Key Clinical Takeaways: 

• Design/Population: HERIZON-GEA-01 is a global, open-label, phase 3 trial that randomized 914 previously untreated patients with HER2-positive metastatic gastroesophageal adenocarcinoma, irrespective of PD-L1 status, to zanidatamab plus chemotherapy with or without tislelizumab or to trastuzumab plus chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS).
• Key Outcomes: Both zanidatamab-containing regimens significantly improved median PFS compared with trastuzumab plus chemotherapy, exceeding 12 months in both arms. Zanidatamab plus tislelizumab plus chemotherapy also produced a statistically significant and clinically meaningful OS benefit, while zanidatamab plus chemotherapy demonstrated a strong favorable OS trend at interim analysis.
• Clinical Relevance: These results establish zanidatamab as a more effective HER2-targeted backbone than trastuzumab in the first-line treatment of HER2-positive metastatic gastroesophageal adenocarcinoma. The addition of tislelizumab further enhances survival outcomes, supporting zanidatamab-based therapy as a new standard of care in this setting.

According to results from the phase 3 HERIZON-GEA-01 trial, zanidatamab-based treatment demonstrated a promising survival benefit among previously untreated patients with HER2-positive metastatic gastroesophageal adenocarcinoma.

These findings were presented by Elena Elimova, MD, Princess Margaret Cancer Centre, Toronto, Ontario, Canada, at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, California.

In this open-label study, 914 patients, regardless of PD-L1 status, were randomized 1:1:1 to receive zanidatamab plus tislelizumab plus chemotherapy (n = 302), zanidatamab plus chemotherapy (n = 304), or trastuzumab plus chemotherapy (n = 308). Chemotherapy consisted of capecitabine plus oxaliplatin or fluorouracil plus cisplatin. Dual primary end points were progression-free survival (PFS) and overall survival (OS).

At a median follow-up of 26 months, median PFS was 12.4 months in the zanidatamab plus tislelizumab plus chemotherapy arm (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.51 to 0.78; P < .0001), 12.4 months in the zanidatamab plus chemotherapy arm (HR, 0.65; 95% CI, 0.52 to 0.81; P < .0001), and 8.1 months in the trastuzumab plus chemotherapy arm. The 18-month PFS rates were 43.9%, 38.0%, and 20.9%, respectively. Median OS was 26.4 months in the zanidatamab plus tislelizumab plus chemotherapy arm, 24.4 months in the zanidatamab plus chemotherapy arm, and 19.2 months in the trastuzumab plus chemotherapy arm. The 24-month OS rates were 54.3%, 50.3%, and 38.8%, respectively.

Grade ≥ 3 treatment-related adverse events were reported in 71.8% of patients in the zanidatamab plus tislelizumab plus chemotherapy arm, 59% of patients in the zanidatamab plus chemotherapy arm, and 59.6% of patients in the trastuzumab plus chemotherapy arm. The most common grade ≥ 3 treatment-related adverse events occurring in > 10% of patients included diarrhea, hypokalemia, anemia, neutrophil count decrease, and platelet count decrease. Treatment-related adverse events led to treatment discontinuation in 11.9% of patients in the zanidatamab plus tislelizumab plus chemotherapy arm, 8.5% of patients in the zanidatamab plus chemotherapy arm, and 2.3% of patients in the trastuzumab plus chemotherapy arm.

“The trial is ongoing with additional OS analyses planned for zanidatamab [plus chemotherapy],” concluded Dr Elimova et al. “These results support zanidatamab as a new standard in HER2-targeting agents, potentially replacing [trastuzumab], as well as the use of tislelizumab.”

Source: 

Elimova E, Rha SY, Shitara K, et al. 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. Presented at ASCO Gastrointestinal Cancers Symposium. January 8 - 12, 2026; San Francisco, California. LBA285.