Zongertinib (BI 1810631), a novel HER2-specific tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim, has shown promising results in patients with pretreated non-small cell lung cancer (NSCLC) harboring HER2 mutations. The Beamion LUNG-1 trial, a phase 1a/1b study, demonstrated significant clinical activity and a manageable safety profile, paving the way for a phase 3 confirmatory trial. These findings offer hope for a more effective and tolerable treatment option for this challenging subset of lung cancer patients.
Clinical Efficacy of Zongertinib in Pretreated NSCLC
The Beamion LUNG-1 trial (NCT04886804) evaluated the safety and efficacy of zongertinib in patients with HER2 aberration-positive solid tumors and HER2 mutation-positive NSCLC. In a prespecified interim analysis of phase 1b, 42 patients with pretreated HER2-mutant NSCLC were randomized to 120 mg or 240 mg once daily. The objective response rate (ORR) in the phase 1b portion of the trial was 73.9% and 91.3%, respectively.
According to study author Gerrina Ruiter, MD, PhD, "Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated [NSCLC] with a HER2[TKD] mutation, including in those with brain metastases."
Safety and Tolerability Profile
Zongertinib was generally well-tolerated, with most treatment-related adverse events (TRAEs) being grade 1 or 2. The most common TRAE was diarrhea, with 24% of patients experiencing grade 1 and 5% experiencing grade 2. Serious TRAEs occurred in 5% of patients, with no adverse events leading to treatment discontinuation. Notably, no cases of interstitial lung disease (ILD) or pneumonitis were reported. This favorable safety profile is attributed to zongertinib's selective binding to the HER2 tyrosine kinase domain, sparing wild-type EGFR and thus avoiding EGFR-mediated toxicities.
Ongoing Phase 3 Trial: Beamion LUNG-2
Based on the encouraging efficacy and tolerability data from the Beamion LUNG-1 trial, a phase 3 confirmatory study, Beamion LUNG-2 (NCT06151574), is currently underway. This randomized, active-controlled, multi-center trial will evaluate orally administered zongertinib compared with standard of care as first-line treatment in patients with unresectable, locally advanced, or metastatic non-squamous NSCLC harboring HER2 tyrosine kinase domain mutations. The trial aims to further establish the role of zongertinib in the treatment landscape of HER2-mutant NSCLC.
HER2-Targeted Therapies in NSCLC: Addressing Unmet Needs
NSCLC comprises approximately 85% of all diagnosed lung cancers, with HER2 mutations occurring in about 3% of cases. These mutations are associated with female sex, Asian ethnicity, never-smoking history, adenocarcinoma histology, and a higher incidence of brain metastases. Current standard first-line chemotherapy with or without immunotherapy has limited efficacy in patients with HER2-mutant NSCLC. While HER2-targeted agents like trastuzumab deruxtecan (Enhertu) have shown promise in the second-line setting, there remains a critical unmet medical need for selective, orally available, and well-tolerated HER2 TKIs that effectively target HER2 mutants while limiting toxicity. Zongertinib represents a significant step forward in addressing this need, offering a potential new treatment option for patients with HER2-mutant NSCLC.
