Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): final analysis of a randomised, open-label, international, phase 3 study

Abstract

Background: The phase 3 CARES-310 trial showed significant improvements in progression-free survival (primary analysis) and overall survival (interim analysis) with the anti-PD-1 antibody camrelizumab plus the oral vascular endothelial growth factor receptor 2 inhibitor rivoceranib versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Here, we present the final analysis of overall survival, and updated data on progression-free survival, secondary efficacy endpoints, and safety.

Methods: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions. Eligible patients were aged 18 years or older, with unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were randomly assigned (1:1) using a centralised interactive response system to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. The study is complete and was registered with ClinicalTrials.gov, NCT03764293.

Findings: Between June 28, 2019, and March 24, 2021, 543 patients (457 [84%] males; 450 [83%] were Asian) were randomly assigned to receive camrelizumab-rivoceranib (n=272) or sorafenib (n=271). At final analysis on June 14, 2023, the median follow-up was 22·1 months (IQR 11·9-30·3) in the camrelizumab-rivoceranib group and 14·9 months (7·2-28·3) in the sorafenib group. Median overall survival was 23·8 months (95% CI 20·6-27·2) with camrelizumab-rivoceranib and 15·2 months (13·2-18·5) with sorafenib (hazard ratio [HR] 0·64 [95% CI 0·52-0·79]; one-sided p<0·0001). Median progression-free survival was 5·6 months (95% CI 5·5-7·4) with camrelizumab-rivoceranib and 3·7 months (3·1-3·7) with sorafenib (HR 0·54 [0·44-0·67]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (104 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 42 [16%]), increased aspartate aminotransferase (47 [17%] vs 14 [5%]), and increased alanine aminotransferase (38 [14%] vs eight [3%]). Treatment-related serious adverse events were reported in 69 (25%) of 272 patients in the camrelizumab-rivoceranib group and 18 (7%) of 269 patients in the sorafenib group. Treatment-related deaths occurred in one patient each in the camrelizumab-rivoceranib group (multiple organ dysfunction syndrome) and sorafenib group (respiratory failure and circulatory collapse).

Interpretation: At final analysis, camrelizumab plus rivoceranib continued to show clinically meaningful survival improvement compared with sorafenib, with manageable safety. The extended follow-up further confirmed the benefit-to-risk profile of camrelizumab plus rivoceranib, supporting the combination as a new first-line treatment option for unresectable hepatocellular carcinoma.

Funding: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.