In an interview with Targeted Oncology, Arndt Vogel, MD, managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, discusses the clinical use of zanidatamab in biliary tract cancer (BTC), highlighting the importance of patient profiling, the specific biomarker requirements for treatment, and the unique mechanism of action of the drug.
To be effective with targeted therapies like zanidatamab, a critical first step is to accurately profile patients for specific genetic alterations. For zanidatamab, the key biomarker is HER2 overexpression. While this overexpression is often caused by genetic amplifications, a crucial component of patient selection involves immunohistochemistry (IHC). Vogel emphasizes the necessity of a 3+ HER2 overexpression score via IHC for these HER2-directed therapies to be clinically effective in BTC. This requirement is distinct from other cancer types, such as breast cancer, where patients with lower HER2 expression may also derive benefit from HER2-targeted agents. In BTC, the clinical data appears to strongly favor a high level of HER2 expression for optimal therapeutic response.
Zanidatamab is a specialized type of antibody. While other HER2-targeted drugs include monoclonal antibodies like trastuzumab and TKIs, zanidatamab’s design offers a unique advantage. TKIs, which block the receptor from within the cell, have not shown the same level of efficacy as antibody-based therapies in this context.
Zanidatamab is a bispecific antibody that binds to 2 distinct HER2 molecules simultaneously, effectively cross-linking the receptors on the cell surface. This innovative mechanism of action appears to be highly effective at inhibiting the HER2 signaling pathway. By cross-linking the HER2 receptors, zanidatamab not only blocks downstream signaling that promotes cell growth and survival but may also induce immunogenic cell death, a process that triggers an anti-tumor immune response. While a direct head-to-head comparison with trastuzumab alone is challenging, the efficacy data for zanidatamab in BTC is compelling, suggesting its bispecific nature provides a potent therapeutic effect. This novel approach represents a significant advancement in targeting HER2-positive BTC, offering a promising new avenue for treatment.