FDA Approves Zanidatamab-hrii Plus Tislelizumab-jsgr for HER2-Positive Gastroesophageal Adenocarcinoma
Key Points
- FDA approved zanidatamab-hrii in combination with fluoropyrimidine- and platinum-containing chemotherapy plus tislelizumab-jsgr for first-line treatment of adults with HER2-positive, unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.
- In the HERIZON-GEA-01 trial, the zanidatamab-hrii/tislelizumab-jsgr regimen significantly improved overall survival (OS) and progression-free survival (PFS) compared with trastuzumab plus chemotherapy.
- The FDA also approved companion diagnostic devices to identify patients with HER2-positive tumors eligible for zanidatamab-hrii-based treatment.
On August 25, 2026, the US Food and Drug Administration (FDA) approved zanidatamab-hrii (Ziihera; Jazz Pharmaceuticals) in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr (Tevimbra; BeOne Medicines USA, Inc.) for the first-line treatment of adults with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma. Zanidatamab-hrii was also approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with HER2 IHC 3+ unresectable locally advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma.
The approvals were supported by findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147), which randomized patients with unresectable locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma to trastuzumab plus chemotherapy, zanidatamab-hrii plus chemotherapy, or zanidatamab-hrii plus tislelizumab-jsgr and chemotherapy.
In patients with HER2 IHC 3+ or IHC 2+/ISH+ tumors, the zanidatamab-hrii/tislelizumab-jsgr-containing regimen significantly improved OS and PFS compared with trastuzumab plus chemotherapy. Median OS was 26.4 months versus 19.2 months, respectively (HR, 0.72; 95% CI, 0.57-0.90; P = .0043), while median PFS was 12.4 versus 8.1 months (HR, 0.63; 95% CI, 0.51-0.78; P < .0001).
Zanidatamab-hrii plus chemotherapy alone also demonstrated a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy. In the HER2 IHC 3+ subgroup, median PFS was 14.2 months with zanidatamab-hrii versus 7.6 months with trastuzumab (HR, 0.55; 95% CI, 0.43-0.69). Interim OS results for the zanidatamab-hrii arm were not statistically significant at the time of the PFS analysis. Exploratory analyses suggested that the treatment effect in patients with HER2 IHC 2+/ISH+ tumors was primarily driven by those with IHC 3+ disease.
The zanidatamab-hrii prescribing information includes a boxed warning for diarrhea and embryo-fetal toxicity, along with warnings for left ventricular dysfunction and infusion-related reactions (IRRs). Tislelizumab-jsgr carries warnings for immune-mediated adverse reactions, IRRs, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. The recommended zanidatamab-hrii dose is weight-based, while tislelizumab-jsgr is 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 FDA also approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for identifying patients with HER2-positive gastric, GEJ, and esophageal adenocarcinoma eligible for zanidatamab-hrii treatment. The review was conducted under Project Orbis in collaboration with Health Canada and the United Kingdom’s Medicines and Healthcare products Regulatory Agency, with priority review, Real-Time Oncology Review, and the Assessment Aid used to facilitate the FDA review.