Zanidatamab (dual-HER2 bispecific) + PD-1 tislelizumab delivers OS gains regardless of PD-L1 in 1L HER2+ mGEA

Zanidatamab is a HER2-targeted bispecific antibody that binds two HER2 epitopes; in HERIZON-GEA-01 (Phase 3; NCT05152147), it was combined with platinum/fluoropyrimidine chemotherapy (CAPOX or FP) plus the anti–PD-1 tislelizumab versus trastuzumab + chemotherapy in previously untreated HER2+ locally advanced/metastatic gastroesophageal adenocarcinoma (zanidatamab+tisl+CT n=302; tras+CT n=308; 26-month median follow-up). In the ITT population, zanidatamab+tisl+CT improved mPFS to 12.4 vs 8.1 months (HR 0.63, p<0.001) and mOS to 26.4 vs 19.2 months (HR 0.72, p=0.004)—an OS that exceeds the current 1L benchmark of pembrolizumab+trastuzumab+chemo in KEYNOTE-811 (mOS 20.0 vs 16.8 months; HR 0.80) and materially outperforms historical trastuzumab+chemo ToGA-era expectations (mOS 13.8 months). PD-L1 subgroup analyses (VENTANA SP263; TAP and CPS) suggested benefit was maintained in PD-L1–negative (e.g., TAP<1%: mPFS 18.5 vs 7.9 months; mOS 29.7 vs 15.8 months) and PD-L1–positive disease (TAP≥1%: mPFS 11.3 vs 8.3 months; mOS 26.4 vs 21.2 months), though post-progression therapy imbalances (more subsequent checkpoint inhibitor and HER2-targeted therapy in the tras+CT arm) complicate clean OS interpretation across PD-L1 strata.