FDA Approves New Combination Treatments for Advanced HER2-Positive Gastric and Esophageal Cancers
The FDA has approved two new first-line combination treatments for unresectable locally advanced or metastatic HER2-positive gastric, gastroesophageal junction and esophageal adenocarcinoma. In the Phase 3 trial, the triple combination raised median overall survival from 19.2 to 26.4 months.
25 August 2026 — The U.S. Food and Drug Administration (FDA) approved two new targeted treatment approaches for the first-line treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma.
With this approval, the use of zanidatamab-hrii (Ziihera) and tislelizumab-jsgr (Tevimbra) together with chemotherapy has entered the standard treatment options for specific patient groups.
The Approved Treatment Indications
The approval announced by the FDA contains two different combination regimens based on the HER2 expression level of the patient (IHC 3+ or IHC 2+/ISH+):
- Triple Combination (Zanidatamab + Tislelizumab + Chemotherapy): For the first-line treatment of HER2-positive patients (IHC 3+ or IHC 2+/ISH+), zanidatamab and tislelizumab used together with fluoropyrimidine- and platinum-containing chemotherapy.
- Doublet Combination (Zanidatamab + Chemotherapy): For the first-line treatment of patients whose HER2 positivity is at the IHC 3+ level only, zanidatamab used together with chemotherapy.
Alongside these treatments, the companion diagnostic devices PATHWAY anti-HER-2/neu (4B5) and VENTANA HER2 Dual ISH DNA Probe Cocktail were also approved by the FDA, so that HER2 positivity can be determined accurately.
The HERIZON-GEA-01 Trial and Survival Data
These approvals are based on the results of HERIZON-GEA-01, a global, randomized, open-label Phase 3 clinical trial. Patients in the study were divided into three treatment arms:
- Arm A (Control Group): Trastuzumab + Chemotherapy (CAPOX or FP)
- Arm B: Zanidatamab + Chemotherapy
- Arm C: Zanidatamab + Tislelizumab + Chemotherapy
The results showed that the new combinations provided statistically significant improvements over standard treatment (Arm A) in both Overall Survival (OS) and Progression-Free Survival (PFS):
| Treatment Arm | Median Overall Survival (OS) | Median Progression-Free Survival (PFS) |
|---|---|---|
| Arm A: Trastuzumab + Chemotherapy (standard treatment) | 19.2 months | 8.1 months |
| Arm C: Zanidatamab + Tislelizumab + Chemotherapy | 26.4 months | 12.4 months |
For Arm B, a clear gain was obtained particularly in the patient subgroup with HER2 IHC 3+ tumors: median progression-free survival rose from 7.6 months with standard treatment to 14.2 months with the zanidatamab and chemotherapy combination.
Safety and Side Effect Profile
The FDA approval also drew attention to the safety profiles of the drugs:
- Zanidatamab: The product information contains a boxed warning for the risks of severe diarrhea and embryo-fetal toxicity. Precautions to be taken against left ventricular dysfunction and infusion reactions are also specified.
- Tislelizumab: Warnings are given on matters such as immune-mediated adverse reactions, infusion reactions and embryo-fetal toxicity.
💬 Reviewed Under Project Orbis
This review was conducted under the FDA Project Orbis initiative, which enables concurrent assessment by international regulatory bodies (including the Canadian and UK health authorities). The drugs were also reviewed with priority under Fast Track, Breakthrough Therapy and Orphan Drug designations.
Conclusion
For many years, HER2-positive patients with gastric and esophageal cancers were managed largely with a single trastuzumab-based standard regimen. With this approval, the treatment decision is no longer based solely on whether HER2 is positive or not, but on what level that positivity reaches. The gain of roughly seven months in overall survival shows that a detailed and accurate HER2 assessment has become as decisive as the choice of treatment itself.