Zymeworks Inc. announced positive efficacy and safety results from the Phase 3 HERIZON-GEA-01 trial evaluating Ziihera®? (zanidatamab-hrii) in combination with chemotherapy, with or without the PD-1 inhibitor Tevimbra®? (tislelizumab), as first-line treatment for adults with HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), including cancers of the stomach, gastroesophageal junction and esophagus.
The data will be presented as a late-breaking oral presentation at the 2026 ASCO Gastrointestinal Cancers Symposium (ASCO-GI) in San Francisco on January 8, 2026 from 8:57- 9:07 am PST (abstract number: LBA285). The study found that both investigational arms?Ziihera plus tislelizumab and chemotherapy, and Ziihera plus chemotherapy?led to a statistically significant and clinically meaningful prolongation of progression-free survival (PFS), with approximately a 35% reduction in the risk of disease progression or death compared to trastuzumab plus chemotherapy, resulting in a median PFS of over one year, more than four months longer than the control arm. Ziihera plus tislelizumab and chemotherapy also demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit, with a median OS of 26.4 months, the longest reported in a Phase 3 trial in GEA, representing a more than seven-month improvement and a 28% reduction in the risk of death versus trastuzumab plus chemotherapy.
At the first interim analysis, Ziihera plus chemotherapy showed a median OS of over two years, with a strong trend toward statistical significance compared to trastuzumab plus chemotherapy, with an additional planned OS interim analysis expected in mid-2026. The OS and PFS benefits were generally consistent across major prespecified subgroups, including geographic region and PD-L1 status, for both investigational arms. The safety profile of Ziihera in combination with chemotherapy, with or without tislelizumab, was consistent with the known effects of HER2-directed therapy and immunotherapy, and no new safety signals were identified. Duration of treatment was longest on the Ziihera plus tislelizumab and chemotherapy arm.
Rates of Grade 3 treatment-related adverse events (TRAEs) were 71.8% with Ziihera plus tislelizumab and chemotherapy, 59.0% with Ziihera plus chemotherapy, and 59.6% with trastuzumab plus chemotherapy. Discontinuations due to Ziihera- or trastuzumab-related adverse events were 11.9% with Ziihera plus tislelizumab and chemotherapy, 8.5% with Ziihera plus chemotherapy, and 2.3% in the trastuzumab plus chemotherapy arm. The most common Grade 3 TRAE was diarrhea, occurring in 24.5% of patients with Ziihera plus tislelizumab and chemotherapy, 20.0% with Ziihera plus chemotherapy, and 12.9% in the trastuzumab plus chemotherapy arm; however, discontinuation due to treatment-related diarrhea was uncommon (4.1%, 1.3%, and 0%, respectively), and treatment-emergent diarrhea generally occurred early and resolved within three weeks.
The manageable safety profile supports the feasibility of these combinations in the first-line metastatic setting. Under existing arrangements with Jazz and BeOne Medicines, Zymeworks is eligible to receive substantial near-term milestone payments totaling $440.0 million related to future regulatory approvals in GEA?$250.0 million in the United States, $100.0 million in Europe, $75.0 million in Japan, and $15.0 million in China?and expects royalty revenue from Ziihera sales to increase as additional regulatory approvals are obtained globally. Zymeworks may also be eligible for future milestones and increased royalties from the development, regulatory approval, and commercialization of additional indications for Ziihera, including breast cancer.
