The U.S. Food and Drug Administration on August 25 approved zanidatamab-hrii (Ziihera), a bispecific HER2-directed antibody, in two first-line combination regimens for adults with unresectable locally advanced or metastatic HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. Jazz Pharmaceuticals said the approval is based on the Phase 3 HERIZON-GEA-01 trial, which showed median overall survival of 26.4 months versus 19.2 months for the Ziihera plus tislelizumab (Tevimbra) and chemotherapy arm versus trastuzumab plus chemotherapy. The approval triggered a $250 million milestone payment to Zymeworks, the originator of zanidatamab.
Trial Results
HERIZON-GEA-01 (NCT05152147) randomized 914 patients 1:1:1 to three arms: trastuzumab with chemotherapy; zanidatamab-hrii with chemotherapy; or zanidatamab-hrii with tislelizumab-jsgr and chemotherapy. The dual primary endpoints were progression-free survival and overall survival. Both Ziihera-containing arms improved PFS versus trastuzumab plus chemotherapy, with median PFS of 12.4 months versus 8.1 months (35% reduction in progression or death risk) in the overall HER2-positive population. For OS in the tislelizumab triplet arm, Jazz cited median OS of 26.4 versus 19.2 months and a 28% reduction in the risk of death.
Approval Specifics
The Ziihera plus tislelizumab and chemotherapy regimen is labeled for HER2 IHC 3+ or IHC 2+/ISH+ disease as detected by an FDA-authorized test, regardless of PD-L1 status. The Ziihera plus chemotherapy regimen is labeled for IHC 3+ disease. FDA also approved two companion diagnostic devices — the Pathway anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the Ventana HER2 Dual ISH DNA Probe Cocktail — to identify eligible patients. The FDA conducted the review under Project Orbis in collaboration with Health Canada and the UK's MHRA.
Economics
Zymeworks, which originated zanidatamab and licensed Jazz exclusive rights in specified territories, filed an August 25, 2026 Form 8-K reporting that the GEA approval earned a $250 million milestone from Jazz. The filing said Zymeworks remains eligible for up to $1.3 billion in additional regulatory and commercial milestones plus tiered royalties of 10% to 20% on Jazz net sales in Jazz's licensed territories. The Ziihera prescribing information includes a boxed warning for diarrhea, including fatal cases, and embryo-fetal toxicity, plus warnings for left ventricular dysfunction and infusion-related reactions.
What to Watch Through Year-End
Three checkpoints follow. Real-world uptake of Ziihera plus tislelizumab versus continued use of trastuzumab-based first-line care, which NCCN guideline updates will track through Q4 2026, will determine whether the new standard displaces the old one in community oncology. The full OS readout for the Ziihera plus chemotherapy arm, expected later this year per the NEJM publication, will clarify whether the OS benefit extends to the non-tislelizumab combination. And launch pricing for Ziihera in the U.S. market, not yet disclosed in Jazz's approval wire, will be the first concrete data point for payers and oncology practice managers planning 2027 budgets.
