On August 25, 2026, the U.S. Food and Drug Administration (FDA) approved zanidatamab-hrii (Ziihera) for two indications, including:
- in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr (Tevimbra), as first-line treatment for adults with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-approved test, and
- in combination with fluoropyrimidine- and platinum-containing chemotherapy, as first-line treatment for adults with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-approved test.
The FDA also approved two companion diagnostic devices, the PATHWAY anti–HER2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, for identifying patients with HER2-positive (IHC3+ or IHC2+/ISH+) gastric, gastroesophageal junction, and esophageal adenocarcinoma for treatment with zanidatamab, consistent with the approved drug labeling.
Efficacy and Safety
Efficacy for zanidatamab was evaluated in the randomized, three-arm, open-label, active-comparator, global HERIZON-GEA-01 trial (ClinicalTrials.gov identifier NCT05152147) in patients with unresectable locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma, including those with gastric, gastroesophageal junction, and esophageal adenocarcinoma. Patients were randomly assigned (1:1:1) to one of three treatment arms:
- Arm A: trastuzumab with investigator’s choice of combination therapy of capecitabine and oxaliplatin (CAPOX) or fluorouracil and platinum
- Arm B: zanidatamab in combination with CAPOX or fluorouracil and platinum
- Arm C: zanidatamab in combination with tislelizumab and CAPOX or fluorouracil and platinum
The dual major efficacy outcome measures were progression-free survival assessed by blinded independent central review per RECIST v1.1. and overall survival.
Efficacy results showed statistically significant improvements in overall survival and progression-free survival for Arm C (zanidatamab and tislelizumab–containing arm) vs Arm A (trastuzumab arm) in patients with HER2 IHC3+ or IHC2+/ISH+ tumors. Median overall survival was 26.4 months (95% confidence interval [CI] = 21.5–30.3) in Arm C and 19.2 months (95% CI = 16.8–21.8) in Arm A (hazard ratio [HR] = 0.72, 95% CI = 0.57–0.90; P = .0043), and the median progression-free survival was 12.4 months (95% CI: 9.8, 18.5) in Arm C vs 8.1 months (95% CI = 7.0–8.9) in Arm A (HR = 0.63, 95% CI = 0.51–0.78; P < .0001).
Arm B (zanidatamab arm) showed a statistically significant improvement in progression-free survival compared with Arm A. Overall survival interim results were not statistically significant at the time of the progression-free survival analysis. Based on exploratory analyses in the HER2 IHC 2+/ISH+ population, the treatment effect in Arm B was primarily attributed to the subgroup of patients with HER2 IHC 3+ tumors. In patients with IHC 3+ tumors, the median progression-free survival was 14.2 months (95% CI = 11.7–16.7) in Arm B and 7.6 months (95% CI = 6.9–8.5) in Arm A (HR = 0.55, 95% CI = 0.43–0.69).
The zanidatamab prescribing information includes a boxed warning for diarrhea and embryo-fetal toxicity, as well as warnings and precautions for left ventricular dysfunction and infusion-related reactions. The tislelizumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
Recommended Dosage
The recommended zanidatamab dose is based on body weight. For patients with a body weight of less than 70 kg, the recommended dose is 1,800 mg every 3 weeks or 1,200 mg every 2 weeks. For patients with a body weight greater than or equal to 70 kg, the recommended dose is 2,400 mg every 3 weeks or 1,600 mg every 2 weeks. The recommended tisletizumab dose is 150 mg every 2 weeks, 200 mg every 3 weeks, 300 mg every 4 weeks, or 400 mg every 6 weeks until disease progression or unacceptable toxicity.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, allowing for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada (HC) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review. Zanidatamab previously received Fast Track, Breakthrough Therapy, and Orphan Drug designations.
