Zanidatamab-containing regimens prolonged progression-free survival (PFS) and overall survival in the first-line setting in patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma, new phase 3 findings showed.

The HERIZON-GEA-01 trial demonstrated that zanidatamab plus chemotherapy, with or without the PD-1 inhibitor tislelizumab, led to a median PFS of more than 1 year and a median overall survival of more than 2 years — the first phase 3 study to demonstrate this, said study chief Elena Elimova, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, during a press briefing at the ASCO Gastrointestinal Cancers Symposium 2026.

“These are practice-changing results that offer a new treatment option for patients with HER2-positive upper GI [gastrointestinal] cancers,” Rachna Shroff, MD, MS, co-leader of the GI clinical research team at the University of Arizona Cancer Center in Tucson, Arizona, said in a conference statement.

Filling an ‘Urgent’ Need

Roughly 20% of patients with gastroesophageal adenocarcinoma, including cancers of the stomach, gastroesophageal junction, and esophagus, have tumors that are HER2-positive, and many patients with metastatic gastroesophageal adenocarcinoma experience disease progression within a year of treatment.

There is an “urgent” unmet need for novel HER2-directed strategies to improve outcomes in this patient population, Elimova explained.

Zanidatamab is a dual HER2-targeted bispecific antibody that binds to two distinct sites on HER2 (extracellular domains 2 and 4), prompting “cross-linking of HER2 proteins and receptor clustering on the cell surface, which leads to multiple mechanisms of action,” Elimova explained.

In HERIZON-GEA-01, 914 patients with untreated metastatic or locally advanced unresectable gastroesophageal adenocarcinoma were randomly allocated to one of three groups: zanidatamab and chemotherapy with tislelizumab; zanidatamab and chemotherapy; or trastuzumab and chemotherapy, a standard option for this patient population. Chemotherapy included physician’s choice of capecitabine plus oxaliplatin; 5-fluorouracil plus cisplatin was also an option.

All patients on zanidatamab received prophylaxis against diarrhea, a known side effect of zanidatamab, and all participants received prophylaxis to prevent infusion-related reactions.

Demographics and clinical characteristics were balanced across the three treatment groups. Most patients in the study were male, about half came from Asian regions, most had the de novo metastatic disease, 83% of the patients had IHC 3+ disease, and about 30% had tumor area positivity scores under 1%.

After a median follow-up of over 2 years, PFS was significantly longer in both zanidatamab-containing groups than in the trastuzumab arm. Median PFS was 12.4 months in patients who received zanidatamab and chemotherapy with or without tislelizumab vs 8.1 months in patients who received trastuzumab.

“This is a landmark because we surpassed the PFS of 12 months” with zanidatamab, Elimova said.

Overall, zanidatamab reduced the risk for cancer progression or death by 35% (hazard ratio [HR], 0.65; P < .0001) in the zanidatamab plus chemotherapy arm and by 37% in the triple therapy arm (HR, 0.63; P < .0001), with the benefits observed across key subgroups, including geographic region and PD-L1 status.

In addition, at this first interim analysis, there was a “strong trend” toward improved overall survival with zanidatamab plus chemotherapy vs trastuzumab plus chemotherapy (median of 24.4 vs 19.2 months; HR, 0.80; P = .0564). The same positive overall survival trend emerged with zanidatamab plus tislelizumab plus chemotherapy vs trastuzumab plus chemotherapy (median of 26.4 vs 19.2 months; HR, 0.72; P = .0043).

On the key secondary endpoint of antitumor activity, responses were “deeper and more durable” in the zanidatamab-containing groups, Elimova said.

Notably, the median duration of response in the zanidatamab plus tislelizumab and chemotherapy approached 21 months, which “is unheard of in this patient population,” she said. Median duration of response was about 14 months with zanidatamab plus chemotherapy and about 8 months with trastuzumab plus chemotherapy.

The overall safety profiles were consistent with the known safety profiles of each treatment. About 72% of patients in the zanidatamab plus tislelizumab plus chemotherapy group experienced a grade 3 or higher adverse event vs about 59% in the other two groups.

About 12% of patients on triple therapy and 8.5% of patients on zanidatamab plus chemotherapy stopped treatment due to adverse events compared to 2.3% of patients on trastuzumab. Treatment-related adverse events leading to death occurred in one patient in the zanidatamab plus chemotherapy group, seven (2.4%) patients in the triple therapy group, and four patients in the control group (1.3%).

Diarrhea was the most common treatment-related adverse event in all three treatment groups, but HER2-targeted therapy was rarely discontinued due to treatment-related diarrhea.

The researchers have an additional planned overall survival interim analysis in mid-2026 for zanidatamab plus chemotherapy, but based on the current analysis, zanidatamab “should replace trastuzumab” in this patient population, Elimova said. “I think that’s what our study shows — that it’s a better HER2-targeted agent.”

Shroff agreed. “I think what we can safely say is that we have a new anti-HER2 agent and that we have found a better way to target HER2,” she said.

This study was sponsored by Jazz Pharmaceuticals and conducted jointly with BeOne Medicines. Elimova reported to have consulted for Jazz Pharmaceuticals and other pharmaceutical companies. Shroff reported to have consulted for Exelixis, Merck, QED Therapeutics, Incyte, AstraZeneca, and other companies.