Zanidatamab (Ziihera®): A Comprehensive Monograph on a First-in-Class Bispecific HER2-Directed Antibody

Executive Summary

Zanidatamab represents a significant advancement in the field of targeted oncology, establishing a new class of therapy as a biparatopic, human epidermal growth factor receptor 2 (HER2)-directed antibody. Marketed under the brand name Ziihera®, this engineered biologic possesses a novel mechanism of action that distinguishes it from prior generations of HER2-targeted agents. By simultaneously engaging two distinct, non-overlapping epitopes on the HER2 receptor, zanidatamab induces unique receptor clustering, leading to rapid internalization, downregulation, and a multi-pronged, immune-mediated attack on tumor cells that includes potent complement-dependent cytotoxicity (CDC)—a mechanism largely absent in its predecessors.

The clinical value of this unique pharmacology was definitively established in the pivotal HERIZON-BTC-01 trial, a global Phase 2b study in patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). The trial demonstrated compelling and durable clinical activity, particularly in the subgroup of patients with high HER2 expression (immunohistochemistry [IHC] 3+), with an objective response rate exceeding 50% and a median overall survival of over 18 months. These results, coupled with a manageable and tolerable safety profile devoid of chemotherapy-associated toxicities, address a profound unmet medical need in a patient population with historically poor outcomes.