- The HERIZON-GEA-01 open-label, phase 3 clinical trial was designed to compare first-line treatment with the bispecific antibody zanidatamab plus chemotherapy with or without PD‐1 monoclonal antibody tislelizumab compared to standard of care in previously untreated patients with HER2-positive advanced gastric cancer.
- Published in The New England Journal of Medicine, results of interim analysis demonstrate that the investigational combination reduced the risk of disease progression or death in these patients by up to 37%.
- Showing promising antitumor activity, the dual action of HER2-targeted therapy and anti-PD-1 immunotherapy could lead to a new therapeutic option for this patient population.
The open-label, phase 3 HERIZON-GEA-01 clinical trial was designed to evaluate HER2-targeted bispecific antibody zanidatamab combined with chemotherapy with or without tislelizumab immunotherapy versus standard therapy with trastuzumab plus chemotherapy in patients with previously untreated HER2-positive (HER2+) advanced gastric cancer.
Co-authored by Josep Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron University Hospital and VHIO’s Director, and reported today in The New England Journal of Medicine*, findings from interim analysis at 25.9 months’ median follow-up show that the investigational combination led to significantly longer progression-free survival (PFS)
Approximately 20% of patients with advanced gastroesophageal adenocarcinoma, which includes gastric, gastroesophageal junction, and esophageal adenocarcinomas, have HER2+ tumors.
“For over a decade, first-line standard of care for these patients has been platinum-based chemotherapy plus the HER2-targeted monoclonal therapy, trastuzumab. More recently, adding immunotherapy with PD-1 inhibitor pembrolizumab to trastuzumab plus chemotherapy has led to prolonged survival, but only in a subgroup of patients and with a modest clinical benefit, ” observed Josep Tabernero.
The HER2-targeted bispecific antibody zanidatamab was designed to exert the dual blockade of HER2, binding simultaneously to two regions of the receptor. In early phase studies, its combination with the PD-1 immune checkpoint inhibitor tislelizumab has demonstrated promising antitumor across various tumor types, including gastric cancer. Preliminary data suggest that the dual inhibition of the HER2 and PD-1 pathways could further improve outcomes compared to targeting only one of these pathways.
In HERIZON-GEA-01, 934 patients with previously untreated HER2+ advanced gastroesophageal adenocarcinoma were randomized 1:1:1 to receive zanidatamab plus chemotherapy with or without tislelizumab, or trastuzumab with chemotherapy.
The primary endpoint of the trial was PFS, defined as the time from the start of treatment until disease recurrence. At interim analysis, the zanidatamab-based treatment combinations improved outcomes compared to standard of care, with a median PFS of 12.4 months in both investigational cohorts versus 8.1 months in patients assigned to trastuzumab and chemotherapy.
In patients who received the combination therapy with tislelizumab, the investigators observed a median overall survival (OS) of 26.4 months compared to 19.2 months in the control group. While the combination of zanidatamab plus chemotherapy showed a trend toward improved OS, the difference was not statistically significant in this interim analysis. Regarding safety, serious adverse effects were frequently observed in all groups, especially with the triplet combination, but with an overall profile considered as manageable.
“Our data provide the first comparative evidence that zanidatamab’s dual mechanism of action leads to improved clinical outcomes compared to trastuzumab, in this population of patients with advanced HER2+ gastroesophageal adenocarcinoma. Results support zanidatamab as a new and promising HER2-targeted treatment in the first-line setting for HER2-positive gastric and gastroesophageal junction adenocarcinoma. The clinically relevant survival benefit further supports the triple combination of zanidatamab, tislelizumab and chemotherapy as a potential new therapeutic option for this patient population,” concluded Tabernero.
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Reference
*Kohei Shitara, MD*; Elena Elimova, MD*; Tianshu Liu, MD, PhD; Josep Tabernero, MD, PhD; Keun-Wook Lee, MD; Michael Schenker, MD; Niall Tebbutt, PhD, MRCP, FRACP; Jaffer Ajani, MD, FASCO; Norhidayu Salimin, MD; Geoffrey Ku, MD, MBA; Jong Gwang Kim, MD, PhD; Inmaculada Ales Diaz, MD; Jingdong Zhang, MD; Filippo Pietrantonio, MD; Li-Yuan Bai, MD; Samuel Le Sourd, MD; Jun Zhao, MD, PhD; Cinta Hierro, MD; Andrew Kiberu, MD; Filip Van Herpe, MD; Yuanyuan Bao, MSc; Hanze Zhang, PhD; Lin Yang, PhD; Vincent Li, MBBS, MMed; Elaina M. Gartner, MD; Ye Chen, MD; Jonathan Grim, MD, PhD; Sun Young Rha, MD†; Lin Shen, MD†. Zanidatamab with and without Tislelizumab in HER2-Positive Gastric Cancer. Published May 27, 2026. N Engl J Med 2026;394:2002-2014. VOL. 394 NO. 20
* Co–first authors; † Co–senior authors
