抗体偶联药物在胆道癌中的应用：当前证据、新兴靶点与未来方向

文献信息

中文摘要

目的： 胆道癌（BTC）是一组异质性恶性肿瘤，全身治疗选择有限且预后较差。尽管免疫化疗已成为一线标准，二线治疗仍不充分。抗体偶联药物（ADC）已成为一种有前景的治疗方式，利用抗原特异性靶向递送强效细胞毒性载荷。本综述对BTC中的ADC格局进行了全面的多靶点评估。
近期发现： Trastuzumab deruxtecan（T-DXd）在DESTINY-PanTumor02（ORR 22%）和HERB（ORR 36.4%）试验支持下，于2024年获得FDA肿瘤不可知性批准，用于包括BTC在内的HER2阳性实体瘤。Zanidatamab在HERIZON-BTC-01中达到41.3%的ORR，获得BTC特异性监管批准。BL-B01D1是一种EGFR×HER3双特异性ADC，在BTC队列中显示出初步BTC活性（ORR 28.6%），未报告间质性肺病，但样本量和随访仍有限，而其鼻咽癌III期试验为双特异性ADC确立了概念验证。BL-M05D1的I期结果（ASCO 2026）为Claudin18.2 ADC在BTC中提供了首个临床证据（ORR 42.5%）。Trop2导向的ADC因69.5%的高表达率而在实体瘤中显示理论适用性，但缺乏BTC特异性临床数据。B7-H3和CD44v5代表具有早期临床或临床前验证的新兴靶点。本综述为在BTC中快速演变的多靶点ADC格局提供了统一框架。关键挑战仍然存在，包括缺乏III期随机试验、肿瘤异质性、最佳生物标志物指导的患者选择以及与免疫治疗的合理联合策略。HER2检测的标准化和更广泛的分子谱分析对于实现ADC在这一历史上难治性疾病中的临床潜力至关重要。胆道梗阻和肝功能障碍在BTC中常见，需要ADC特异性药代动力学警惕和分级毒性监测。

英文摘要

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.