Clinical Summary:

• 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 trastuzumab plus chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS).

• Key Outcomes: Both zanidatamab-containing regimens significantly improved PFS compared with trastuzumab plus chemotherapy, with median PFS exceeding 12 months in both arms. Zanidatamab plus tislelizumab and chemotherapy also significantly improved OS, while OS numerically favored zanidatamab plus chemotherapy at the interim analysis.

• Clinical Relevance: These findings support zanidatamab as a new HER2-targeted backbone for first-line HER2-positive metastatic gastroesophageal adenocarcinoma. The significant survival benefit with the tislelizumab-containing regimen further supports incorporating immunotherapy with zanidatamab and chemotherapy in this setting.

Results from the phase 3 HERIZON-GEA-01 trial demonstrated that zanidatamab-based regimens improved progression-free survival (PFS) compared with trastuzumab plus chemotherapy in previously untreated patients with HER2-positive metastatic gastroesophageal adenocarcinoma, with a significant overall survival (OS) benefit also observed with zanidatamab plus tislelizumab and chemotherapy.

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 trial, 914 patients, irrespective of PD-L1 status, were randomized 1:1:1 to receive zanidatamab plus tislelizumab and chemotherapy (n = 302), zanidatamab plus chemotherapy (n = 304), or trastuzumab plus chemotherapy (n = 308). Chemotherapy consisted of capecitabine plus oxaliplatin or fluorouracil plus cisplatin. The dual primary end points were PFS and OS.

At a median follow-up of 26 months, median PFS was 12.4 months with zanidatamab plus tislelizumab and chemotherapy (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.51-0.78; P < .0001) and 12.4 months with zanidatamab plus chemotherapy (HR, 0.65; 95% CI, 0.52-0.81; P < .0001), compared with 8.1 months with trastuzumab plus chemotherapy. The 18-month PFS rates were 43.9%, 38.0%, and 20.9%, respectively.

Median OS was 26.4 months with zanidatamab plus tislelizumab and chemotherapy, 24.4 months with zanidatamab plus chemotherapy, and 19.2 months with trastuzumab plus chemotherapy. The 24-month OS rates were 54.3%, 50.3%, and 38.8%, respectively. The OS benefit with zanidatamab plus tislelizumab and chemotherapy was statistically significant, while OS numerically favored zanidatamab plus chemotherapy at this interim analysis, with additional OS follow-up planned.

Grade ≥3 treatment-related adverse events occurred in 71.8% of patients receiving zanidatamab plus tislelizumab and chemotherapy, 59% receiving zanidatamab plus chemotherapy, and 59.6% receiving trastuzumab plus chemotherapy. The most common grade ≥3 treatment-related adverse events occurring in more than 10% of patients included diarrhea, hypokalemia, anemia, decreased neutrophil count, and decreased platelet count.

Treatment-related adverse events led to treatment discontinuation in 11.9% of patients receiving zanidatamab plus tislelizumab and chemotherapy, 8.5% receiving zanidatamab plus chemotherapy, and 2.3% receiving trastuzumab plus chemotherapy.

“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.