FDA Approves Zanidatamab-Based Regimens for First-Line HER2+ Gastric Cancers

The FDA has approved zanidatamab-hrii (Ziihera) in 2 indications:¹

1. in combination with tislelizumab-jsgr (Tevimbra) and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with unresectable, locally advanced or metastatic HER2-positive gastric cancer, gastroesophageal junction (GEJ), or esophageal adenocarcinoma (GEA)
2. in combination with fluoropyrimidine-, and platinum-containing chemotherapy for the first-line treatment of HER2-positive unresectable, locally advanced, or metastatic gastric cancer , GEJ, or GEA.

Status for both diseases must be confirmed by an FDA approved test. Notably, the FDA has also approved 2 companion diagnostic devices for identifying patients with HER2-positive gastric cancer, GEJ, or GEA for treatment with zanidatamab:

1. The PATHWAY anti-HER2/neu (45B) Rabbit Monoclonal Primary Antibody
2. The VENTANA HER2 Dual ISH DNA Probe Cocktail

A supplemental biologics license application (sBLA) was submitted and granted priority review under a real-time oncology review (RTOR) pathway in April 2026.² The sBLA was based on findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147), which compared zanidatamab-based regimens with trastuzumab (Herceptin) plus chemotherapy in the first line treatment of this patient population. The FDA also previously granted breakthrough therapy designation to zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab, in this indication.

What's new in the approval?

The recommended dose of zanidatamab is body weight-based: patients who weigh less than 70 kg should receive 1800 mg every 3 weeks or 1200 mg every 2 weeks, and those who weigh 70 kg or more should receive 2400 mg every 3 weeks or 1600 mg every 2 weeks.

Tislelizumab is recommended at 150 mg every 2 weeks, 200 mg every 3 weeks, 300 mg every 4 weeks, or 400 mg every 6 weeks until disease progression or unacceptable toxicity.

The prescribing information for zanidatamab includes a boxed warning for diarrhea and embryo-fetal toxicity; warnings and precautions are included for left ventricular dysfunction and infusion-related reactions. The prescribing information for tislelizumab includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

“This approval is a major step forward for [patients] with HER2+ advanced GEA. [Zanidatamab] is now the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor and chemotherapy approved for all HER2-positive advanced GEA patients, regardless of PD-L1 status, establishing a new standard of care in first-line treatment,” Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, stated in a news release on the approval.³ “The HERIZON-GEA-01 results include the longest median overall survival [OS] reported in a phase 3 trial in this setting, at 26.4 months. We are grateful to the gastric cancer community, including patients, caregivers, investigators and advocacy organizations, whose partnership made this possible.”

What data supported the FDA approval of zanidatamab?

In HERIZON-GEA-01, the combination of zanidatamab, tislelizumab, and chemotherapy met the trial's dual primary end points of progression-free survival (PFS) and OS.⁴ According to findings presented at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, the median PFS reached 12.4 months (95% CI, 9.8-18.5) with zanidatamab plus tislelizumab and chemotherapy vs 8.1 months (95% CI, 7.0-8.9) with trastuzumab plus chemotherapy (HR, 0.63; 95% CI, 0.51-0.78; P <.0001). The median OS was 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8), respectively (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). The zanidatamab plus chemotherapy arm without tislelizumab also improved outcomes vs the control arm, achieving a median OS of 24.4 months. The OS and PFS benefit with zanidatamab-based regimens was observed regardless of PD-L1 status.

Regarding safety, grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 71.8% of patients who received zanidatamab plus tislelizumab and chemotherapy, 59% of those who received zanidatamab plus chemotherapy, and 59.6% of those who received trastuzumab plus chemotherapy. TRAEs led to discontinuation of any treatment component in 42.5%, 34.4%, and 29.1% of patients in each arm, respectively. No new safety signals were identified relative to the known profiles of the individual agents.

How was the HERIZON-GEA-01 trial designed?

HERIZON-GEA-01 is a randomized, open-label, multicenter phase 3 trial that enrolled 914 patients across approximately 300 sites in more than 30 countries.⁵ Patients were randomly assigned 1:1:1 to receive trastuzumab plus physician's choice of chemotherapy (arm A), intravenous zanidatamab plus tislelizumab and physician's choice of chemotherapy (arm B), or zanidatamab plus physician's choice of chemotherapy (arm C). Treatment continued in 21-day cycles until disease progression, unacceptable toxicity, or death. Randomization was stratified by geographic region, HER2 status, and ECOG performance status.

Eligible patients were 18 years or older with histologically confirmed, unresectable, locally advanced or metastatic HER2-positive adenocarcinoma of the stomach, GEJ, or esophagus, with HER2 positivity defined as an immunohistochemistry score of 3+ or a score of 2+ confirmed by in situ hybridization. Patients could not have received prior treatment for locally advanced or metastatic disease or prior HER2-targeted treatment, though prior immunotherapy was permitted.

What other regulatory and clinical developments support zanidatamab in HER2-positive cancers?

Zanidatamab received approval from the FDA in November 2024 for previously treated HER2-positive biliary tract cancer based on results from the phase 2b HERIZON-BTC-01 trial (NCT05152147).⁶ The European Commission also granted zanidatamab conditional marketing authorization for HER2-positive biliary tract cancer in July 2025.⁷

References

1. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. News release. FDA. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/mrdtd9xc
2. Jazz Pharmaceuticals announces FDA acceptance and priority review of supplemental biologics license application for Ziihera (zanidatamab-hrii) combinations in first-line HER2-positive locally advanced or metastatic GEA. News release. Jazz Pharmaceuticals plc. April 27, 2026. Accessed August 24, 2026. https://tinyurl.com/3h3rxvj2
3. U.S. FDA approves Ziihera® (zanidatamab-hrii) with and without tislelizumab plus chemotherapy in first-line HER2+ advanced gastroesophageal adenocarcinoma. News release. Jazz Pharmaceuticals plc. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/4d7s97mm
4. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026;44(suppl 4):LBA285. doi:10.1200/JCO.2026.44.2_suppl.LBA285
5. A study of zanidatamab in combination with chemotherapy plus or minus tislelizumab in patients with HER2-positive advanced or metastatic gastric and esophageal cancers (HERIZON-GEA-01). ClinicalTrials.gov. Updated July 17, 2026. Accessed August 24, 2026. https://tinyurl.com/vsvd53x7
6. Jazz Pharmaceuticals announces U.S. FDA approval of Ziihera® (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). News release. Jazz Pharmaceuticals. November 20, 2024. Accessed August 24, 2026. https://shorturl.at/k6u8A
7. Jazz Pharmaceuticals receives European Commission marketing authorization for Ziihera (zanidatamab) for the treatment of advanced HER2-positive biliary tract cancer. News release. Jazz Pharmaceuticals plc. July 1, 2025. Accessed August 24, 2026. https://tinyurl.com/2ytfkxc8