Zanidatamab Plus Chemotherapy Improves OS at Second Interim Analysis of HERIZON-GEA-01 in First-Line HER2+ GEA

The addition of zanidatamab-hrii (Ziihera) to chemotherapy produced a statistically significant and clinically meaningful improvement in overall survival (OS) vs trastuzumab plus chemotherapy in top-line data from the second interim analysis of the phase 3 HERIZON-GEA-01 trial (NCT05152147) in patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA).¹ The result met the remaining primary end point analysis of the study for the zanidatamab-plus-chemotherapy arm.

The second interim analysis also provided longer follow-up for the tislelizumab-jsgr (Tevimbra) plus zanidatamab and chemotherapy regimen, which demonstrated an improved OS HR, continued durable outcomes, and was associated with a generally manageable safety profile. These findings support data from the first interim analysis, at which the triplet met both the progression-free survival (PFS) and OS end points, with the OS benefit observed across PD-L1 and HER2 expression levels.

Results from the second interim analysis have been submitted for presentation at a medical meeting in the fourth quarter of 2026.

“We now have compelling phase 3 evidence of statistically significant and clinically meaningful OS results across both HERIZON-GEA experimental arms, reinforcing the opportunity to improve outcomes for patients beginning first-line treatment,” Mark Lanasa, MD, PhD, chief medical officer of solid tumors at BeOne Medicines, stated in a news release.

The second interim analysis readout arrived days after the FDA approval of both regimens in this setting, which was based on data from the first interim analysis.¹˒²

What led to the FDA approval of the HERIZON-GEA-01 regimens?

On August 25, 2026, the FDA approved zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab as first-line therapy for adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, as detected by an FDA-approved test.² The agency concurrently approved zanidatamab plus chemotherapy for adult patients with HER2-positive (IHC 3+) disease in the same setting, along with companion diagnostic devices to identify patients eligible for these regimens.

At the first interim analysis, the triplet of zanidatamab, tislelizumab, and chemotherapy (arm C) generated statistically significant improvements in OS and PFS vs trastuzumab plus chemotherapy (arm A) among patients with HER2 IHC 3+ or IHC 2+/ISH+ disease. The median OS was 26.4 months (95% CI, 21.5-30.3) in arm C vs 19.2 months (95% CI, 16.8-21.8) in arm A (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). The median PFS by blinded independent central review (BICR) was 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9), respectively (HR, 0.63; 95% CI, 0.51-0.78; P < .0001).

Patients in the zanidatamab-plus-chemotherapy arm (arm B) had a statistically significant improvement in PFS vs those in arm A at the first interim analysis, although the OS benefit in arm B was not statistically significant at the time of that analysis. Based on findings from exploratory analyses, the treatment effect in arm B was primarily attributed to the subgroup of patients with HER2 IHC 3+ tumors; among those patients, the median PFS was 14.2 months (95% CI, 11.7-16.7) in arm B vs 7.6 months (95% CI, 6.9-8.5) in arm A (HR, 0.55; 95% CI, 0.43-0.69).

What is the design of HERIZON-GEA-01?

HERIZON-GEA-01 is a global, randomized, open-label trial evaluating zanidatamab plus chemotherapy, with and without tislelizumab, vs standard-of-care trastuzumab plus chemotherapy as first-line treatment for adults with advanced or metastatic HER2-positive GEA.¹ The trial randomly assigned 914 patients across approximately 300 sites in more than 30 countries to 1 of 3 arms: zanidatamab plus chemotherapy and tislelizumab; zanidatamab plus chemotherapy; or trastuzumab plus chemotherapy.

Eligible patients had unresectable locally advanced, recurrent, or metastatic HER2-positive adenocarcinoma of the stomach or esophagus, including the GEJ, defined as HER2 IHC 3+ or IHC 2+ with ISH positivity per central assessment. Chemotherapy consisted of investigator’s choice of capecitabine plus oxaliplatin or fluorouracil plus platinum.² The dual primary end points were PFS by BICR and OS.¹

What was the safety profile of the zanidatamab-based regimens in HERIZON-GEA-01?

The safety profile of both zanidatamab-containing regimens at the second interim analysis was generally consistent with that observed at the first interim analysis and with the known profiles of the individual components, with no new safety signals identified. The zanidatamab prescribing information includes a boxed warning for diarrhea and embryo-fetal toxicity, as well as warnings and precautions for left ventricular dysfunction and infusion-related reactions.²

Zanidatamab is a bispecific HER2-directed antibody that binds 2 extracellular domains of HER2, and tislelizumab is a humanized anti–PD-1 monoclonal antibody.¹

References

1. BeOne Medicines announces new phase 3 survival data reinforcing benefit of Ziihera-containing regimens in first-line HER2+ gastroesophageal cancer. News release. BeOne Medicines Ltd. August 2026. Accessed August 2026. https://www.businesswire.com/
2. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. FDA. August 25, 2026. Accessed August 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanidatamab-hrii-and-tislelizumab-jsgr-her2-positive-gastric-gastroesophageal-junction