HER2-positive gastroesophageal adenocarcinoma includes gastric, gastroesophageal junction, and esophageal adenocarcinomas that test positive for HER2. For more than a decade, platinum-based chemotherapy plus trastuzumab has been a standard first-line treatment for patients with HER2-positive advanced gastroesophageal adenocarcinoma.
However, outcomes in this patient population have remained modest, with median progression-free survival of approximately 10 months and median overall survival of approximately 20 months in recent studies.
The phase 3 HERIZON-GEA-01 trial evaluated zanidatamab plus chemotherapy, with or without tislelizumab, as first-line treatment for patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma.
The study was published on May 27, 2026, in The New England Journal of Medicine.
Title: Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer
Authors: Kohei Shitara, Elena Elimova, Tianshu Liu, Josep Tabernero, Keun-Wook Lee, Michael Schenker, Niall C. Tebbutt, Jaffer Ajani, Norhidayu Salimin, Geoffrey Ku, Jong Gwang Kim, Inmaculada Ales Diaz, Jingdong Zhang, Filippo Pietrantonio, Li-Yuan Bai, Samuel Le Sourd, Jun Zhao, Cinta Hierro, Andrew Kiberu, Filip Van Herpe, Yuanyuan Bao, Hanze Zhang, Lin Yang, Vincent Li, Elaina M. Gartner, Ye Chen, Jonathan Grim, Sun Young Rha, and Lin Shen, for the HERIZON-GEA-01 Investigators.
Why This Study Matters
Approximately 20% of patients with advanced gastroesophageal adenocarcinoma have HER2-positive tumors, defined as an immunohistochemical score of 3+ or an immunohistochemical score of 2+ with positive in situ hybridization.
Zanidatamab differs from trastuzumab in that it binds to extracellular domains 2 and 4 of HER2. In preclinical studies, this dual binding led to HER2 receptor clustering, antibody-mediated internalization and degradation of HER2, reduced downstream signaling, and immune-mediated cytotoxicity.
Tislelizumab is an anti-PD-1 antibody. The rationale for combining HER2-directed therapy with PD-1 inhibition comes from preclinical models in which HER2-directed antibodies induced tumor immunogenicity and enhanced the efficacy of PD-1 blockade through increased antigen presentation and T-cell activation.
Read more about Tislelizumab (Tevimbra): Uses in Cancer, Side Effects, Dosage, Expectations on OncoDaily.
Study Design
HERIZON-GEA-01 was an international, open-label, randomized, active-comparator phase 3 trial. The study enrolled adults with histologically confirmed, unresectable locally advanced, recurrent, or metastatic HER2-positive adenocarcinoma of the stomach, gastroesophageal junction, or esophagus.
Patients were required to have centrally confirmed HER2-positive disease, defined as IHC 3+ or IHC 2+ with ISH-positive status. They also had to have an ECOG performance-status score of 0 or 1. Patients who had previously received systemic therapy for advanced or metastatic disease were not eligible, and prior treatment with HER2-targeted agents or checkpoint inhibitors in any context was not allowed.
Patients were randomly assigned in a 1:1:1 ratio to receive zanidatamab plus tislelizumab and chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. Chemotherapy was selected by investigators and consisted of either capecitabine plus oxaliplatin or fluorouracil plus cisplatin.
The two primary endpoints were progression-free survival, assessed by blinded independent central review, and overall survival.
Patient Population
From December 3, 2021, through February 17, 2025, 914 patients underwent randomization at 225 sites in 33 countries. A total of 302 patients were assigned to zanidatamab plus tislelizumab and chemotherapy, 304 to zanidatamab plus chemotherapy, and 308 to trastuzumab plus chemotherapy.
Baseline demographic and clinical characteristics were balanced across the three groups. Most patients had tumors with a HER2 IHC score of 3+. PD-L1 status was assessed in 92.9% of patients, and a PD-L1 tumor area positivity score of at least 1% was reported in 61.9% of patients in the zanidatamab plus tislelizumab group, 58.6% in the zanidatamab plus chemotherapy group, and 61.0% in the trastuzumab plus chemotherapy group. Most patients received capecitabine plus oxaliplatin as the chemotherapy backbone.
PFS Outcomes
At a median follow-up of 25.9 months, progression-free survival assessed by blinded independent central review was longer with both zanidatamab-containing regimens than with trastuzumab plus chemotherapy. Median progression-free survival was 12.4 months with zanidatamab plus tislelizumab and chemotherapy, 12.4 months with zanidatamab plus chemotherapy, and 8.1 months with trastuzumab plus chemotherapy.
Compared with trastuzumab plus chemotherapy, the hazard ratio for disease progression or death was 0.63 (95% CI, 0.51 to 0.78) with zanidatamab plus tislelizumab and chemotherapy and 0.65 (95% CI, 0.52 to 0.81) with zanidatamab plus chemotherapy. Both comparisons had a P value of less than 0.001.
