Zanidatamab + chemo posts 76% ORR and 36.5-mo OS as 1L HER2-positive gastro-oesophageal therapy

Zanidatamab, a bispecific HER2-targeted antibody that dimer-locks domains 2 & 4, was combined with CAPOX, FP or mFOLFOX6 in a single-arm, multicentre phase 2 study (NCT03929666). Among 46 treatment-naïve, metastatic HER2-positive gastro-oesophageal adenocarcinoma patients (IHC 3+ or IHC 2+/FISH+), investigator-assessed confirmed ORR hit 76.2% (DCR 88%) with a median DoR of 18.7 months. Median PFS reached 12.5 months and median OS an eye-catching 36.5 months after 48 months’ median follow-up. Grade 3/4 treatment-related AEs occurred in 65%—dominated by diarrhoea (39%, mitigated to 24% after mandatory loperamide) and hypokalaemia (22%); 13% stopped zanidatamab, and no treatment-related deaths occurred. For context, the historical trastuzumab-chemo benchmark from the ToGA trial delivered mOS 13.8 months and ORR ~47%, so this bispecific-chemo combo more than doubles survival in a selected cohort, albeit without the randomised controls or PD-1 backbone used in KEYNOTE-811.