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

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⁺PD1^hi 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⁺PD1^hi 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 cryoablation may trigger abscopal antitumor immunity in ICC when combined with lenvatinib and PD1 blockade. ClinicalTrials.gov registration: NCT05010668 .