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

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: Perioperative camrelizumab plus rivoceranib significantly improved EFS compared with surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence.

Funding: Shanghai Hospital Development Center and Jiangsu Hengrui Pharmaceuticals.