Phase 3 HERIZON-GEA-01 data showed zanidatamab, tislelizumab, and chemotherapy significantly improved survival in first-line HER2-positive gastroesophageal adenocarcinoma, with benefits observed regardless of PD-L1 status.
Written By: Mahathi Palivela, PharmD
Reviewed By: Pharmacally Editorial Team
BeOne Medicines has reported pivotal Phase 3 HERIZON-GEA-01 (NCT05152147) findings demonstrating that the triplet regimen of zanidatamab (ZIIHERA®), tislelizumab (TEVIMBRA®), and chemotherapy significantly improved overall survival and progression-free survival compared with trastuzumab plus chemotherapy in patients with previously untreated advanced or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA).
The results were published in The New England Journal of Medicine and will be presented during an oral session at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Disease Context
HER2-positive GEA accounts for approximately 20% of gastroesophageal cancers and continues to carry a poor prognosis despite HER2-targeted therapy. Zanidatamab is a bispecific HER2-directed antibody that binds two distinct HER2 epitopes, while tislelizumab is a PD-1 inhibitor that enhances antitumor immune responses.
Trial Design and Population
The global, randomized Phase 3 trial enrolled 914 patients across more than 30 countries. Investigators compared zanidatamab plus chemotherapy, with or without tislelizumab, against standard trastuzumab plus chemotherapy in the first-line setting.
Efficacy Outcomes
The triplet regimen delivered the strongest efficacy results. Median overall survival reached 26.4 months compared with 19.2 months for the trastuzumab-based control arm. Median progression-free survival was 12.4 months, while median duration of response extended to 20.7 months. Zanidatamab plus chemotherapy also improved outcomes, achieving a median overall survival of 24.4 months. Both zanidatamab-containing treatment arms achieved a median progression-free survival of 12.4 months.
Subgroup Analyses
New subgroup analyses presented at ASCO further strengthened the findings. After 26 months of follow-up, the addition of tislelizumab improved progression-free and overall survival regardless of PD-L1 expression. Among PD-L1-negative patients, median overall survival reached 29.7 months versus 15.8 months with standard therapy. Median progression-free survival in this subgroup improved to 18.5 months compared with 7.9 months in the control arm. Investigators described the findings as potentially practice-changing, noting that benefits extended across both PD-L1-positive and PD-L1-negative populations.
Safety Profile
Safety findings remained consistent with the known profiles of HER2-targeted therapy and immunotherapy. No new safety signals emerged. Grade 3 or higher diarrhea was the most common treatment-related adverse event, occurring in 24.5% of patients receiving the triplet regimen. Treatment discontinuation due to drug-related diarrhea remained low at 4.1%, with most events occurring early during treatment.
Regulatory Status
The U.S. Food and Drug Administration has accepted a supplemental Biologics License Application for tislelizumab in combination with zanidatamab and chemotherapy for first-line HER2-positive GEA and granted priority review.
China’s National Medical Products Administration has also accepted supplemental applications for both zanidatamab and tislelizumab, positioning the regimen for potential regulatory decisions in major markets.
The HERIZON‑GEA‑01 trial was conducted jointly by BeOne Medicines and Jazz Pharmaceuticals. BeOne owns tislelizumab and holds regional rights to zanidatamab across parts of Asia‑Pacific, while Jazz commercializes zanidatamab in the United States, Europe, and other global markets under a licensing agreement with Zymeworks. Both companies are advancing regulatory submissions based on the Phase 3 findings, underscoring the global momentum behind the regimen.
Reference
About the Writer
Mahathi Palivela (LinkedIn) is pursuing PharmD and has a strong interest in Clinical Pharmacy and Patient safety. She is passionate about handling and analyzing patient data, and translating clinical insights into clear, meaningful summaries. She aims to apply this interest in Medical Writing and Pharmacovigilance, focusing on improving patient outcomes through careful data interpretation and communication.