Antibody-Drug Conjugates in Biliary Tract Cancer: Current Evidence, Emerging Targets, and Future Directions.

PURPOSE OF REVIEW: Biliary tract cancer (BTC) is a heterogeneous group of malignancies with limited systemic treatment options and poor prognosis. While immunochemotherapy has become the first-line standard, second-line therapy remains inadequate. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic modality leveraging antigen-specific targeting to deliver potent cytotoxic payloads. This review provides a comprehensive, multi-target appraisal of the ADC landscape in BTC.

RECENT FINDINGS: Trastuzumab deruxtecan (T-DXd), supported by DESTINY-PanTumor02 (ORR 22%) and HERB (ORR 36.4%) trials, received 2024 FDA tumor-agnostic approval for HER2-positive solid tumors including BTC. Zanidatamab achieved 41.3% ORR in HERIZON-BTC-01, securing BTC-specific regulatory approval. BL-B01D1, an EGFR×HER3 bispecific ADC, demonstrated preliminary BTC activity (ORR 28.6%) without reported interstitial lung disease in the BTC cohort, though sample size and follow-up remain limited, while its phase III nasopharyngeal carcinoma trial established proof of concept for bispecific ADCs. BL-M05D1 phase I results (ASCO 2026) provided the first clinical evidence for Claudin18.2 ADCs in BTC (ORR 42.5%). Trop2-directed ADCs show theoretical applicability across solid tumors given 69.5% high-expression prevalence, but BTC-specific clinical data are absent. B7-H3 and CD44v5 represent emerging targets with early clinical or preclinical validation. This review provides a unified framework for navigating the rapidly evolving multi-target ADC landscape in BTC. Critical challenges remain, including the absence of phase III randomized trials, tumor heterogeneity, optimal biomarker-guided patient selection, and rational combination strategies with immunotherapy. Standardization of HER2 testing and broader molecular profiling will be essential to realize the clinical potential of ADCs in this historically treatment-refractory disease. Biliary obstruction and hepatic impairment, common in BTC, require ADC-specific pharmacokinetic vigilance and graded toxicity monitoring.