FDA Approves Ziihera Regimens in First-Line HER2+ Advanced GEA

The Food and Drug Administration (FDA) has approved two zanidatamab-hrii (Ziihera)-containing regimens as first-line treatment for adults with HER2-positive (HER2+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.

Specifically, the FDA approved zanidatamab-hrii combined with tislelizumab-jsgr (Tevimbra) and fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2+ immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization (ISH+) tumors [1, 2]. The FDA also approved zanidatamab-hrii in combination with fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2+ IHC 3+ tumors. Concurrently, the FDA approved two companion diagnostic devices to identify eligible patients: the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail.

This review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative collaborating with Health Canada and United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA). The FDA utilized the Real-Time Oncology Review (RTOR) pilot program and Assessment Aid to streamline data submission.

Clinical Evidence: The HERIZON-GEA-01 Trial

These approvals are supported by results from the Phase 3 HERIZON-GEA-01 (NCT05152147) trial, which randomized (1:1:1) patients with advanced HER2+ GEA to three arms:

• Arm A: Trastuzumab combined with investigator's choice of capecitabine and oxaliplatin (CAPOX) or fluorouracil and platinum (FP).
• Arm B: Zanidatamab-hrii in combination with CAPOX or FP.
• Arm C: Zanidatamab-hrii combined with tislelizumab-jsgr and CAPOX or FP.

The trial's dual primary outcomes were progression-free survival (PFS) and overall survival (OS). Arm C showed statistically significant improvements over Arm A: median OS was 26.4 months versus 19.2 months (hazard ratio [HR] 0.72; p=0.0043) and median PFS was 12.4 months versus 8.1 months (HR 0.63; p<0.0001). Survival benefits were consistent across key subgroups, regardless of PD-L1 status.

For Arm B, the combination of Ziihera and chemotherapy showed a statistically significant PFS benefit over Arm A. However, OS interim results were not statistically significant at the time of PFS analysis. Exploratory analyses in the HER2 IHC 2+/ISH+ population suggested the clinical benefit of Arm B was primarily driven by patients with IHC 3+ tumors. Specifically, among patients with IHC 3+ tumors, Arm B demonstrated a median PFS of 14.2 months compared to 7.6 months in Arm A (HR 0.55).

Dosing Schedules and Administration

Oncology nurses must be familiar with the distinct, weight-based and interval dosing schedules of this new regimen:

• Zanidatamab-hrii: Recommended dosing is based on body weight. For patients weighing less than 70 kg, the dose is 1,800 mg every three weeks (Q3W) or 1,200 mg every two weeks (Q2W). For patients weighing 70 kg or more, the recommended dose is 2,400 mg Q3W or 1,600 mg Q2W.
• Tislelizumab-jsgr: The recommended dose is 150 mg Q2W, 200 mg Q3W, 300 mg Q4W, or 400 mg Q6W administered intravenously.

Vital Nursing Implications: Boxed Warnings and Safety Management

Because these regimens combine a novel bispecific antibody, immunotherapy, and cytotoxic chemotherapy, oncology nurses play a central role in safety monitoring, toxicity grading, and patient education.

The prescribing information for zanidatamab-hrii contains Boxed Warnings for severe diarrhea and embryo-fetal toxicity. In clinical trials, diarrhea occurred in 85% of patients receiving the triplet regimen (Grade 3/4: 26.1%) and 81% of patients receiving the doublet (Grade 3/4: 21.3%). The risk of severe and life-threatening diarrhea is higher in patients aged 65 years or older. Nurses must ensure mandatory loperamide prophylaxis is initiated in cycle one for all patients. Loperamide should begin at the first loose stool when zanidatamab-hrii is administered with chemotherapy. If patients are receiving the FOLFOX regimen, the fluorouracil bolus must not be administered.

Oncology nurses must also monitor for Left Ventricular Dysfunction (LVD), as zanidatamab-hrii can cause decreases in left ventricular ejection fraction (LVEF). Ejection fraction must be assessed prior to treatment initiation and at regular intervals during therapy. Additionally, because infusion-related reactions (IRRs) occurred in over 20% of patients, nurses must administer premedication prior to each zanidatamab-hrii dose and monitor closely during administration.

Finally, nurses must monitor for tislelizumab-jsgr-specific toxicities, including immune-mediated adverse reactions (such as pneumonitis, colitis, and hepatitis) and complications arising from allogeneic hematopoietic stem cell transplantation. Women of reproductive potential should be advised to use effective contraception during treatment and for four months after the last dose of zanidatamab-hrii.

References

1. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. US Food and Drug Administration. August 25, 2026. Accessed August 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanidatamab-hrii-and-tislelizumab-jsgr-her2-positive-gastric-gastroesophageal-junction
2. U.S. FDA Approves Ziihera® (zanidatamab-hrii) with and without Tislelizumab plus Chemotherapy in First-Line HER2+ Advanced Gastroesophageal Adenocarcinoma. Press Release. Dublin, Ireland: Jazz Pharmaceuticals plc; August 25, 2026.