The estimated progression-free survival rate at 18 months was 43.9% with zanidatamab plus tislelizumab and chemotherapy, 38.0% with zanidatamab plus chemotherapy, and 20.9% with trastuzumab plus chemotherapy.
OS Outcomes
At the first interim analysis of overall survival, zanidatamab plus tislelizumab and chemotherapy showed longer overall survival than trastuzumab plus chemotherapy.
Median overall survival was 26.4 months with zanidatamab plus tislelizumab and chemotherapy compared with 19.2 months with trastuzumab plus chemotherapy. The hazard ratio for death was 0.72 (95% CI, 0.57 to 0.90), with a P value of 0.004. The estimated overall survival rate at 24 months was 54.3% with zanidatamab plus tislelizumab and chemotherapy and 38.8% with trastuzumab plus chemotherapy.
In the zanidatamab plus chemotherapy group, median overall survival was 24.4 months (95% CI, 20.4 to 30.0). At this interim analysis, the comparison with trastuzumab plus chemotherapy did not meet the prespecified criteria for statistical significance. The hazard ratio for death was 0.80 (95% CI, 0.64 to 1.01), with a P value of 0.06. Further prespecified analyses are planned to assess overall survival with zanidatamab plus chemotherapy.
Read more about Zanidatamab (Ziihera) Updates: Uses in Cancer, Side Effects, Dosage, Expectations on OncoDaily.
Tumor Response
Confirmed objective response, assessed by blinded independent central review, was reported in 70.7% of patients receiving zanidatamab plus tislelizumab and chemotherapy, 69.6% of patients receiving zanidatamab plus chemotherapy, and 65.7% of patients receiving trastuzumab plus chemotherapy. Confirmed complete response occurred in 19.6%, 17.1%, and 11.0% of patients in the three groups, respectively.
Among patients with a confirmed objective response, median duration of response was 20.7 months with zanidatamab plus tislelizumab and chemotherapy, 14.3 months with zanidatamab plus chemotherapy, and 8.3 months with trastuzumab plus chemotherapy.
Safety Profile
The safety population included 294 patients in the zanidatamab plus tislelizumab and chemotherapy group, 305 in the zanidatamab plus chemotherapy group, and 302 in the trastuzumab plus chemotherapy group. Grade 3 or higher adverse events were reported in 83.3% of patients receiving zanidatamab, tislelizumab, and chemotherapy, 73.8% receiving zanidatamab plus chemotherapy, and 74.5% receiving trastuzumab plus chemotherapy.
Serious adverse events occurred in 58.5%, 49.2%, and 42.4% of patients, respectively. Diarrhea was the most common grade 3 or higher adverse event and was more frequent with zanidatamab-containing regimens, occurring in 24.8% and 20.0% of patients in the zanidatamab groups versus 12.9% in the trastuzumab group.
Grade 3 or higher infusion-related reactions were uncommon. Left ventricular dysfunction occurred in 8.8%, 6.2%, and 4.3% of patients, respectively. In the zanidatamab plus tislelizumab and chemotherapy group, immune-mediated adverse events occurred in 37.8% of patients, mostly grade 1 or 2. Grade 5 drug-related adverse events occurred in 2.4%, 0.3%, and 1.3% of patients, respectively.
Read more about HERIZON-GEA-01 Trial at ASCO GI 2026 on OncoDaily.
Study Limitations
HERIZON-GEA-01 was open-label because of differences in treatment schedules and required prophylactic measures, although progression-free survival was assessed by blinded independent central review. Subgroup analyses were exploratory and were not powered to support definitive conclusions for individual patient subgroups. The comparator was trastuzumab plus chemotherapy, which reflected the standard of care when the study was designed. The trial did not directly compare zanidatamab-based treatment with pembrolizumab-containing first-line regimens.
Additional follow-up is needed, particularly for overall survival with zanidatamab plus chemotherapy. Black patients were underrepresented, and no patients were enrolled from the United States or the Middle East.
Key Takeaways
In the phase 3 HERIZON-GEA-01 trial, zanidatamab plus chemotherapy, with or without tislelizumab, led to longer progression-free survival than trastuzumab plus chemotherapy in patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma.
At the first interim analysis, zanidatamab plus tislelizumab and chemotherapy also led to longer overall survival than trastuzumab plus chemotherapy. Overall survival with zanidatamab plus chemotherapy alone did not meet the prespecified criteria for statistical significance at this interim analysis.
Diarrhea was a common adverse event and occurred more often with zanidatamab-containing regimens. The incidence of grade 3 or higher adverse events was 83.3% with zanidatamab plus tislelizumab and chemotherapy, 73.8% with zanidatamab plus chemotherapy, and 74.5% with trastuzumab plus chemotherapy.
The full article is available in The New England Journal of Medicine.