Perioperative camrelizumab plus rivoceranib versus surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence (CARES-009): a randomised phase 2/3 trial.

Abstract

Surgical resection is the preferred curative approach for patients with early-stage hepatocellular carcinoma, but recurrence remains a major challenge. Consequently, neoadjuvant and adjuvant therapies have been proposed to reduce tumour burden and mitigate the risk of recurrence. The CARES-009 trial aimed to evaluate perioperative camrelizumab plus rivoceranib in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence. This multicentre, open-label, randomised, phase 2/3 trial enrolled patients with hepatocellular carcinoma classified as China Liver Cancer Staging (CNLC) stage Ib-IIIa without Vp4 portal vein tumour thrombosis (corresponding to Barcelona Clinic Liver Cancer stage A with tumour >5 cm, stage B, or stage C without Vp4 involvement or extrahepatic metastasis) at 16 hospitals in China. Patients were randomly assigned (1:1) to receive perioperative therapy or surgery alone and were stratified by CNLC stage and hepatitis B virus (HBV) infection status. The perioperative group received two cycles of neoadjuvant camrelizumab plus rivoceranib, followed by surgery and adjuvant camrelizumab plus rivoceranib. The primary endpoint was event-free survival (EFS) and was assessed by investigators (who were not masked to group assignment) in the intention-to-treat population. Safety was evaluated in the as-treated population. This trial is registered with ClinicalTrials.gov (NCT04521153) and is ongoing. Between March 25, 2021, and Jan 29, 2024, 294 patients (87% male; 99% Han Chinese) were randomly assigned to the perioperative group (n=148) or surgery alone group (n=146). At a prespecified interim analysis, with a median follow-up of 21·3 months, median EFS was 42·1 months (95% CI 23·2-not estimable [NE]) in the perioperative group versus 19·4 months (14·9-NE) in the surgery alone group (hazard ratio 0·59, 95% CI 0·41-0·85; p=0·0040). Grade 3 or worse treatment-related adverse events occurred in 53 (38%) patients in the perioperative group and no patients in the surgery alone group. Two treatment-related deaths occurred during neoadjuvant therapy in the perioperative group: one due to hepatic failure, assessed as possibly related to treatment, and one due to combined hepatic and renal failure, with the causality deemed indeterminate. Perioperative camrelizumab plus rivoceranib significantly improved EFS compared with surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence. Shanghai Hospital Development Center and Jiangsu Hengrui Pharmaceuticals.