Zanidatamab (dual HER2 bispecific; ECD2/4) + chemo in 1L HER2+ mGEA shows early ERBB2 ctDNA clearance tied to 12.5-mo mPFS

Zanidatamab is a dual HER2-targeted bispecific antibody (binding HER2 extracellular domains 2 and 4) evaluated with platinum/fluoropyrimidine chemotherapy (mFOLFOX6, CAPOX, or 5-FU/cisplatin) in a Phase 2, 1L HER2+ advanced/metastatic gastroesophageal adenocarcinoma trial (NCT03929666; n=46; 89% centrally confirmed HER2+). Confirmed ORR was 76.2% (95% CI 60.5–87.9) with median PFS 12.5 months (95% CI 8.2–21.8)—numerically above historical trastuzumab + chemo benchmarks from ToGA (ORR ~47%, mPFS 6.7 months) in a similar 1L HER2+ population, noting cross-trial differences and that modern practice often adds PD-1 for eligible patients. Baseline plasma ERBB2 amplification by ctDNA NGS showed 94% concordance with tissue FISH (34/36); among patients with detectable baseline ERBB2 amplification, median PFS was 18.6 months (95% CI 12.0–NE), and all responders/SD with available samples had undetectable on-treatment ERBB2 amplification, while PD/SD on-treatment samples showed persistence/recurrence of ERBB2 alterations plus PI3K/AKT and RAS/MAPK co-alterations; 94% (15/16) of matched samples had >80% ctDNA drop on-treatment (Guardant Infinity panel).