Author information
1Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine and Nanjing Medical University, Nanjing, China. Electronic address: qinsk@csco.org.cn.
2State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
3Department of Interventional Radiology, Hunan Cancer Hospital, Changsha, China.
4Department of Gastroenterology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China.
5Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
6Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China.
7Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
8Department of General Surgery, Anhui Provincial Hospital, Hefei, China.
9Sichuan Cancer Hospital and Institute, Sichuan Cancer Centre, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
10Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Liver Cancer Centre, Guangzhou, China.
11Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
12Department of Integrative Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China.
13Department of Medical Oncology, Peking University International Hospital, Beijing, China.
14Department of Thoracic Oncology, Jilin Cancer Hospital, Jilin, China.
15Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
16Department for Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University and Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.
17Department of Hepatology, The Sixth People's Hospital of Shenyang, Shenyang, China.
18Cancer Centre, The First Hospital of Jilin University, Jilin, China.
19Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
20Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China.
21Department of Antitumor Drug Therapy, Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan, Ufa, Russia.
22Department of Infecious Disease and Hepatology, Wroclaw Medical University, Centrum Badan Klinicznych Piotr Napora, Wroclaw, Poland.
23Department of Liver and Pancreas Gland Oncosurgery, Regional Centre of Oncology, Kharkiv, Ukraine.
24Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy.
25Department of Chemotherapy, State Budgetary Institution of Healthcare Regional Oncology Dispensary, Irkutsk, Russia.
26Department of Surgery, Communal Non-commercial Enterprise Odesa Regional Clinical Hospital of Odesa Regional Council, Odesa, Ukraine.
27Department of Chemotherapy, The Municipal Enterprise Volyn Regional Medical Oncology Centre of the Volyn Regional Council, Lutsk, Ukraine.
28Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Medical Foundation Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
29Jiangsu Hengrui Pharmaceuticals, Shanghai, China.
30Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
31Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Centre, Houston, Texas, USA.
32Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
DOI: 10.1016/S0140-6736(23)00961-3
Abstract
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 tumours, 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 randomised, 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. Randomisation was done via a centralised interactive response system. 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 in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293).
Findings: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 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 [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [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 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, 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.
Funding: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.