Zongertinib (HER2-selective irreversible TKI) hits 76% ORR and 14.4-mo PFS as 1L HER2-mutant NSCLC option

Zongertinib is an oral, irreversible HER2 (ERBB2) tyrosine kinase inhibitor designed to spare wild-type EGFR, evaluated in the Phase 1a/1b Beamion LUNG-1 multicohort trial (NCT04886804) at 120mg QD in previously untreated advanced/metastatic nonsquamous HER2-mutant NSCLC (cohort 2; n=74). At the August 21, 2025 data cutoff, blinded independent central review confirmed ORR 76% (95% CI, 65–84), median DoR 15.2 months, and median PFS 14.4 months—well above typical first-line chemo-immunotherapy PFS benchmarks in unselected nonsquamous NSCLC (e.g., pembrolizumab+pemetrexed/platinum mPFS ≈8.8 months), and also numerically stronger than post-platinum HER2-directed ADC activity reported for trastuzumab deruxtecan in HER2-mutant NSCLC (ORR 55%, mPFS 8.2 months). Any-grade AEs were 99% with grade ≥3 AEs 45%, but treatment-related grade ≥3 AEs were 19%; in an exploratory active brain metastases cohort (cohort 4; n=30), confirmed intracranial ORR was 47% (RANO-BM) with treatment-related grade ≥3 AEs 17%.