Results from a new phase 3 study found that for patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastroesophageal adenocarcinoma* (mGEA), the combination of zanidatamab (Ziihera®; Jazz Pharmaceuticals)** and chemotherapy, with or without the PD-1 inhibitor tislelizumab (Tevimbra®; BeOne Medicines), as a first-line treatment option, can slow cancer growth and may help them live longer.
The research findings were presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held January 8-10, 2026, in San Francisco, California.
GEA, including cancers of the stomach, gastroesophageal junction, and esophagus, is the fifth most common cancer worldwide, and approximately 20% of patients have HER2+ disease.[1][2][3]
HER2+ GEA has high morbidity and mortality, and patients are urgently in need of new treatment options. The overall prognosis for patients with GEA remains poor, with a global five-year survival rate of less than 30% for gastric cancer and about 19% for GEA.[4]
“Advanced GEA represents one of the most common tumor types worldwide and remains an aggressive cancer with a poor prognosis,” noted Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology, and principal trial investigator at the National Cancer Center Hospital East, Kashiwa, Japan.
Study
The HERIZON-GEA-01 study (NCT05152147) included 914 patients diagnosed with metastatic or locally advanced unresectable GEA who had not yet received treatment for their cancer. The participating patients were randomly assigned to one of three treatment groups: zanidatamab and chemotherapy with tislelizumab; zanidatamab and chemotherapy; or trastuzumab and chemotherapy, the standard of care at the time the study was designed.
After a median follow-up of 26 months, the median progression-free survival was 12.4 months in patients who received zanidatamab and chemotherapy with or without tislelizumab vs. 8.1 months in patients who received trastuzumab.
Overall, zanidatamab reduced the risk of cancer progression or death by about 35%. After 18 months of treatment, the cancer had not grown or spread in about 44% of patients who received zanidatamab, tislelizumab, and chemotherapy; it had not grown or spread in 38% of patients who received zanidatamab and chemotherapy; and it had not grown or spread in about 21% of those in the trastuzumab group.
The median overall survival (OS) was 26.4 months in patients who received the combination of zanidatamab, tislelizumab, and chemotherapy.
The OS data were not statistically significant at the time of this analysis for patients who received zanidatamab with chemotherapy, but researchers observed a trend toward OS benefit in this group as well.
Adverse events
- About 72% of patients in the zanidatamab, tislelizumab, and chemotherapy group experienced a grade 3 or higher adverse event compared to about 59% in the other two groups.
- About 12% of patients in the zanidatamab, tislelizumab, and chemotherapy group and 8.5% of patients in the zanidatamab with chemotherapy group stopped treatment compared to 2.3% of patients in the trastuzumab group.
- The most common serious side effects in the zanidatamab groups were diarrhea, potassium deficiency (hypokalemia), and low levels of red blood cells (anemia). In the trastuzumab group, diarrhea, anemia, decreased white blood cell counts, and decreased platelet counts were most common. Since diarrhea is a known side effect of zanidatamab, patients in these groups received a drug to help lessen or prevent it.
Truly unprecedented
“Reaching more than two years of median overall survival in a global Phase 3 trial for HER2+ metastatic GEA is truly unprecedented,” said Elena Elimova, M.D., Princess Margaret Cancer Centre, the presenting author of the late-breaking data.
“The HERIZON-GEA-01 results represent the longest survival outcomes in a Phase 3 trial ever reported in this setting, with the zanidatamab plus tislelizumab and chemotherapy regimen improving median overall survival by more than seven months versus the control arm,” Elimova added.
“The fact that both zanidatamab plus chemotherapy and zanidatamab plus tislelizumab and chemotherapy achieved median progression-free survival beyond one year further reinforces the depth and durability of benefit. These findings signal a meaningful step forward for patients who have historically faced very limited long-term outcomes,” she further noted.
Practice-changing
“The results of the HERIZON-GEA-01 study are practice-changing,” said Geoffrey Ku, M.D., associate attending physician on the Gastrointestinal Oncology Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center and study co-author.
“In addition to the progression-free survival and overall survival benefits, the remarkably long duration of response and consistent benefit across relevant subgroups, including PD-L1 positive and negative tumors, strongly suggest that zanidatamab plus chemotherapy, with or without tislelizumab, should become the new standard of care for patients with HER2+ first-line locally advanced unresectable or metastatic GEA,” Ku concluded.
“Despite the adoption of newer therapies in recent years, outcomes for patients with metastatic gastroesophageal adenocarcinoma have remained modest. This is the first phase 3 trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2-positive first-line treatment for these patients,” said lead study author Elena Elimova, MD, of Princess Margaret Cancer Centre in Toronto, Canada.
“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 3 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.” Shitara concluded.
Next Steps
The researchers have an additional planned OS interim analysis in mid-2026 for zanidatamab plus chemotherapy. Zanidatamab is also being investigated across many different types of treatments in multiple HER2-expressing solid tumors.
This study was sponsored by Jazz Pharmaceuticals and conducted jointly with BeOne Medicines.
Note: * HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), including cancers of the stomach, gastroesophageal junction and esophagus.
** Zanidatamab is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. The binding of zanidatamab to HER2 leads to internalization, thereby reducing HER2 expression on the tumor cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.
Clinical trial
A Study of Zanidatamab in Combination With Chemotherapy Plus or Minus Tislelizumab in Patients With HER2-positive Advanced or Metastatic Gastric and Esophageal Cancers (HERIZON-GEA-01) -ClinicalTrials.gov ID NCT05152147
Highlights of Prescribing Information
Zanidatamab (Ziihera®; Jazz Pharmaceuticals) [Prescribing Information]
Tislelizumab (Tevimbra®; BeOne Medicines)[Prescribing Information]
Reference
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[2] Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, Chong JL, López-Sanchez RI, Price T, Gladkov O, Stoss O, Hill J, Ng V, Lehle M, Thomas M, Kiermaier A, Rüschoff J. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015 Jul;18(3):476-84. doi: 10.1007/s10120-014-0402-y. Epub 2014 Jul 20. PMID: 25038874; PMCID: PMC4511072.
[3] Stroes CI, van den Ende T, Derks S, van Laarhoven HWM. A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead. Cancer Treat Rev. 2021 Sep;99:102249. doi: 10.1016/j.ctrv.2021.102249. Epub 2021 Jun 16. PMID: 34171733.
[4] Battaglin F, Naseem M, Puccini A, Lenz HJ. Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell Int. 2018 Jul 11;18:99. doi: 10.1186/s12935-018-0594-z. PMID: 30008616; PMCID: PMC6042434.
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