The U.S. Food and Drug Administration (FDA) has approved two Ziihera (zanidatamab-hrii)-containing regimens for the first-line treatment of adults with HER2-positive unresectable locally advanced or metastatic gastroesophageal adenocarcinoma (GEA). The approval was announced by Jazz Pharmaceuticals on August 25, 2026.
The approval includes:
- Ziihera plus Tevimbra (tislelizumab-jsgr) and fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2-positive tumors classified as IHC 3+ or IHC 2+/ISH+.
- Ziihera plus fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2 IHC 3+ tumors.
Gastroesophageal adenocarcinoma in this indication includes cancers of the stomach, gastroesophageal junction, and esophagus. The Ziihera plus tislelizumab and chemotherapy regimen is approved across the eligible HER2-positive population regardless of PD-L1 status.
HERIZON-GEA-01 Trial Supports FDA Approval
The approval is supported by results from the randomized, open-label Phase 3 HERIZON-GEA-01 trial (NCT05152147), which evaluated zanidatamab-based treatment as first-line therapy for previously untreated HER2-positive advanced gastroesophageal adenocarcinoma.
A total of 914 patients were randomized in a 1:1:1 ratio to receive:
- zanidatamab plus tislelizumab and chemotherapy;
- zanidatamab plus chemotherapy; or
- trastuzumab plus chemotherapy.
At a median follow-up of 25.9 months, median progression-free survival (PFS) was 12.4 months in both zanidatamab-containing groups, compared with 8.1 months with trastuzumab plus chemotherapy.
For patients receiving zanidatamab plus tislelizumab and chemotherapy, the hazard ratio for disease progression or death was 0.63, corresponding to a 37% reduction in risk compared with trastuzumab plus chemotherapy.
For zanidatamab plus chemotherapy, the hazard ratio was 0.65, representing a 35% reduction in the risk of progression or death. Both PFS comparisons were statistically significant.
Overall Survival Reaches 26.4 Months With Ziihera, Tislelizumab and Chemotherapy
The combination of zanidatamab, tislelizumab, and chemotherapy also produced a statistically significant improvement in overall survival (OS). Median OS was 26.4 months with zanidatamab plus tislelizumab and chemotherapy, compared with 19.2 months with trastuzumab plus chemotherapy. The hazard ratio for death was 0.72, corresponding to a 28% reduction in the risk of death.
Median OS with zanidatamab plus chemotherapy was 24.4 months. However, at the interim analysis, the OS difference compared with trastuzumab plus chemotherapy did not reach statistical significance, with a hazard ratio of 0.80 and P value of 0.06. Additional analyses are planned as the trial continues.
The HERIZON-GEA-01 results were published in the New England Journal of Medicine in May 2026.
Safety of Ziihera-Based Regimens
Grade 3 or higher adverse events occurred in 83.3% of patients receiving zanidatamab plus tislelizumab and chemotherapy, 73.8% receiving zanidatamab plus chemotherapy, and 74.5% receiving trastuzumab plus chemotherapy.
Diarrhea was the most common grade 3 or higher adverse event, occurring in 24.8%, 20.0%, and 12.9% of patients in the three treatment groups, respectively.
The U.S. Prescribing Information for Ziihera contains boxed warnings for diarrhea and embryo-fetal toxicity.
About Ziihera
Ziihera is a bispecific HER2-targeted antibody designed to bind two distinct extracellular sites on the HER2 protein.
The drug was previously approved by the FDA in November 2024 for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer, as detected by an FDA-approved test.
The latest FDA decision expands the role of zanidatamab into the first-line treatment of HER2-positive advanced gastroesophageal adenocarcinoma, providing new treatment options for patients with HER2-driven gastric, gastroesophageal junction, and esophageal cancers.
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