FDA Approves Ziihera Combinations for HER2-Positive GEA

The U.S. Food and Drug Administration (FDA) has approved two Ziihera (zanidatamab-hrii)-based treatment regimens for the first-line treatment of adults with unresectable locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA).

The approval was announced by Jazz Pharmaceuticals and covers two treatment combinations. The first combines Ziihera with Tevimbra (tislelizumab-jsgr) and fluoropyrimidine- and platinum-based chemotherapy for patients with HER2-positive tumors classified as IHC 3+ or IHC 2+/ISH+. The second combines Ziihera with fluoropyrimidine- and platinum-based chemotherapy for patients with HER2-positive IHC 3+ tumors.

GEA includes cancers of the stomach, gastroesophageal junction and esophagus. It is one of the most common cancers worldwide and is often linked to poor outcomes, particularly when diagnosed at an advanced stage. Around 20% of patients have HER2-positive disease.

The FDA approval is based on results from the Phase 3 HERIZON-GEA-01 trial, which evaluated Ziihera-based combinations against trastuzumab plus chemotherapy.

In the overall HER2-positive population, the Ziihera-containing regimens improved progression-free survival (PFS), reducing the risk of disease progression or death by 35%. Median PFS reached 12.4 months compared with 8.1 months for patients receiving trastuzumab plus chemotherapy.

The combination of Ziihera, tislelizumab-jsgr and chemotherapy also showed a significant overall survival benefit. The treatment reduced the risk of death by 28%, with median overall survival reaching 26.4 months compared with 19.2 months for trastuzumab plus chemotherapy.

The 26.4-month median overall survival represents an improvement of more than seven months and, according to Jazz Pharmaceuticals, is the longest median overall survival reported in a Phase 3 trial for HER2-positive advanced GEA.

Treatment benefits were generally consistent across major patient groups, including different geographic regions and PD-L1 status. This suggests the treatment may provide benefits regardless of whether a patient’s tumor is PD-L1 positive or negative.

The safety profile of the Ziihera-based regimens was consistent with earlier studies of zanidatamab. Diarrhea was the most common side effect and was mainly reported early during treatment. Patients received preventive loperamide during the first treatment cycle, while additional antidiarrheal treatment and dose adjustments were used when needed. Few patients discontinued Ziihera because of side effects.

The FDA decision gives doctors a new first-line treatment option for adults with HER2-positive advanced or metastatic gastroesophageal adenocarcinoma. The approval also highlights the importance of HER2 testing when patients are diagnosed with advanced or metastatic GEA, as the results can help guide treatment selection.

The HERIZON-GEA-01 trial is still ongoing, with additional analyses planned. The trial results have been published in the New England Journal of Medicine and presented at major oncology meetings, including ASCO GI 2026 and the 2026 American Society of Clinical Oncology Annual Meeting.

The approval expands the use of Ziihera in HER2-positive GEA and strengthens its role as a targeted treatment option in the first-line setting.