Zanidatamab Plus Chemotherapy Improves Overall Survival in HER2-Positive Advanced Gastroesophageal Adenocarcinoma

Clinical Summary:

• Design/Population: The HERIZON-GEA-01 is a global, randomized, open-label phase 3 trial evaluating zanidatamab plus chemotherapy, with or without tislelizumab, vs trastuzumab plus chemotherapy as first-line treatment for patients with HER2-positive unresectable locally advanced, recurrent, or metastatic gastroesophageal adenocarcinoma.
• Key Outcomes: At the second interim analysis, zanidatamab plus chemotherapy demonstrated a statistically significant and clinically meaningful overall survival (OS) improvement compared with trastuzumab plus chemotherapy. With longer follow-up, the OS benefit with zanidatamab plus tislelizumab and chemotherapy also remained statistically significant and clinically meaningful, with an improved OS hazard ratio compared with the first interim analysis.
• Clinical Relevance: The updated survival findings strengthen the evidence supporting zanidatamab as a first-line HER2-targeted backbone in advanced HER2-positive gastroesophageal adenocarcinoma and further support the recently FDA-approved zanidatamab-based regimens, although detailed results from the second interim analysis have not yet been reported.

Second interim results from the phase 3 HERIZON-GEA-01 trial showed that zanidatamab plus chemotherapy significantly improved overall survival (OS) compared with trastuzumab plus chemotherapy as first-line treatment for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma. 

In this open-label trial, 914 patients with unresectable locally advanced, recurrent, or metastatic HER2-positive gastroesophageal adenocarcinoma, including adenocarcinomas of the stomach, gastroesophageal junction, and esophagus were randomized to receive zanidatamab plus chemotherapy and tislelizumab, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. HER2 positivity was defined as IHC 3+ or IHC 2+/ISH+ by central assessment. The dual primary end points were progression-free survival (PFS) by blinded independent central review and OS.

At the second interim analysis, zanidatamab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared with trastuzumab plus chemotherapy. According to the reported topline findings, the OS hazard ratio improved from the first interim analysis. Numerical OS results from the second interim analysis were not provided.

Longer follow-up also continued to support zanidatamab plus tislelizumab and chemotherapy. The combination maintained a statistically significant, clinically meaningful, and durable OS improvement compared with trastuzumab plus chemotherapy, with the OS hazard ratio improving relative to the first interim analysis. Detailed updated survival estimates were not reported.

The safety profile of zanidatamab plus chemotherapy was generally consistent with the known safety profiles of the individual agents and previously reported HERIZON-GEA-01 findings, with no new safety signals identified.

The updated findings follow the August 25, 2026 FDA approval of zanidatamab plus tislelizumab and fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for adults with HER2-positive IHC 3+ or IHC 2+/ISH+ unresectable locally advanced or metastatic gastroesophageal adenocarcinoma. Zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy was also approved in the same setting for patients with HER2 IHC 3+ disease.

“These HERIZON-GEA-01 results show that [zanidatamab]-based regimens extend OS, demonstrating definitive superiority of [zanidatamab] over trastuzumab and setting a new benchmark for what a first-line HER2-targeted therapy can achieve," stated Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan.

The second interim analysis has been submitted for presentation at a major medical meeting in the fourth quarter of 2026 and will also be submitted to global health authorities.

Source: 

PR Newswire. Ziihera® (zanidatamab-hrii) plus chemotherapy demonstrates statistically significant overall survival benefit versus trastuzumab plus chemotherapy in first-line HER2+ advanced GEA. Published online: August 31, 2026. Accessed on: August 31, 2026. https://www.prnewswire.com/news-releases/ziihera-zanidatamab-hrii-plus-chemotherapy-demonstrates-statistically-significant-overall-survival-benefit-versus-trastuzumab-plus-chemotherapy-in-first-line-her2-advanced-gea-302864427.html