/Ib Beamion LUNG-1 study, the findings from the phase Ia indicate that zongertinib had a manageable tolerability profile with preliminary signals of efficacy in pretreated patients with HER2-altered solid tumours, including HER2-mutated non-small cell lung cancer (NSCLC). These results support the ongoing recruitment into the phase Ib expansion portion of the study.
However, the total number of patients treated with currently available HER2 antibody-drug conjugates was rather low according to Dr. John V. Heymach of the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues, who published the findings on 3 March 2025 in the JCO.
The authors wrote in the background that HER2-targeted agents have had less of an impact in NSCLC than in breast and gastric cancers. Only 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-tumour approval, patients with HER2-overexpressing tumours (immunohistochemistry of 3+). HER2-mutated NSCLC accounts for 2-5% of all cases of NSCLC, is associated with poor prognosis and high rates of brain metastases, and is very challenging to treat.
HER2 mutations in NSCLC mostly occur in the tyrosine kinase domain (TKD), and insertions in exon 20 predominate. Although HER2 exon 20 insertion mutations are sensitive to trastuzumab deruxtecan and other antibody-drug conjugates, such as trastuzumab emtansine, they are generally resistant to HER2 tyrosine kinase inhibitors (TKIs); early-phase studies with agents including afatinib, dacomitinib, and neratinib demonstrated disappointing response rates.
Pyrotinib and poziotinib are active against exon 20 insertion mutations and have demonstrated activity in patients with HER2-mutated NSCLC, but are associated with high rates of off-target EGFR wild-type related toxicities, such as diarrhoea and, in the case of poziotinib, rash. Zongertinib is a novel TKI that selectively and irreversibly inhibits HER2 and spares EGFR, thereby limiting associated toxicities.
Phase Ia of the Beamion LUNG-1 study assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumours, including NSCLC. Primary endpoints were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); tumour response was a secondary endpoint.
As of 23 May 2024, 105 patients were treated. Two DLTs occurred during the MTD evaluation 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 diarrhoea (50%/1%), rash (16%/2%), anaemia (10%/0%), decreased appetite (10%/1%), and increased alanine transaminase (10%/4%).
The confirmed investigator-assessed overall response rate (ORR) across all doses/tumours was 30% (95% confidence interval [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).
The authors wrote that zongertinib also demonstrated activity in tumour types other than NSCLC. Of 12 patients with breast cancer included in the study, four had confirmed responses and one had an unconfirmed response. Responses were observed both in patients with HER2 overexpression and/or amplification as well as those who had HER2 mutations. At data cut-off, treatment was ongoing in three of the responding patients. Responses were noted in a range of other tumour types.
Several clinical trials are planned, or are ongoing, that are assessing zongertinib across tumour types. Beamion LUNG-2 is an open-label phase III randomised study comparing first-line zongertinib versus standard-of-care in patients with HER2 TKD-mutated NSCLC. Beamion PANTUMOR-1 is an ongoing phase II basket study that will assess zongertinib in various HER2-mutated or HER2-amplified/HER2-overexpressing cancers. The phase Ib/II Beamion BCGC-1 study is assessing zongertinib plus trastuzumab deruxtecan or trastuzumab emtansine in patients with previously treated HER2-positive breast or gastro-oesophageal cancer.
The findings were previously presented at ELCC 2023, AACR 2023, ASCO 2023, WCLC 2023, ESMO 2023, ASCP 2024, ECP 2024, and ASCO 2024.
The study was supported by Boehringer Ingelheim.
Reference
Heymach JV, Opdam F, Barve M, et al. HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study. JCO; Published online 3 March 2025. DOI: https://doi.org/10.1200/JCO-24-01727