FDA Approves Zanidatamab Regimens for First-Line HER2-Positive Advanced Gastroesophageal Adenocarcinoma

The FDA approved 2 regimens containing zanidatamab (Ziihera; Jazz Pharmaceuticals) for the first-line treatment of adults with unresectable locally advanced or metastatic HER2-positive (HER2+) gastroesophageal adenocarcinoma (GEA), expanding the role of the dual HER2-targeted bispecific antibody into an earlier treatment setting.¹

The first regimen combines zanidatamab with tislelizumab (Tevimbra; BeOne Medicines) and fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2-positive disease defined as immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization (ISH)+. The second combines zanidatamab with fluoropyrimidine- and platinum-containing chemotherapy for patients with IHC 3+ disease.¹

The zanidatamab, tislelizumab, and chemotherapy regimen is approved regardless of programmed death ligand 1 (PD-L1) status.¹

Phase 3 Trial Supports First-Line Approval

The approval is supported by findings from the global, open-label phase 3 HERIZON-GEA-01 trial (NCT05152147), which enrolled 914 patients with previously untreated, centrally confirmed HER2-positive advanced GEA. Patients were randomly assigned to zanidatamab plus tislelizumab and chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy.²

At a median follow-up of approximately 26 months, median progression-free survival (PFS) was 12.4 months with zanidatamab plus tislelizumab and chemotherapy compared with 8.1 months with trastuzumab plus chemotherapy. The corresponding hazard ratio (HR) for disease progression or death was 0.63 (95% CI, 0.51-0.78; P < .001).²˒³

Patients receiving zanidatamab plus chemotherapy without tislelizumab also achieved a median PFS of 12.4 months, representing a significant improvement compared with the trastuzumab-based control regimen (HR, 0.65; 95% CI, 0.52-0.81; P < .001).²

The survival findings further differentiated the tislelizumab-containing regimen. Median overall survival (OS) was 26.4 months with zanidatamab, tislelizumab, and chemotherapy compared with 19.2 months with trastuzumab and chemotherapy, corresponding to a 28% reduction in the risk of death (HR, 0.72; 95% CI, 0.57-0.90; P = .004).²˒³

At the interim analysis, median OS with zanidatamab plus chemotherapy was 24.4 months. The difference compared with trastuzumab plus chemotherapy had not reached statistical significance (HR, 0.80; 95% CI, 0.64-1.01; P = .06), and additional OS analyses are planned.²

Safety and Pharmacy Considerations

Diarrhea is a prominent safety consideration with zanidatamab-containing regimens. The prescribing information includes boxed warnings for diarrhea and embryo-fetal toxicity.¹

Among patients receiving zanidatamab with chemotherapy and tislelizumab in clinical studies, diarrhea occurred in 85%, including grade 3 events in 24% and grade 4 events in 2.1%. Fatal outcomes related to diarrhea occurred in 1.5% of patients. With zanidatamab plus chemotherapy, diarrhea occurred in 81%, including grade 3 events in 20% and grade 4 events in 1.3%.¹

Antidiarrheal prophylaxis with loperamide is recommended during cycle 1 for patients receiving zanidatamab with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab. Patients should also be counseled to maintain adequate fluid intake and promptly report diarrhea. Treatment interruption, dose reduction, or discontinuation may be required depending on severity.¹

The label also includes precautions regarding infusion-related reactions, left ventricular dysfunction, and embryo-fetal toxicity. Premedication is recommended before each zanidatamab infusion to reduce the risk of infusion-related reactions.¹

Expanding the Role of Dual HER2 Targeting

Zanidatamab is a bispecific antibody designed to bind 2 distinct extracellular domains of HER2. The agent was originally granted accelerated approval in November 2024 for adults with previously treated, unresectable or metastatic HER2-positive IHC 3+ biliary tract cancer.⁴

The new approval moves zanidatamab into the first-line GEA setting and provides an alternative to trastuzumab-based HER2 targeting. Approximately 20% of patients with GEA have HER2-positive disease, underscoring the potential reach of the newly approved regimens.¹

HERIZON-GEA-01 demonstrates that replacing trastuzumab with zanidatamab can extend PFS, while the addition of tislelizumab produced a significant OS improvement. The findings establish a new first-line option for patients with HER2-positive advanced GEA and expand the treatment population eligible for zanidatamab-based therapy.

References

1. Jazz Pharmaceuticals. U.S. FDA approves Ziihera (zanidatamab-hrii) with and without tislelizumab plus chemotherapy in first-line HER2+ advanced gastroesophageal adenocarcinoma. Published August 25, 2026. Accessed August 25, 2026.https://investor.jazzpharma.com/news-releases/news-release-details/us-fda-approves-ziiherar-zanidatamab-hrii-and-without

2. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729

3. Elimova E, Rha SY, Shitara K, et al. Zanidatamab plus chemotherapy with or without tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026;44(suppl 2):LBA285. doi:10.1200/JCO.2026.44.2_suppl.LBA285. https://ascopubs.org/doi/10.1200/JCO.2026.44.2_suppl.LBA285

4. FDA. Drug Trials Snapshots: Ziihera. Updated November 20, 2024. Accessed August 25, 2026. https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-ziihera