At an unresectable metastatic or locally advanced stage, the prognosis for gastroesophageal adenocarcinoma is particularly poor, with a 5-year relative survival of between 5 and 7%. Around 20% of these tumors present overexpression of the HER2 receptor, a biomarker which has enabled the introduction of targeted therapies in this indication. Thus, first-line treatment of HER2-positive forms is classically based on chemotherapy based on platinum salts combined with trastuzumab, a monoclonal antibody directed against HER2. However, despite this approach, and despite the recent addition of anti-PD1 immunotherapies in certain patients, the majority of them experience tumor progression within a year following treatment initiation. Hence the conduct of the Herizon-GEA-01 study with zanidatamab (1). This next-generation bispecific antibody targets two distinct epitopes of the HER2 receptor. This dual targeting aims for a more complete inhibition of HER2 signaling and to potentiate the mechanisms of antibody-dependent cellular cytotoxicity.
More durable tumor control, particularly in combination with immunotherapy
The Herizon-GEA-01 trial is an international, randomized phase 3 study that included 914 patients with HER2-positive, metastatic or locally advanced unresectable gastroesophageal adenocarcinoma who had not received any prior systemic treatment. Patients were randomly allocated to three therapeutic strategies: zanidatamab combined with chemotherapy and tislelizumab (anti-PD1); zanidatamab combined with chemotherapy alone; or trastuzumab combined with chemotherapy, corresponding to the standard of care in effect when the study was designed.
The primary endpoint was progression-free survival (time from randomization to objective disease progression or death from any cause). Secondary endpoints included overall survival, disease control rate and safety assessment.
After a median follow-up of 26 months, median progression-free survival reached 12.4 months in patients treated with zanidatamab, with or without tislelizumab, compared to 8.1 months in those receiving trastuzumab (p < 0.0001). This difference corresponds to an approximately 35% reduction in the risk of tumor progression or death.
At 18 months of follow-up, 44% of patients treated with the combination of zanidatamab, tislelizumab and chemotherapy were still free of disease progression, compared to 38% in the zanidatamab plus chemotherapy group and only 21% in the trastuzumab group. These data suggest more durable tumor control with zanidatamab, particularly when combined with immunotherapy.
Concerning overall survival, the median reached 26.4 months in the zanidatamab, tislelizumab and chemotherapy arm, compared to 19.2 months in the chemotherapy and trastuzumab arm (p = 0.0043). If the overall survival data were not yet statistically significant for the zanidatamab arm without immunotherapy at the time of analysis (p = 0.0564), a favorable trend was nevertheless observed, suggesting a potential benefit to be confirmed during subsequent interim analyses.
What tolerance?
The safety profile of zanidatamab was found to be generally in line with expectations. Adverse events of grade 3 or higher were reported in 72% of patients receiving triple therapy including tislelizumab, compared to approximately 59% in the other two groups. Permanent treatment interruptions due to toxicity concerned 12% of patients in the zanidatamab with immunotherapy arm, 8.5% in the zanidatamab with chemotherapy alone arm and 2.3% in the trastuzumab arm.
The most common severe adverse reactions observed with zanidatamab were diarrhea, hypokalemia and anemia. Diarrhea, a well-identified adverse effect of this molecule, was managed by appropriate prophylactic and therapeutic measures, allowing treatment to be maintained in the majority of patients.
Progress to be confirmed
Thus, the Herizon-GEA-01 trial appears to be an important advance in the management of metastatic HER2-positive gastroesophageal adenocarcinoma. This is the first phase 3 trial demonstrating the superiority of a new anti-HER2 targeted therapy compared to trastuzumab in first line. The significant improvement in progression-free survival, combined with encouraging signals on overall survival, positions zanidatamab as a potential future therapeutic standard. Additional analyzes of overall survival expected in 2026 will be decisive in confirming the extent of the clinical benefit and specifying the definitive place of this therapeutic strategy.
(1) ASCO Gastrointestinal Cancers Symposium, janvier 2026. Abstract LBA285. Elimova E, et al., on behalf of the Herizon-GEA-01 Study Group. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from Herizon-GEA-01
date:2026-02-12 04:17:00
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