FDA Approves Zanidatamab (Ziihera): HER2 Bispecific Antibody Plus Immunotherapy for First-Line Gastric Cancer

　　1.Overview and Regulatory Highlights

　　On August 25,2026,the U.S.FDA officially approved zanidatamab-hrii(brand name:Ziihera)for adult patients with HER2-positive,unresectable,locally advanced or metastatic gastric,gastroesophageal junction(GEJ),or esophageal adenocarcinoma.This approval introduces two first-line combination regimens,marking a new era of"bispecific+immunotherapy"for HER2-positive gastroesophageal tumors.

　　The review utilized the FDA's Orbis international collaborative project and RTOR(Real-Time Oncology Review)program,accelerating patient access.Two companion diagnostic devices were also approved to detect HER2 expression levels(IHC 3+vs.IHC 2+/ISH+),ensuring precise patient selection.

　　2.Manufacturers and Mechanism of Action

　　Ziihera is commercialized in the U.S.by Jazz Pharmaceuticals.It is a bispecific antibody that simultaneously binds two distinct domains(ECD2 and ECD4)of the HER2 receptor,enhancing signal blockade and promoting antibody-dependent cellular cytotoxicity(ADCC).

　　Tislelizumab-jsgr(brand name:Tevimbra),a PD-1 immune checkpoint inhibitor submitted by BeOne Medicines USA,is combined in one of the regimens.By blocking the PD-1/PD-L1 pathway,it restores T-cell mediated anti-tumor immunity,creating a synergistic"targeted+immune"effect.

　　3.Indications and Patient Stratification

　　Based on HER2 expression,two indications were granted:

　　Zanidatamab+Tislelizumab+Fluoropyrimidine/Platinum Chemotherapy:For all HER2-positive(IHC 3+or IHC 2+/ISH+)adult patients.This regimen is independent of PD-L1 status.

　　Zanidatamab+Fluoropyrimidine/Platinum Chemotherapy:Restricted to patients with HER2 IHC 3+high expression.

　　4.HERIZON-GEA-01 Phase III Clinical Data

　　The approval was supported by the global,open-label Phase III trial HERIZON-GEA-01(NCT05152147),comparing three arms against a control arm of trastuzumab plus chemotherapy.

　　Triplet Regimen(Zanidatamab+Tislelizumab+Chemo):Met dual primary endpoints.Median OS was 26.4 months vs.19.2 months for control(HR=0.72,p=0.0043);median PFS was 12.4 months vs.8.1 months(HR=0.63,p<0.0001).

　　Doublet Regimen(Zanidatamab+Chemo):Showed significant PFS improvement over control,particularly in the IHC 3+subgroup;interim OS analysis did not yet reach statistical significance.

　　5.Safety Warnings and Dosing

　　Black Box Warnings:Zanidatamab carries warnings for severe diarrhea and embryo-fetal toxicity.Monitoring for left ventricular dysfunction and infusion reactions is also required.Tislelizumab requires vigilance for immune-mediated adverse reactions and transplantation-related complications.

　　Dosing:

　　Weight<70 kg:1800 mg every 3 weeks or 1200 mg every 2 weeks.

　　Weight≥70 kg:2400 mg every 3 weeks or 1600 mg every 2 weeks.

　　Tislelizumab offers flexible dosing schedules based on clinical judgment.

　　6.Clinical Significance

　　This approval represents the first HER2 bispecific antibody±PD-1 combination for HER2-positive gastroesophageal adenocarcinoma.With a median OS of 26.4 months,it breaks the therapeutic ceiling of the trastuzumab era and sets a new benchmark for first-line treatment.