Promising results with zongertinib in advanced-stage HER2-mutant NSCLC

ERBB2 (commonly known as HER2) is mutated in 2–4% of non-small-cell lung cancers (NSCLCs). The HER2-targeted antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improves both progression-free survival (PFS) and overall survival in patients with advanced-stage NSCLC harbouring these alterations. However, T-DXd comes with a considerable risk of interstitial lung disease (ILD; including fatal events) and a high risk of grade ≥3 treatment-related adverse events (TRAEs). Now, results from phase Ib of the Beamion LUNG-1 trial show that the HER2-selective tyrosine-kinase inhibitor zongertinib is efficacious and safe in this setting.

The results currently presented are from three trial cohorts involving patients with previously treated nonsquamous NSCLC with HER2 mutations that affect either the tyrosine kinase domain (cohorts 1 and 5) or other domains (exploratory cohort 3; n = 20). Patients in cohort 5 (n = 31) had previously received a HER2-targeted ADC. Initially, patients in cohort 1 were randomly assigned to receive zongertinib at a dose of either 120 mg (n = 75) or 240 mg (n = 55), and those in cohorts 3 and 5 received the 240-mg dose. After dose-selection analysis in cohort 1, all patients received 120 mg. Objective response rate (ORR) was the primary end point.