In a largely Asian phase III study (CARES-310) reported in The Lancet, Qin et al found that the combination of camrelizumab and rivoceranib (also known as apatinib) significantly prolonged progression-free and overall survival vs sorafenib in the first-line treatment of unresectable or metastatic hepatocellular carcinoma.

The oral tyrosine kinase inhibitor apatinib is approved in China for the treatment of gastric cancer. The same drug by the name of rivoceranib was granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) for adenoid cystic carcinoma in 2021, and a new drug application for the agent was recently accepted by the FDA in the hepatocellular carcinoma setting.

Study Details

In the open-label CARES-310 trial, 543 patients from sites in 13 countries were randomly assigned between June 2019 and March 2021 to receive camrelizumab at 200 mg every 2 weeks plus rivoceranib at 250 mg once daily (n = 272) or sorafenib at 400 mg twice daily (n = 271). Treatment continued until disease progression or unacceptable toxicity.

Approximately 83% of patients in each group were from Asian countries or regions. The primary endpoints were progression-free survival on blinded independent review committee assessment and overall survival in the intention-to-treat population.

Progression-Free and Overall Survival

At primary analysis for progression-free survival, median follow-up was 7.8 months (interquartile range = 4.1–10.6 months). Median progression-free survival was 5.6 months (95% confidence interval [CI] = 5.5–6.3 months) in the combination group vs 3.7 months (95% CI = 2.8–3.7 months) in the sorafenib group (hazard ratio [HR] = 0.52, 95% CI = 0.41–0.65, P < .0001). Hazard ratios were 0.57 (95% CI = 0.46–0.71) among 449 patients from Asian regions and 0.56 (95% CI = 0.33–0.94) among 94 patients from non-Asian regions.

At interim analysis for overall survival, median overall survival was 22.1 months (95% CI = 19.1–27.2 months) in the combination group vs 15.2 months (95% CI = 13.0–18.5 months) in the sorafenib group (HR = 0.62, 95% CI = 0.49–0.80, P < .0001). Hazard ratios were 0.66 (95% CI = 0.51–0.86) among patients from Asian regions and 0.55 (95% CI = 0.29–1.02) among those from non-Asian regions.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 81% of the combination group vs 52% of the sorafenib group. The most common such events in the combination group were hypertension (38% vs 15% in the sorafenib group), increased aspartate aminotransferase (AST; 17% vs 5%), increased alanine aminotransferase (ALT; 13% vs 3%), and palmar-plantar erythrodysesthesia syndrome (12% vs 15%).

Serious treatment-related adverse events occurred in 24% vs 6%; the most common events in the combination group included increased AST, increased bilirubin, upper gastrointestinal hemorrhage, and increased ALT (3% each). Treatment-related death occurred in one patient in the combination group, from multiple organ dysfunction syndrome, and one patient in the sorafenib group, from respiratory failure and circulatory collapse.

The investigators concluded: “Camrelizumab plus rivoceranib [apatinib] 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.”

Shukui Qin, MD, of the Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine and Nanjing Medical University, China, is the corresponding author of The Lancet article.

Disclosure: The study was funded by Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics. For full disclosures of the study authors, visit thelancet.com.