Ziihera Combinations Show Significant Survival Benefits in Phase III HER2+ GEA Trial

Jazz Pharmaceuticals has shared new, positive results from its Phase III HERIZON-GEA-01 trial (NCT05152147) assessing the safety and efficacy of Ziihera (zanidatamab-hrii) alongside chemotherapy, with or without the PD-1 inhibitor Tevimbra (tislelizumab), as treatment for HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), including cancers of the stomach, gastroesophageal junction and esophagus.¹

Ziihera combinations demonstrate significant PFS gains

According to the breaking results, both Ziihera plus chemotherapy and Ziihera plus tislelizumab and chemotherapy achieved significant improvements in progression-free survival (PFS) compared to the control arm, trastuzumab plus chemotherapy.

• Ziihera plus tislelizumab and chemotherapy significantly improved overall survival (OS), while Ziihera plus chemotherapy showed a clinically meaningful OS benefit with a strong trend toward significance at this initial analysis.
• A follow-up interim OS analysis for the Ziihera + chemotherapy arm is planned for mid-2026.
• Both PD-L1-positive and PD-L1-negative patients experienced PFS and OS benefits with the Ziihera + tislelizumab + chemotherapy regimen.
• Ziihera + chemotherapy and Ziihera + tislelizumab + chemotherapy improved objective response rate and duration of response compared with the control arm.
• These response-based secondary endpoints supported the primary efficacy findings across both Ziihera-containing regimens.

In a company press release, Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology, and principal trial investigator at the National Cancer Center Hospital East, Kashiwa, Japan, said: "Advanced GEA represents one of the most common tumor types worldwide and remains an aggressive cancer with a poor prognosis. Based on the positive results seen in the HERIZON-GEA-01 trial, the zanidatamab plus chemotherapy combination, with and without tislelizumab, has the potential to become the new standard of care for patients in HER2+ first-line locally advanced unresectable or metastatic GEA. This is the first Phase III trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2+ first-line GEA."

HERIZON-GEA-01 trial design

HERIZON-GEA-01 is a global, randomized, open-label Phase III study.

• The trial enrolled 914 patients across ~300 sites in more than 30 countries.
• Eligible patients had unresectable locally advanced, recurrent, or metastatic HER2+ gastroesophageal adenocarcinomas confirmed by IHC 3+ or IHC 2+ with ISH positivity.
• Participants were randomized to three arms: Ziihera + chemotherapy + tislelizumab, Ziihera + chemotherapy, or trastuzumab + chemotherapy.
• Dual primary endpoints are PFS per blinded independent central review and OS.

FDA approval in biliary tract cancer

Ziihera was approved by the FDA for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC) based on results from the Phase IIb HERIZON-BTC-01 trial (NCT04466891) in November 2024.²

In a statement from the time, Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, said: “The approval of Ziihera, which previously received Breakthrough Therapy Designation from the FDA for this indication, is an important advance and offers the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with BTC. We look forward to advancing research of zanidatamab in BTC and other HER2-expressing solid tumors, with the goal of improving outcomes for more people diagnosed with these difficult-to-treat HER2-positive cancers."

New Phase III data in GEA build on earlier Phase II outcomes

Earlier in September 2024, Jazz shared positive Phase II trial (NCT03929666) outcomes of Ziihera in GEA. Results from the study showed:³

• In 41 patients treated with zanidatamab plus chemotherapy, median PFS was 15.2 months (95% CI: 9.5-33.4).
• Median overall survival (OS) is not yet mature after 41.5 months median follow-up.
• Kaplan-Meier-estimated 24-month OS was 65% (95% CI: 48-78).
• Kaplan-Meier-estimated 30-month OS was 59% (95% CI: 41-73).

References

1. Positive HERIZON-GEA-01 Phase 3 Results Support Ziihera® (zanidatamab-hrii) as HER2-Targeted Agent-of-Choice and Ziihera Combination Regimens as New Standard of Care in First-Line HER2-Positive Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma. News release. Jazz Pharmaceuticals. November 17, 2025. Accessed November 18, 2025. https://www.prnewswire.com/news-releases/positive-herizon-gea-01-phase-3-results-support-ziihera-zanidatamab-hrii-as-her2-targeted-agent-of-choice-and-ziihera-combination-regimens-as-new-standard-of-care-in-first-line-her2-positive-locally-advanced-or-metastatic-gastr-302616437.html

2. 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 November 18, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-ziiherar

3. Jazz Pharmaceuticals Presents Updated Phase 2 Data for Zanidatamab Demonstrating Increased mPFS in HER2-Positive Metastatic Gastroesophageal Adenocarcinoma at ESMO 2024. News release. Jazz Pharmaceuticals. September 16, 2024. Accessed November 18, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-presents-updated-phase-2-data-zanidatamab