Phase 3 HERIZON-GEA-01 Data Published in NEJM Reinforce Zanidatamab’s Potential in HER2-Positive Gastroesophageal Cancer

Jazz Pharmaceuticals announced that additional analyses from the Phase 3 HERIZON-GEA-01 trial, published in The New England Journal of Medicine, are providing further evidence that zanidatamab-containing regimens may improve outcomes for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA). The publication expands on data first presented during the 2026 ASCO Gastrointestinal Cancers Symposium and further characterizes the efficacy and safety profile of zanidatamab in combination with chemotherapy, with or without the PD-1 inhibitor tislelizumab.¹˒²

HER2-positive disease accounts for approximately 20% of GEA cases and has historically been associated with poor long-term outcomes despite advances in targeted therapy.⁴ Patients with advanced GEA continue to face significant mortality, creating demand for more effective first-line treatment approaches.⁴

What did the HERIZON-GEA-01 trial show?

The global Phase 3 study enrolled 914 patients across more than 30 countries and compared two zanidatamab-containing regimens against trastuzumab plus chemotherapy, the historical standard of care. Investigators reported that both zanidatamab-containing treatment arms significantly improved progression-free survival (PFS) compared with trastuzumab-based therapy. Median PFS reached 12.4 months in the zanidatamab arms compared with 8.1 months in the control arm, corresponding to a hazard ratio of approximately 0.63 to 0.65.¹˒²

The combination of zanidatamab, tislelizumab, and chemotherapy also demonstrated a statistically significant overall survival (OS) benefit. Median OS reached 26.4 months compared with 19.2 months for patients receiving trastuzumab plus chemotherapy.¹˒²

According to trial investigators, expanded subgroup analyses published in the journal showed generally consistent benefits across clinically relevant patient populations, including geographic regions, performance status categories, and PD-L1 expression levels.¹˒²

How did patients with PD-L1-negative disease perform?

One of the more notable findings involved patients with PD-L1-negative tumors, a population that has historically derived limited benefit from immune checkpoint inhibitor-based approaches.

Additional analyses scheduled for presentation at the 2026 American Society of Clinical Oncology Annual Meeting demonstrated improved PFS and OS with zanidatamab plus tislelizumab and chemotherapy regardless of PD-L1 status. In PD-L1-negative patients, median OS reached 29.7 months compared with 15.8 months in the trastuzumab control arm.¹ Similar improvements were observed among PD-L1-positive patients.¹

Investigators suggested these findings may reflect zanidatamab’s unique mechanism of action, which combines dual HER2 targeting with immune-mediated antitumor activity through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.¹

What did the safety analysis reveal?

The publication also included expanded safety analyses. Researchers reported that adverse events observed with zanidatamab-containing regimens were generally consistent with the known safety profiles of the individual treatment components. Gastrointestinal adverse events, including diarrhea, most commonly occurred early in treatment and were generally manageable, with relatively few patients discontinuing HER2-targeted therapy because of toxicity.¹˒²

In addition, analyses of subsequent therapies showed that patients in the trastuzumab arm more frequently required additional HER2-targeted treatments and immune checkpoint inhibitors following disease progression, providing important context for the observed survival outcomes.¹

What could the findings mean for clinical practice?

The publication arrives as Jazz Pharmaceuticals seeks to expand the role of zanidatamab beyond its currently approved indication in HER2-positive biliary tract cancer. The company has submitted HERIZON-GEA-01 data to the National Comprehensive Cancer Network for consideration in future clinical practice guidelines and is pursuing regulatory review for first-line HER2-positive GEA.¹

If adopted into clinical practice, the results could represent a significant shift in first-line treatment for HER2-positive gastroesophageal cancer. The consistency of benefit across patient subgroups, combined with durable survival outcomes, suggests zanidatamab-containing regimens may establish a new benchmark for HER2-directed therapy in this setting.

References

1. Phase 3 HERIZON-GEA-01 Results Published in The New England Journal of Medicine Show Durable and Consistent Survival Benefit with Ziihera (zanidatamab-hrii) Combinations in First-Line HER2+ Locally Advanced or Metastatic GEA. (2026 May 27). Jazz Pharmaceuticals. https://investor.jazzpharma.com/news-releases/news-release-details/phase-3-herizon-gea-01-results-published-new-england-journal
2. Shitara K, et al. (2026 May 27.) Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2517729
3. Positive HERIZON-GEA-01 Phase 3 Results Support Ziihera as HER2-Targeted Agent-of-Choice in First-Line HER2-Positive Gastroesophageal Adenocarcinoma. (2025 Nov 17). Jazz Pharmaceuticals. https://investor.jazzpharma.com/news-releases/news-release-details/positive-herizon-gea-01-phase-3-results-support-ziiherar
4. Battaglin F, et al. (2018 Jul 11). Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell International. https://pmc.ncbi.nlm.nih.gov/articles/PMC6042434/