FDA approves two Ziihera zanidatamab-hrii regimens for first-line HER2-positive gastroesophageal adenocarcinoma, including a PD-L1-independent triplet.
Written By: Siddhi Bhadekar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration (FDA) has approved two Ziihera® (zanidatamab-hrii)-containing regimens for the first-line treatment of adults with unresectable, locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA), including gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.
The first regimen combines Ziihera with Tevimbra® (tislelizumab-jsgr) and fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2 IHC 3+ or IHC 2+/ISH+ tumors. The second combines Ziihera with the same chemotherapy backbone for patients with HER2 IHC 3+ tumors. HER2 status must be confirmed using an FDA-approved test.
The Ziihera plus tislelizumab regimen does not require a minimum PD-L1 level. Jazz Pharmaceuticals reported that treatment effects were generally consistent across prespecified subgroups, including PD-L1 status, supporting the use of the triplet in the approved HER2-positive population.
The approval also expands treatment options for people with advanced HER2-positive GEA. Martha Raymond, MA, CEO and founder of GI Cancers Alliance, highlighted the importance of understanding HER2 status when patients and families navigate treatment decisions and described the approval as a much-needed additional option for people with HER2-positive disease.
HERIZON-GEA-01 Results
The approval was supported by HERIZON-GEA-01 (NCT05152147), a randomized, three-arm, open-label, global Phase 3 trial. Patients were randomized to trastuzumab plus CAPOX or FP, Ziihera plus CAPOX or FP, or Ziihera plus tislelizumab and CAPOX or FP.
In the overall HER2 IHC 3+/IHC 2+/ISH+ population, Ziihera plus tislelizumab and chemotherapy produced a statistically significant overall survival benefit versus trastuzumab plus chemotherapy. Median overall survival was 26.4 months versus 19.2 months, with a hazard ratio of 0.72 (95% CI, 0.57-0.90; p=0.0043), representing a 28% reduction in the risk of death.
Median progression-free survival was 12.4 months versus 8.1 months, respectively, with a hazard ratio of 0.63 (95% CI, 0.51-0.78; p<0.0001). Jazz described the 26.4-month median overall survival as the longest reported in a Phase 3 trial in HER2-positive advanced GEA.
The Ziihera plus chemotherapy arm also significantly improved PFS versus trastuzumab plus chemotherapy. In the exploratory HER2 IHC 3+ subgroup, median PFS was 14.2 months versus 7.6 months, with a hazard ratio of 0.55 (95% CI, 0.43-0.69). Interim OS results for this arm were not statistically significant at the time of the PFS analysis, with additional analyses planned.
The consistency of treatment effects across PD-L1 subgroups was also highlighted by Geoffrey Ku, M.D., a HERIZON-GEA-01 study co-author and associate attending physician at Memorial Sloan Kettering Cancer Center. He noted that similar outcomes in PD-L1-positive and PD-L1-negative tumors could allow the regimen to benefit a broader HER2-positive population and emphasized the importance of HER2 testing in advanced or metastatic GEA to guide treatment selection.
Safety and Regulatory Details
Ziihera carries boxed warnings for diarrhea and embryo-fetal toxicity. Diarrhea is predominantly early in onset and can be severe, life-threatening, or fatal. The prescribing information directs clinicians to administer loperamide prophylaxis during Cycle 1 for patients receiving Ziihera with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab. Additional antidiarrheal treatment and dose modifications may be required. The prescribing information also includes warnings and precautions for left ventricular dysfunction and infusion-related reactions.
Ziihera is a bispecific HER2-directed antibody that binds two extracellular sites on HER2, promoting receptor internalization and activating complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.
FDA simultaneously 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 eligible HER2-positive gastric, GEJ, and esophageal adenocarcinoma patients.
The FDA review was conducted under Project Orbis and used the Real-Time Oncology Review pilot and Assessment Aid. The application received Priority Review, and zanidatamab-hrii had previously received FDA Fast Track, Breakthrough Therapy, and Orphan Drug designations.
Reference
About the Writer
Siddhi Rajendra Bhadekar (Linkedin) is an M.Pharm professional with expertise in medical and scientific writing, literature review, publication writing, and evidence synthesis, supported by four peer-reviewed publications.
She brings working knowledge of ICH-GCP, MedDRA, pharmacovigilance, ADR/AE reporting, clinical data management, and regulatory documentation.
With experience across pharmaceutical R&D, Quality Control, and Quality Assurance, she combines scientific research skills with strong attention to accuracy and detail.
Her background in manuscript development, publication planning, and scientific communication enables her to translate complex healthcare information into clear, reliable content.