Jazz Pharma’s bispecific antibody zanidatamab receives FDA Priority Review for HER2+ gastric cancer

Jazz Pharmaceuticals plc (Nasdaq: JAZZ), headquartered in Dublin, announced that the US FDA has accepted for filing with Priority Review a supplemental Biologics License Application (sBLA) for Ziihera (zanidatamab-hrii), a bispecific antibody that binds two distinct extracellular domains of HER2, in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without the PD-1 inhibitor tislelizumab, for the first-line treatment of adults with HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or gastroesophageal adenocarcinoma (GEA). The FDA has set a PDUFA target action date of August 25, 2026. The sBLA is also under review via the Real-Time Oncology Review (RTOR) program.

Priority Review compresses the standard FDA review clock from twelve to six months and is reserved for therapies that may offer meaningful improvement over available options for serious conditions. Zanidatamab previously received two Breakthrough Therapy designations from the FDA — one as a single agent in previously treated HER2 gene-amplified biliary tract cancer (BTC), and one in combination with chemotherapy with or without tislelizumab for first-line HER2-positive unresectable locally advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma — along with two Fast Track designations and Orphan Drug designations for BTC, gastric/GEJ cancer, and esophageal cancer from both the FDA and the European Medicines Agency.

The sBLA is supported by data from the Phase III HERIZON-GEA-01 trial (NCT05152147), a global, randomized, open-label study conducted jointly with BeOne Medicines across approximately 300 sites in more than 30 countries. The trial enrolled 914 patients with unresectable locally advanced, recurrent, or metastatic HER2-positive GEA, defined as 3+ HER2 expression by immunohistochemistry (IHC) or 2+ IHC with in situ hybridization (ISH) positivity per central assessment. Patients were randomized to three arms: zanidatamab plus chemotherapy and tislelizumab; zanidatamab plus chemotherapy; or trastuzumab plus chemotherapy. Dual primary endpoints were progression-free survival (PFS) per blinded independent central review and overall survival (OS).

Results presented at the 2026 ASCO Gastrointestinal Cancers Symposium in January 2026 showed that the zanidatamab plus chemotherapy doublet arm achieved a median OS of 24.4 months versus approximately 19.2 months in the trastuzumab plus chemotherapy control arm (HR 0.80, p=0.0564**)**, which did not meet the pre-specified threshold for statistical significance. The triplet arm of zanidatamab, tislelizumab, and chemotherapy produced a median OS of 26.4 months (HR 0.72, p=0.0043), which was a significant improvement. HERIZON-GEA-01 was also reported as the first Phase III study in metastatic GEA to achieve a median PFS exceeding one year, at 12.4 months (both zanidatamab arms) vs 8.1 months (control).

Zanidatamab is being developed by Jazz Pharmaceuticals and BeOne under license from originator Zymeworks. The molecule’s mechanism distinguishes it from trastuzumab and other approved HER2-directed agents. By binding simultaneously to two non-overlapping extracellular domains of HER2, zanidatamab drives receptor internalization and a reduction in surface HER2 expression, while also inducing complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Trastuzumab binds a single HER2 epitope and lacks the dual-domain engagement and associated internalization mechanism that characterizes zanidatamab’s design. Pertuzumab, which is approved in HER2-positive breast cancer, targets a different single domain and is not approved in gastric cancer.

Ziihera currently carries US FDA approval — granted under accelerated approval — for adults with previously treated unresectable or metastatic HER2-positive (IHC 3+) BTC, based on overall response rate and duration of response. Continued approval in that indication remains contingent on confirmatory trial data. The GEA sBLA under Priority Review represents a distinct and broader potential use, with randomized OS data rather than a response-based accelerated pathway.

Research context

GEA — encompassing cancers of the stomach, gastroesophageal junction, and esophagus — ranks as the fifth most common cancer globally, with approximately 20% of patients carrying HER2-positive disease. Five-year survival rates remain below 30% for gastric cancer and approximately 19% for GEA broadly. The current standard of care in HER2-positive first-line metastatic disease has been trastuzumab plus chemotherapy since the ToGA trial established its OS benefit over a decade ago, with pembrolizumab subsequently added in PD-L1-positive populations following the KEYNOTE-811 data. The HERIZON-GEA-01 triplet arm’s OS hazard ratio of 0.72 against a trastuzumab-based control represents a direct head-to-head comparison in this setting, a design that differs from KEYNOTE-811, which added pembrolizumab to a trastuzumab-containing backbone rather than replacing the HER2-directed agent. The doublet arm (HR 0.80) did not meet the pre-specified threshold for statistical significance. The triplet data are also notable for showing numerical improvement across both PD-L1-positive and PD-L1-negative tumors, a distinction the company has highlighted.