Cryoablation plus sintilimab and lenvatinib in advanced or metastatic intrahepatic cholangiocarcinoma: a phase 2 trial

作者：Sijia Gu, Qiyu Luo, Yalei Zhang, Ling Qian, Kai Chen, Fei Liang, Yudi Hu, Runye Zhou, Yating Wang, Jingjing Liu, Zhouyu Ning, Litao Xu, Zhiqiang Meng, Li Ye, Peng Wang · 发表于：Nature Cancer · 年份：2025 · DOI：10.1038/s43018-025-01058-2 · 被引用次数：12 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Hepatocellular Carcinoma Treatment and Prognosis、Metastasis and carcinoma case studies

Treatment options for advanced or metastatic intrahepatic cholangiocarcinoma (ICC) are limited. In this single-arm, phase 2 trial (CASTLE-01, NCT05010668 ), 28 participants with advanced or metastatic ICC who have progressed after chemotherapy were treated with cryoablation, followed by anti-PD1 sintilimab (200 mg every 3 weeks) plus lenvatinib (8–12 mg per day) 2 weeks later. The objective response rate assessed by Response Evaluation Criteria in Solid Tumors version 1.1 was 75.0% (95% confidence interval (CI): 59–91%), meeting the prespecified primary endpoint. Secondary endpoints of disease control rate, median progression-free survival and overall survival were respectively 100% (95% CI: 100–100%), 16.8 months (95% CI: 11.5–not reached (NR)) and 25.4 months (95% CI: 13.3–NR). Treatment was well tolerated. Post hoc multiomics analysis of paired pretreatment and on-treatment tumor biopsies suggested that cryoablation increased the tumor immunogenicity and dendritic cell activation, followed by triggering continuous replenishment of intratumoral CD8+PD1hi effectors from peripheral blood. The addition of lenvatinib transitioned endothelial cells into inflamed venules to boost lymphocyte influx and targeted tumor stroma to promote CD8+PD1hi effectors penetrating into tumor cell nests. Therefore, cryoablation combined with sintilimab plus lenvatinib represents a promising approach for the treatment of advanced or metastatic ICC. These findings also support the notion that cryoa...