Clinical Summary: 

• Design/Population: The phase 3 HERIZON-GEA-01 trial evaluated zanidatamab plus chemotherapy, with or without tislelizumab, versus trastuzumab plus chemotherapy in patients with previously untreated HER2-positive metastatic gastroesophageal adenocarcinoma. This analysis reports updated overall survival (OS) findings from the second planned interim analysis.
• Key Outcomes: Zanidatamab plus chemotherapy significantly improved OS compared with trastuzumab plus chemotherapy, reducing the risk of death by 24%. The addition of tislelizumab was associated with numerically longer median OS compared with zanidatamab plus chemotherapy alone, although the difference did not reach statistical significance. The survival benefit of the triplet versus trastuzumab plus chemotherapy was sustained with longer follow-up.
• Clinical Relevance: These findings reinforce zanidatamab-based regimens as first-line treatment options for HER2-positive metastatic gastroesophageal adenocarcinoma. The updated results support the survival benefit of zanidatamab plus chemotherapy while suggesting additional benefit from tislelizumab that requires further evaluation.

Updated results from the phase 3 HERIZON-GEA-01 trial demonstrated that zanidatamab plus chemotherapy significantly improved overall survival (OS) compared with trastuzumab plus chemotherapy in patients with previously untreated HER2-positive metastatic gastroesophageal adenocarcinoma, reinforcing zanidatamab-based regimens as first-line treatment options. 

These findings were presented by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, at the European Society for Medical Oncology (ESMO) Congress.

In this trial, 914 patients were randomized 1:1:1 to receive either zanidatamab plus chemotherapy, zanidatamab plus tislelizumab and chemotherapy, or trastuzumab plus chemotherapy. Patients received 1800 mg of zanidatamab intravenously every 3 weeks if they weighed less than 70 kg or 2400 mg if they weighed at least 70 kg, in combination with capecitabine and oxaliplatin or fluorouracil and cisplatin. Patients assigned to the triplet regimen also received 200 mg of tislelizumab intravenously every 3 weeks. 

At the second interim analysis, OS comparisons were conducted sequentially, first comparing zanidatamab plus chemotherapy with trastuzumab plus chemotherapy, followed by zanidatamab plus tislelizumab and chemotherapy versus zanidatamab plus chemotherapy.

At a median follow-up of 35.3 months, median OS was 22.9 months in the zanidatamab plus chemotherapy arm and 19.6 months in the trastuzumab plus chemotherapy arm, reducing the risk of death by 24% (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.62 to 0.93; P = .0088).

The addition of tislelizumab to zanidatamab plus chemotherapy was associated with numerically longer OS. Median OS was 27 months with the triplet regimen compared with 22.9 months with zanidatamab plus chemotherapy alone. However, the difference did not reach statistical significance (HR, 0.81; 95% CI, 0.65 to 1.00; P = .0502).

The OS benefit previously observed with zanidatamab plus tislelizumab and chemotherapy versus trastuzumab plus chemotherapy was maintained with longer follow-up. At the first interim analysis, the HR for OS was 0.72. At the second interim analysis, the HR was 0.65, corresponding to a 35% reduction in the estimated risk of death with the triplet regimen compared with trastuzumab plus chemotherapy.

Estimated 36-month OS was 39.8% in the zanidatamab plus tislelizumab and chemotherapy arm, 31.5% in the zanidatamab plus chemotherapy arm, and 22.9% in the trastuzumab plus chemotherapy arm.

Treatment exposure was longest among patients receiving the triplet regimen. Median treatment duration was 46.6 weeks in the zanidatamab plus tislelizumab and chemotherapy arm, including 40.5 weeks of zanidatamab exposure. In comparison, median treatment duration was 31.1 weeks with zanidatamab plus chemotherapy, including 30.1 weeks of zanidatamab exposure, and 30 weeks with trastuzumab plus chemotherapy, including 28.2 weeks of trastuzumab exposure.

The safety profiles of the zanidatamab-based regimens remained consistent with those observed at the first interim analysis, with no new safety findings reported in the updated analysis. The longer treatment exposure observed with zanidatamab plus tislelizumab and chemotherapy did not result in reported changes to the previously established safety profile. 

As Dr Shitara concluded, “these results continue to support zanidatamab combined with chemotherapy ± tislelizumab as a new HER2-directed 1L standard of care in HER2-positive metastatic gastroesophageal adenocarcinoma.” 

Source: 

Shitara K, et al. Zanidatamab (zani) + chemotherapy (CT) ± tislelizumab (TIS) for first-line (1L) HER2-positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (mGEA): Second interim analysis (IA) from HERIZON-GEA-01. Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. LBA79.