Examining HER2 as a Treatment Target in Biliary Tract Cancer

HER2-targeted therapies represent important treatment options for biliary tract cancers with HER2 amplification in the subsequent-line setting, with 2 distinct agents offering different mechanisms of action. Trastuzumab deruxtecan functions as an antibody-drug conjugate, combining the HER2-targeting specificity of trastuzumab with a cytotoxic payload consisting of a topoisomerase I inhibitor. This “smart missile” approach allows the antibody to bind specifically to HER2-expressing cancer cells, undergo cellular uptake, and deliver the cytotoxic chemotherapy directly to the target cells through a specialized linker system. This mechanism has demonstrated efficacy across multiple cancer types beyond biliary tract malignancies.

Zanidatamab employs a novel bispecific antibody approach, simultaneously targeting 2 different epitopes on the HER2 protein rather than the single subdomain targeted by traditional trastuzumab. This dual-binding mechanism engages both subdomain 4 and subdomain 2, effectively combining the targeting capabilities of trastuzumab and pertuzumab in a single agent. By binding to both the extracellular juxtamembrane domain and the dimerization domain, zanidatamab enhances antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity more effectively than single-epitope targeting approaches.

The toxicity profiles of these agents reflect their distinct mechanisms of action and have important clinical implications for patient management. Trastuzumab deruxtecan carries both HER2-directed toxicities, including cardiac monitoring requirements for reversible cardiomyopathy, and chemotherapy-related adverse effects such as nausea and myelosuppression from its cytotoxic payload. A particularly concerning toxicity is pneumonitis or interstitial lung disease, which requires vigilant monitoring across all disease states. Conversely, zanidatamab exhibits a toxicity profile more similar to antibody-based therapies, requiring cardiac monitoring for HER2-related cardiotoxicity and causing diarrhea related to its dual-epitope binding, but notably avoiding chemotherapy-related adverse effects due to its purely antibody-based structure without cytotoxic conjugation.