Jazz Pharmaceuticals submitted a supplemental Biologics License Application (sBLA) to the US FDA for Ziihera (zanidatamab-hrii) in combination regimens for the first-line treatment of adults with HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or gastroesophageal adenocarcinoma. The FDA accepted the filing and granted Priority Review, with a PDUFA target action date of August 25, 2026.
The sBLA is being reviewed under the FDA's Real-Time Oncology Review program. The filing covers zanidatamab-hrii in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without the PD-1 inhibitor Tevimbra (tislelizumab), a product of BeOne Medicines. The FDA had previously granted Breakthrough Therapy designation to zanidatamab for this combination approach in first-line HER2-positive advanced gastric and esophageal adenocarcinoma, the company said.
The application is supported by data from the HERIZON-GEA-01 trial, a global, randomized, open-label Phase III study conducted jointly with BeOne Medicines. The trial enrolled 914 patients across approximately 300 sites in more than 30 countries, randomizing participants to one of three arms: zanidatamab plus chemotherapy and tislelizumab; zanidatamab plus chemotherapy alone; or trastuzumab plus chemotherapy. Eligible patients had unresectable locally advanced, recurrent, or metastatic HER2-positive gastroesophageal adenocarcinoma, defined as HER2 IHC 3+ or IHC 2+ with ISH positivity per central assessment. The trial carries dual primary endpoints of progression-free survival by blinded independent central review and overall survival. Results were presented in January 2026 at the ASCO Gastrointestinal Cancers Symposium.
The HER2-positive gastroesophageal adenocarcinoma space has undergone substantial change since trastuzumab (Herceptin) became the first HER2-directed therapy approved in this setting in 2010, based on the ToGA trial. The current first-line standard for patients with HER2-positive and PD-L1 CPS of 1 or greater is pembrolizumab (Keytruda) combined with trastuzumab and platinum-fluoropyrimidine chemotherapy, following the KEYNOTE-811 Phase III trial. For the subset of patients with CPS below 1, trastuzumab plus chemotherapy remains the standard. Despite these advances, median overall survival in the metastatic setting remains below 20 months, and HER2 heterogeneity and acquired resistance to trastuzumab continue to limit the durability of response.
Zanidatamab-hrii is mechanistically distinct from trastuzumab. As a bispecific antibody, it binds simultaneously to two non-overlapping extracellular domains of HER2, domains II and IV, compared with trastuzumab's single domain IV binding. This dual-epitope engagement is designed to produce more complete receptor blockade, promote HER2 internalization and downregulation, and induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. The approach is intended to address the limitations of single-epitope HER2 inhibition, including incomplete blockade in tumors with HER2 heterogeneity.
Ziihera already holds US FDA approval in a separate indication: previously treated, unresectable or metastatic HER2-positive biliary tract cancer, where it received accelerated approval based on overall response rate and duration of response. The current sBLA represents the first regulatory submission for zanidatamab-hrii in a gastroesophageal adenocarcinoma setting and, if approved, would position it as the only bispecific HER2-directed antibody in that disease area. Zanidatamab was originally developed by Zymeworks and is being advanced by Jazz Pharmaceuticals and BeOne Medicines under license agreements.