Oral HER2-selective TKI Zongertinib Logs 71% ORR and 12-mo PFS in Pretreated HER2-Mutant NSCLC

Zongertinib (BI 1810631) is an irreversible HER2 tyrosine-kinase inhibitor that spares EGFR. In the phase Ia/Ib Beamion LUNG-1 study (AACR CT050; NCT04886804), 75 previously treated advanced NSCLC patients with HER2 TKD mutations received 120 mg daily: ORR 71% (7% CR, 64% PR), disease-control 96%, median DOR 14.1 mo, and median PFS 12.4 months. In 31 patients who received zongertinib post-ADC exposure, ORR was 48% and PFS was 6.8 months in cohort 5 (n = 31). In 20 patients with non-TKD HER2 mutations, ORR was 30% (cohort 3, n = 20). Grade ≥3 adverse events were uncommon (17% in cohort 1; no ILD, minimal rash/diarrhea).

Trastuzumab deruxtecan, the standard of care for pre-treated HER2-mutant NSCLC from DESTINY-Lung02 trial (NCT03505710), has an ORR of 49% and grade 3 or higher treatment-related adverse events in 39%. The incidence of any drug-related interstitial lung disease (ILD) was 13%.