Zanidatamab Plus Tislelizumab Improves Survival in HER2-Positive Advanced Gastroesophageal Adenocarcinoma

Clinical Summary:

• Design/Population: The phase 3 HERIZON-GEA-01 trial randomized previously untreated patients with HER2-positive advanced gastroesophageal adenocarcinoma to receive either zanidatamab plus chemotherapy with or without tislelizumab or trastuzumab plus chemotherapy.
• Key Outcomes: Zanidatamab-based therapy significantly improved progression-free and overall survival compared with trastuzumab plus chemotherapy. Grade ≥ 3 adverse events were common across arms, with diarrhea more frequent in the zanidatamab-containing arms.
• Clinical Relevance: Zanidatamab plus chemotherapy with or without tislelizumab may represent a new frontline standard, offering improved disease control and a potential survival advantage over trastuzumab-based therapy in HER2-mutated gastroesophageal adenocarcinoma. 

Results from the phase 3 HERIZON-GEA-01 trial demonstrated that zanidatamab plus chemotherapy with or without the addition of tislelizumab significantly improved survival outcomes compared with trastuzumab plus chemotherapy among patients with HER2-positive advanced gastroesophageal adenocarcinoma.

“Zanidatamab, a dual HER2-targeted bispecific antibody, plus chemotherapy both with and without tislelizumab showed encouraging efficacy and safety as firstline therapy in phase 2 studies,” stated Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, and coauthors.

In this open-label study, 914 patients were randomized 1:1:1 to receive either zanidatamab plus tislelizumab and chemotherapy (n = 302), zanidatamab plus chemotherapy (n = 304), or trastuzumab plus chemotherapy (n = 308). Dual primary end points included progression-free survival (PFS) and overall survival (OS). A key secondary end point was safety. 

At a median follow-up of 25.9 months, median PFS was 12.4 months in both the zanidatamab-containing arms and 8.1 months in the trastuzumab plus chemotherapy arm. The hazard ratio (HR) for progression or death was 0.63 in the zanidatamab plus tislelizumab and chemotherapy arm (95% confidence interval [CI], 0.51 to 0.78; P < .001) and 0.65 in the zanidatamab plus chemotherapy arm (95% CI, 0.52 to 0.81; P < 0.001). Median OS was 26.4 months in the zanidatamab plus tislelizumab and chemotherapy arm and 19.2 months in the trastuzumab plus chemotherapy arm (HR 0.72; 95% CI, 0.57 to 0.9; P = .004). The median OS in the zanidatamab plus chemotherapy arm was 24.4 months, and did not significantly differ from trastuzumab plus chemotherapy at this analysis (HR, 0.80; 95% CI, 0.64 to 1.01; P = .06).

Grade ≥3 adverse events were reported in 83.3% of patients in the zanidatamab plus tislelizumab and chemotherapy arm, 73.8% of patients in the zanidatamab plus chemotherapy arm, and 74.5% of patients in the trastuzumab plus chemotherapy arm. The most frequently reported grade ≥3 adverse event was diarrhea, occurring in 24.8%, 20%, and 12.9% of patients, respectively.

“Zanidatamab plus chemotherapy, both with and without tislelizumab, led to longer [PFS] than trastuzumab plus chemotherapy among patients with HER2-positive advanced gastroesophageal adenocarcinoma,” stated Dr Shitara and coauthors. “Further analyses are planned to assess zanidatamab [plus] chemotherapy.”

Source:

Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. Published online: May 26, 2026. doi:10.1056/nejmoa2517729