FDA Approves Zanidatamab-Based Regimens for First-Line HER2-Positive Advanced Gastroesophageal Adenocarcinoma
Clinical Summary:
- Design/Population: HERIZON-GEA-01 was a open-label trial evaluating trastuzumab plus chemotherapy, zanidatamab plus chemotherapy, or zanidatamab plus tislelizumab and chemotherapy in patients with unresectable locally advanced or metastatic HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma.
- Key Outcomes: Zanidatamab plus tislelizumab and chemotherapy significantly improved median overall survival to 26.4 months vs 19.2 months with trastuzumab plus chemotherapy and median progression-free survival to 12.4 vs 8.1 months. Zanidatamab plus chemotherapy also significantly improved progression-free survival, with the benefit primarily observed in patients with HER2 IHC 3+ tumors.
- Clinical Relevance: The approvals establish zanidatamab-based therapy as a new first-line option for HER2-positive advanced gastroesophageal adenocarcinoma, with the tislelizumab-containing regimen supported across IHC 3+ and IHC 2+/ISH+ disease and the chemotherapy-only regimen restricted to IHC 3+ tumors.
On August 25, 2026, the US Food and Drug Administration (FDA) approved zanidatamab (Ziihera; Jazz Pharmaceuticals) in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab (Tevimbra; BeOne Medicines), as first-line treatment for adult patients with HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.
The approval of zanidatamab plus tislelizumab and chemotherapy applies to patients with HER2 IHC 3+ or IHC 2+/ISH+ tumors, while zanidatamab plus chemotherapy without tislelizumab is approved for patients with HER2 IHC 3+ disease. HER2 positivity must be confirmed using an FDA-approved test.
Efficacy was evaluated in the open-label phase 3 HERIZON-GEA-01 trial. Patients were randomized 1:1:1 to receive trastuzumab plus investigator’s choice of capecitabine/oxaliplatin or fluorouracil/platinum chemotherapy, zanidatamab plus chemotherapy, or zanidatamab plus tislelizumab and chemotherapy. The dual primary end points were progression-free survival (PFS) by blinded independent central review and overall survival (OS).
Among patients with HER2 IHC 3+ or IHC 2+/ISH+ tumors, zanidatamab plus tislelizumab and chemotherapy significantly improved OS compared with trastuzumab plus chemotherapy. Median OS was 26.4 months with the zanidatamab-containing triplet and 19.2 months with trastuzumab plus chemotherapy, corresponding to a 28% reduction in the risk of death (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.57 to 0.90; P = .0043).
PFS was also significantly improved. Median PFS was 12.4 months with zanidatamab plus tislelizumab and chemotherapy compared with 8.1 months with trastuzumab plus chemotherapy (HR, 0.63; 95% CI, 0.51 to 0.78; P < .0001).
Zanidatamab plus chemotherapy without tislelizumab also significantly improved PFS compared with trastuzumab plus chemotherapy, although interim OS results were not statistically significant at the time of the PFS analysis. Exploratory analyses suggested that the PFS benefit was primarily driven by patients with HER2 IHC 3+ tumors.
In the IHC 3+ subgroup, median PFS was 14.2 months with zanidatamab plus chemotherapy compared with 7.6 months with trastuzumab plus chemotherapy.
The recommended zanidatamab dose is weight based. Patients weighing less than 70 kg should receive 1800 mg every 3 weeks or 1200 mg every 2 weeks, while patients weighing at least 70 kg should receive 2400 mg every 3 weeks or 1600 mg every 2 weeks. Tislelizumab may be administered at 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.
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. Tislelizumab carries warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
The FDA also approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices to identify patients with HER2 IHC 3+ or IHC 2+/ISH+ gastric, gastroesophageal junction, or esophageal adenocarcinoma eligible for zanidatamab-based treatment.
Source:
US Food and Drug Administration. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. Accessed on August 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanidatamab-hrii-and-tislelizumab-jsgr-her2-positive-gastric-gastroesophageal-junction?utm_medium=email&utm_source=govdelivery
