HER2-targeted bispecific Ab 'Ziihera' shows potential in gastric cancers

Tevimbra + chemotherapy combination…obtained FDA's Priority Review designation

Competition between combination therapies containing immunotherapy + HER2-targeted therapy

'Ziihera,' approved as a biliary tract cancer, is now confirmed to have clinical potential in upper gastrointestinal cancers, including gastric cancer, accelerating the progress for expanded indications.

Based on its dual targeting of HER2, this drug demonstrated a significant improvement in survival compared to existing treatments centered on trastuzumab. Its potential to reorganize the standard first-line treatment has been suggested.

HER2-targeted bispecific antibody 'Ziihera' 

According to industry sources on the 29th, the U.S. Food and Drug Administration (FDA) recently accepted a supplemental Biologics License Application (sBLA) for the expanded indications for Ziihera (zanidatamab) and granted it Priority Review designation. Under the Prescription Drug User Fee Act (PDUFA), the FDA is scheduled to decide on the approval by August 25 of this year.

The specific indication is for the first-line treatment of patients with HER2-positive locally advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, and gastroesophageal adenocarcinoma (GEA).

Ziihera received accelerated approval in the U.S. in 2024 for the treatment of HER2-positive biliary tract cancer and was subsequently approved in South Korea last March.

Ziihera is a new drug developed by the Canadian biopharmaceutical company Zymeworks. Following development, U.S.-based Jazz Pharmaceuticals licensed the development and commercialization rights for the substance from Zymeworks. Under the agreement, BeiGene holds the commercialization rights for Asian regions, including South Korea and China, excluding Japan.

Ziihera is a bispecific antibody that binds two distinct sites on the HER2 receptor. It was developed with a mechanism that simultaneously enhances signal blockade and immune response induction compared to existing monoclonal antibodies.

Notably, this development strategy highlights the potential for combination with BeiGene’s immunotherapy, Tevimbra (tislelizumab). The approach aims to maximize therapeutic effects by proposing a triplet therapy combining HER2-targeted therapy and immunotherapy.

The Phase 3 HERIZON-GEA-01 study, which served as the basis for the Priority Review, enrolled 914 patients with gastric cancer.

The clinical trial was designed to compare the efficacy of existing trastuzumab-based treatments with Ziihera-containing combination therapies and to verify the added effect of an immunotherapy combination strategy.

Patients were divided into a trastuzumab + chemotherapy group and a Ziihera-containing combination group. Within the Ziihera group, subgroups were formed based on whether Tevimbra was co-administered.

The results showed that Ziihera-based treatment reduced the risk of disease progression or death by approximately 35% compared to the existing trastuzumab combination group, raising the median progression-free survival (PFS) to 12.4 months.

In particular, the triplet therapy combining Ziihera and Tevimbra lowered the risk of death by 28%, recording a median overall survival (OS) of 26.4 months. However, this OS result did not meet the prespecified statistical significance threshold in the initial interim analysis, and additional analyses are pending.

First-line treatment of gastric cancer reeorganized around immunotherapy

HER2-targeted therapy in domestic gastric cancer treatment had remained largely unchanged for a long period. Since Herceptin (trastuzumab) was established as a first-line treatment option in 2010, there has been no new treatments to replace it.

While successive efforts were made to develop follow-up options in the field of HER2-targeted therapy, most failed to yield meaningful outcomes in clinical trials. Lapatinib-based combination therapies (with paclitaxel or chemotherapy) and multiple HER2 blockade strategies involving 'Kadcyla (trastuzumab emtansine)' and 'Perjeta (pertuzumab)' suffered successive failures in clinical trials for gastric cancer patients.

Immunotherapy 'Keytruda'

This trend continued for about a decade until it reached a turning point in 2022. With the introduction of Enhertu (trastuzumab deruxtecan) for third-line HER2-positive gastric cancer, a follow-up HER2-targeted treatment option appeared for the first time. However, as the treatment line was limited to the third-line setting, there were limitations in changing the first-line treatment structure.

Meanwhile, the treatment paradigm shifted to be reorganized around immunotherapies. Opdivo was introduced as a first-line treatment option soon after obtaining reimbursement for HER2-negative gastric cancer, and immunotherapy combination strategies became standard.

Furthermore, Keytruda's scope expanded after obtaining approval as a first-line treatment for metastatic HER2-positive gastric cancer, followed by a recent indication expansion to HER2-negative gastric cancer. In particular, Keytruda was the first immunotherapy to obtain approval for HER2-positive gastric cancer, leading to the establishment of the strategy of combining existing HER2-targeted therapy with immunotherapy.

Regarding this, Ziihera is entering the market as a new HER2-targeted option to replace trastuzumab alongside existing immunotherapy combination treatments. This strategy is evaluated as a differentiated approach to existing treatment flows, as Ziihera's strategy aims to replace the HER2-targeted agent in a setting where immunotherapy combinations are the standard.