Antibody-Drug Conjugates in Biliary Tract Cancers

Antibody-drug conjugates (ADCs) are emerging as a class of cancer therapeutics, offering an option for patients with biliary tract cancers (BTCs). ADCs represent a developing standard in precision oncology, with the potential to improve outcomes in difficult-to-treat tumors.

Advances in ADC technology are driving this momentum. A growing pipeline of agents incorporates innovative features such as novel cytotoxic payloads, dual-targeting strategies, and more efficient delivery systems designed to enhance tumor specificity and minimize off-target effects. These next-generation approaches currently demonstrate significant clinical activity across multiple tumor types, signaling the potential to extend similar benefits to BTC.

Emerging targets and platforms are further expanding the therapeutic landscape. Bispecific ADCs targeting HER3 and EGFR demonstrate potential in early development, while B7-H4 and Trop-2 are under active investigation based on preclinical and early clinical data, as demonstrated in the phase II ADC Match study (NCT06311214), which pairs patients with ADC therapies based on molecular profiling of targets including HER2 and Nectin-4.

Ongoing research aims to further enhance ADC effectiveness through improved linker technologies, tumor-selective delivery mechanisms, and dual-payload strategies that combine different therapeutic modalities. Combination approaches, including ADCs paired with immunotherapy, are also being explored to maximize clinical benefit.

Several challenges continue to limit the full potential of ADCs in BTC. The chemo-resistance of biliary cancers, coupled with limited availability of tumor tissue for comprehensive biomarker testing, complicates patient selection and therapeutic optimization. Variability in target antigen expression and inconsistencies in biomarker assessment, particularly in HER2-directed approaches, can lead to misclassification and impact treatment outcomes. In addition, multidrug resistance and suboptimal drug penetration into the tumor microenvironment may reduce ADC efficacy.

These challenges will require improved biomarker standardization, deeper understanding of resistance mechanisms, and continued refinement of ADC design to better translate scientific advances into relevant clinical benefit for patients with BTC.

Source: Meric-Bernstam F. ADCs for biliary tract cancers. Presented at: 2026 Annual Cholangiocarcinoma Foundation Conference. May 1-3, 2026; Salt Lake City, UT.