Jazz Pharmaceuticals announced positive top-line results from the Phase 3 HERIZON-GEA-01 trial evaluating Ziihera (zanidatamab-hrii) in combination with chemotherapy as first-line treatment for HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA). The study demonstrated clinically meaningful and statistically significant improvements in progression-free survival compared to the current standard of care, trastuzumab plus chemotherapy.
Trial Design and Patient Population
The HERIZON-GEA-01 trial (NCT05152147) was a global, randomized, open-label Phase 3 study conducted jointly with BeOne Medicines. The trial randomized 914 patients from approximately 300 trial sites in more than 30 countries to evaluate three treatment arms: Ziihera in combination with chemotherapy and tislelizumab; Ziihera in combination with chemotherapy; and trastuzumab plus chemotherapy as the control arm.
Eligible patients had unresectable locally advanced, recurrent or metastatic HER2-positive GEA, including adenocarcinomas of the stomach or esophagus and the gastroesophageal junction. HER2-positive status was defined as 3+ HER2 expression by immunohistochemistry (IHC) or 2+ HER2 expression by IHC with in situ hybridization (ISH) positivity per central assessment.
Primary Efficacy Results
Both investigational arms demonstrated highly statistically significant and clinically meaningful improvements in progression-free survival (PFS) compared to the control arm. Ziihera plus chemotherapy showed a clinically meaningful and statistically significant improvement in PFS versus trastuzumab and chemotherapy, along with a clinically meaningful effect with a strong trend toward statistical significance for overall survival (OS) at the first interim analysis.
The combination of Ziihera plus tislelizumab and chemotherapy demonstrated clinically meaningful and statistically significant improvements in both OS and PFS versus trastuzumab and chemotherapy. Notably, PFS and OS benefits were observed in both PD-L1 positive and PD-L1 negative subgroups for the Ziihera plus tislelizumab and chemotherapy arm.
Secondary Endpoints and Safety Profile
Both Ziihera plus chemotherapy and Ziihera plus tislelizumab and chemotherapy demonstrated improvements in key secondary endpoints of objective response rate (ORR) and duration of response (DoR) versus the control arm. These endpoints were supportive of the primary efficacy endpoints.
The safety profile of Ziihera in combination with chemotherapy, with or without tislelizumab, was generally consistent with the known safety profile of each agent. No new safety signals were observed in the two investigational combination arms, supporting the overall benefit-risk profile of Ziihera for use in this indication.
Clinical Significance and Expert Commentary
"Advanced GEA represents one of the most common tumor types worldwide and remains an aggressive cancer with a poor prognosis," said Dr. Kohei Shitara, director of the Department of Gastrointestinal Oncology and principal trial investigator at the National Cancer Center Hospital East in Kashiwa, Japan. "Based on the positive results seen in the HERIZON-GEA-01 trial, the zanidatamab plus chemotherapy combination, with and without tislelizumab, has the potential to become the new standard of care for patients in HER2+ first-line locally advanced unresectable or metastatic GEA."
Dr. Shitara emphasized that this represents "the first Phase 3 trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2+ first-line GEA."
Regulatory and Commercial Plans
Jazz Pharmaceuticals expects to submit a supplemental Biologics License Application (sBLA) in the United States in the first half of 2026 to support Ziihera as a first-line treatment for patients with HER2-positive locally advanced or metastatic GEA for use as part of a standard chemotherapy regimen with and without tislelizumab.
"We expect Ziihera to become the new standard of care anti-HER2 therapy for patients with HER2+ first-line metastatic GEA regardless of PD-L1 status," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals.
The company plans to submit these data for presentation at a major medical meeting in the first quarter of 2026 and for publication in a peer-reviewed journal. Jazz will also rapidly submit for adoption in the National Comprehensive Cancer Network Guidelines (NCCN Guidelines).
Disease Background and Unmet Need
Gastroesophageal adenocarcinoma, including cancers of the stomach, gastroesophageal junction, and esophagus, is the fifth most common cancer worldwide. Approximately 20% of patients have HER2-positive disease. HER2-positive GEA has high morbidity and mortality, with patients urgently in need of new treatment options. The overall prognosis for patients with GEA remains poor, with a global five-year survival rate of less than 30% for gastric cancer and about 19% for GEA.
About Ziihera
Ziihera (zanidatamab-hrii) is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a reduction in HER2 expression on the tumor cell surface. The drug induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), resulting in tumor growth inhibition and cell death.
In the United States, Ziihera is currently indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive biliary tract cancer. The FDA granted accelerated approval for this indication based on overall response rate and duration of response.
The FDA has granted Breakthrough Therapy designation for zanidatamab's development in patients with previously treated HER2 gene-amplified biliary tract cancer, and two Fast Track designations: one as a single agent for refractory biliary tract cancer and one in combination with standard-of-care chemotherapy for first-line gastroesophageal adenocarcinoma. Additionally, zanidatamab has received Orphan Drug designations from the FDA for the treatment of biliary tract cancer and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of biliary tract cancer and gastric cancer.
