Clinical Summary: 

• Kohei Shitara, MD, discusses updated results from the randomized phase 3 HERIZON-GEA-01 trial comparing zanidatamab plus chemotherapy, with or without tislelizumab, against trastuzumab plus chemotherapy in patients with HER2-positive gastroesophageal cancer.
• At second interim analysis, zanidatamab plus chemotherapy significantly improved overall survival compared with trastuzumab plus chemotherapy, while the tislelizumab-containing triplet maintained its survival benefit and achieved a 3-year overall survival rate of 40%. Direct comparison of the experimental regimens did not reach statistical significance.
• These findings strengthen the evidence supporting zanidatamab-based first-line treatment strategies for HER2-positive gastroesophageal cancer, while highlighting the potential additional benefit of incorporating immunotherapy and the importance of HER2 expression in treatment selection.

Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, discusses updated results from the phase 3 HERIZON-GEA-01 trial evaluating zanidatamab plus chemotherapy, with or without tislelizumab, compared with trastuzumab plus chemotherapy in patients with HER2-positive gastroesophageal cancer. 

Dr Shitara reviews the significant overall survival improvement observed with zanidatamab plus chemotherapy and the sustained survival benefit of the tislelizumab-containing triplet with longer follow-up. He also discusses the exploratory implications of the direct comparison between the doublet and triplet regimens, differences in benefit according to HER2 expression, and the clinical relevance of these findings for first-line treatment selection.

Transcript: 

Hello, I'm Kohei Shitara. I'm a GI medical oncologist working in Japan. At this ESMO meeting, we reported the results from the second interim analysis from the phase 3 HERIZON-GEA-01 trial.

HERIZON-GEA-01 is a global randomized phase 3 study evaluating zanidatamab as a bispecific anti-HER2 agent in combination with chemotherapy as a doublet, as well as a triplet in combination with tislelizumab, compared with trastuzumab plus chemotherapy in patients with HER2-positive gastroesophageal cancer.

The previous first interim analysis already demonstrated significant PFS improvement with both zanidatamab-containing regimens, as well as the OS improvement with the triplet regimen.

In this updated analysis, at the second interim analysis, zanidatamab plus chemotherapy now significantly improved OS compared with trastuzumab plus chemotherapy. Median OS was 22.9 months versus 19.6 months, with a hazard ratio of 0.76. 

The subgroup analysis showed the benefit in the majority of subgroups, but the benefit appeared mainly in patients with IHC 3+ rather than the 2+ population. 

The triplet with zanidatamab, tislelizumab, and chemotherapy maintained its OS benefit with longer follow-up, with median OS of 27 months, and the hazard ratio was 0.65, which was improved compared with 0.72 at IA1. The 3-year OS rate was now 40% with the triplet. 

Then we could formally compare between triplet and doublet. The hazard ratio was 0.81, with a P = .0502, which didn't reach statistical significance. However, median OS was 4 months longer with the triplet, with higher 2- and 3-year survival rates. 

The 3-year OS rate was 8% higher with the triplet, and there are no new safety findings with this additional follow-up.

In summary, this updated analysis from the HERIZON-GEA-01 trial demonstrated significant OS improvement with the doublet with zanidatamab plus chemotherapy, and the triplet maintained its OS benefit with longer follow-up, with a 3-year OS rate of 40%.

Although the direct comparison between triplet and doublet didn't reach statistical significance, longer median OS and higher 2- and 3-year survival rates support the triplet regimen. Both regimens have already been approved by the US FDA.

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.