Liver and Bile
Lancet. 2023;402(10408):1133-1146
Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): A randomized, open-label, international phase 3 study
Background: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumors, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.
Methods: This randomized, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomization was done via a centralized interactive response system. The primary end points 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 in the intention-to-treat population. Safety was assessed in all patients who received at least 1 dose of the study drugs. The authors report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival.
Findings: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n = 272) or the sorafenib (n = 271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7.8 months (interquartile range [IQR], 4.1–10.6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5.6 months [95% confidence interval {CI}: 5.5–6.3] vs. 3.7 months [95% CI: 2.8–3.7]; hazard ratio [HR] = 0.52 [95% CI: 0.41–0.65]; 1-sided p < 0.0001). At the interim analysis for overall survival (February 8, 2022), median follow-up was 14.5 months (IQR, 9.1–18.7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22.1 months [95% CI: 19.1–27.2] vs. 15.2 months [95% CI: 13.0–18.5]; HR = 0.62 [95% CI: 0.49–0.80]; 1-sided p < 0.0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102/272 patients [38%] in the camrelizumab-rivoceranib group vs. 40/269 patients [15%] in the sorafenib group), palmar-plantar erythrodysesthesia syndrome (33 [12%] vs. 41 [15%]), increased aspartate aminotransferase (45 [17%] vs. 14 [5%]), and increased alanine aminotransferase (35 [13%] vs. 8 [3%]). Treatment-related serious adverse events were reported in 66 patients (24%) in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in 2 patients: 1 patient in the camrelizumab-rivoceranib group (i.e., multiple organ dysfunction syndrome) and 1 patient in the sorafenib group (i.e., respiratory failure and circulatory collapse).
Interpretation: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population.