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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., Competing Interests: Declaration of interests SLC reports honoraria from AstraZeneca, Eisai, Merck Sharp & Dohme, Roche, and Bayer; consulting or advisory roles for AstraZeneca, Eisai, Merck Sharp & Dohme, Bristol Myers Squibb, and Roche; and research funding from Eisai and Ipsen. A-LC reports consulting or advisory roles for Merck Sharp & Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, IPSEN Innovation, BeiGene, and EXE; speaker's bureau for Ono Pharmaceutical, Bayer Yakuhin, Novartis, Amgen Taiwan, and Chugai Pharmaceutical; expert testimony for Merck Sharp & Dohme, Ono Pharmaceutical, Eisai, and IPSEN Innovation; and participation on an advisory board for Abbisko Therapeutics. AV reports personal fees from AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, Bristol Myers Squibb, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, Merck Sharp & Dohme, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo, Jiangsu Hengrui Pharmaceuticals, GSK, and Imaging Equipment (Advanced Accelerator Applications). XLia, CC, and LW were employees of Jiangsu Hengrui Pharmaceuticals at the time of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)