Association of week-2 Contrast-Enhanced Ultrasound Perfusion Changes with Response to Lenvatinib Plus PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma: A Retrospective Exploratory Study.

BACKGROUND: To explore whether early contrast-enhanced ultrasound (CEUS)-derived tumor perfusion changes were associated with subsequent response to Lenvatinib plus PD-1 inhibitors in unresectable hepatocellular carcinoma (HCC). METHODS: This study included 74 patients with unresectable HCC treated with Lenvatinib plus PD-1 inhibitors in routine clinical practice retrospectively. Baseline and early on-treatment CEUS examinations at approximately 2 weeks after treatment initiation were analyzed to quantify tumor perfusion parameters. Objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were study endpoints. Associations between CEUS findings and treatment outcomes were analyzed. RESULTS: ORR of Lenvatinib plus PD-1 inhibitors among 74 patients with HCC was 33.8% (95% CI: 23.2-45.7%) and DCR was 73.0% (95% CI: 61.4-82.6%). Median DoR among the 25 responders was 8.7 months (95% CI: 7.39-10.01 months). After a median follow-up duration of 21.1 months, median PFS was 6.9 months (95% CI: 4.33-9.47 months) and median OS was 21.3 months (95% CI: 14.70-27.90 months). CEUS perfusion analysis showed that baseline tumor enhancement did not significantly differ between eventual responders and non-responders. In contrast, week-2 CEUS-derived perfusion changes, particularly percentage reduction in AUC, were associated with subsequent radiologic response. Using an exploratory cutoff of ≥35% AUC reduction, patients above this threshold showed longer PFS and OS than those below the threshold. These associations remained exploratory because the threshold was derived within a limited retrospective cohort. Treatment was generally well tolerated, no unexpected adverse events occurred, and there were no treatment-related deaths in this cohort. CONCLUSION: In this single-center retrospective exploratory cohort, week-2 CEUS-derived AUC reduction was associated with subsequent radiological response and survival outcomes in patients with unresectable HCC receiving Lenvatinib plus PD-1 inhibitors. These findings should be interpreted as hypothesis-generating and require prospective validation before CEUS-based perfusion changes can be used for clinical decision-making.