Zanidatamab: HER2 receptor double on the hook

Zanidatamab binds simultaneously to extracellular domains 2 and 4 on separate HER2 monomers. This leads to internalization of the antibody-receptor complex and thus to a reduction in HER2 receptor density on the surface of cancer cells. Zanidatamab also induces complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. These mechanisms together lead to inhibition of tumor growth and tumor cell death.

Zanidatamab is contained in Ziihera® from Jazz Pharmaceuticals. The drug is currently indicated as monotherapy for the treatment of adults with unresectable, locally advanced, or metastatic HER2-positive (IHC 3+) biliary cancer who have previously been treated with at least one systemic therapy.

Biliary carcinomas include gallbladder cancer and cholangiocarcinoma. Worldwide, a good quarter of all biliary carcinomas are HER2-positive, which is associated with poorer survival rates compared to HER2-negative disease. Zanidatamab is the first HER2-targeted therapy approved in the EU for HER2-positive biliary carcinomas.

This is based on data from 62 patients with locally advanced, unresectable or metastatic biliary carcinoma who had received at least one prior gemcitabine-containing systemic chemotherapy for advanced disease and who experienced disease progression or intolerance to this therapy after the last prior therapy and whose tumor tested HER2-positive (IHC 3+).

In the single-arm study, patients received zanidatamab at a dose of 20 mg/kg intravenously every two weeks. It was administered until disease progression or unacceptable toxicity. The key efficacy measures were the confirmed objective response rate (cORR) and the duration of response (DoR). The cORR was 52 percent, with most responses being partial. The DoR was just under 15 months. Diarrhea, infusion-related reactions, abdominal pain, anemia, and fatigue are among the most common side effects of the antibody.

Zanidatamab could have a further career in the future. The antibody is being investigated in several clinical trials as a targeted treatment option for patients with solid tumors that express HER2. For example, the antibody has already received orphan drug status from the European Medicines Agency (EMA) for the treatment of gastric cancer.