The US FDA has approved two regimens containing Ziihera (zanidatamab-hrii) for the first-line treatment of adults with unresectable locally advanced or metastatic HER2-positive (HER2+) gastroesophageal adenocarcinoma (GEA), marking the second FDA approval for the bispecific antibody in less than two years. Jazz Pharmaceuticals holds the approval in the US under an exclusive license from Vancouver-based Zymeworks Inc. (Nasdaq: ZYME), which discovered and engineered the molecule using its proprietary Azymetric bispecific antibody platform. The approval triggers a USD 250 million milestone payment to Zymeworks, bringing total payments received from Jazz to USD 650 million.

The two approved regimens are: zanidatamab plus tislelizumab-jsgr (Tevimbra) and fluoropyrimidine- and platinum-containing chemotherapy, for patients with HER2+ IHC 3+ and IHC 2+/ISH+ disease regardless of PD-L1 status; and zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy alone, restricted to HER2+ IHC 3+ patients. Both regimens require HER2 confirmation by an FDA-authorized test. Zanidatamab simultaneously binds two distinct extracellular epitopes on HER2, inducing receptor internalization, downregulation, and immune effector mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

The approval is supported by the Phase III HERIZON-GEA-01 trial in first-line HER2+ GEA. Results were published in the New England Journal of Medicine and presented at ASCO GI 2026. Jaffer A. Ajani of MD Anderson Cancer Center noted a median overall survival exceeding two years with the regimen, with similar outcomes observed irrespective of PD-L1 status. A Phase III confirmatory trial, HERIZON-GEA-301, is ongoing.

The competitive landscape in first-line HER2+ GEA includes pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy, approved by the FDA in March 2025 for patients with a combined positive score of at least 1, and trastuzumab plus chemotherapy, the foundational standard since 2010. Zanidatamab's label carries no PD-L1 restriction for the tislelizumab combination regimen, a differentiation the source highlights. A CHMP positive opinion for zanidatamab in HER2+ biliary tract cancer has also been issued in Europe, while CSPC's Ennituo, another HER2-directed bispecific antibody, has received approval in China for HER2+ gastric cancer.

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