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Toripalimab plus bevacizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HEPATORCH): a randomised, open-label, phase 3 trial

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机构： [1]Zhongshan Hospital, Fudan University, Shanghai, China. [2]Xi'an International Medical Center Hospital of Digestive Diseases, Xi'an, China. [3]Shandong Cancer Hospital, Jinan, China. [4]Anhui Provincial Hospital, Hefei, China. [5]Jilin Cancer Hospital, Changchun, China. [6]Sichuan Cancer Hospital, Chengdu, China. [7]Liaoning Cancer Hospital and Institute, Shenyang, China. [8]West China Hospital, Sichuan University, Chengdu, China. [9]The Second Affiliated Hospital of Nanchang University, Nanchang, China. [10]Hunan Cancer Hospital, Changsha, China. [11]Harbin Medical University Cancer Hospital, Harbin, China. [12]First Affiliated Hospital of Gannan Medical University, Ganzhou, China. [13]Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [14]The Southwest Hospital of Army Medical University, Chongqing, China. [15]Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. [16]Yunnan Cancer Hospital, Kunming, China. [17]Daping Hospital, Army Medical University, Chongqing, China. [18]Peking Union Medical College Hospital, Beijing, China. [19]Xiangya Hospital Central South University, Changsha, China. [20]The First Affiliated Hospital of Bengbu Medical University, Bengbu, China. [21]The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. [22]Shulan (Hangzhou) Hospital, Hangzhou, China. [23]Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. [24]Southern Medical University Nanfang Hospital, Guangzhou, China. [25]Zhongnan Hospital of Wuhan University, Wuhan, China. [26]Nantong Tumor Hospital, Nantong, China. [27]The Second Hospital of Anhui Medical University, Hefei, China. [28]Jilin Guowen Hospital, Changchun, China. [29]Hainan General Hospital, Haikou, China. [30]Yuebei People's Hospital, Shaoguan, China. [31]Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. [32]Changhua Christian Hospital, Changhua, China. [33]Hubei Cancer Hospital, Wuhan, China. [34]Anhui Provincial Cancer Hospital, Hefei, China. [35]Chinese People's Liberation Army General Hospital, Beijing, China. [36]Zhejiang Provincial People's Hospital, Hangzhou, China. [37]The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [38]Zhejiang Cancer Hospital, Hangzhou, China. [39]Mackay Memorial Hospital, Taibei, China. [40]The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [41]The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. [42]Sun Yat-sen Memorial Hospital, Guangzhou, China. [43]The First Affiliated Hospital of Nanchang University, Nanchang, China. [44]Tan Tock Seng Hospital, Singapore. [45]Henan Cancer Hospital, Zhengzhou, China. [46]Gansu Wuwei Tumour Hospital, Wuwei, China. [47]The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [48]The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [49]National Cancer Center and Curie Oncology, Singapore. [50]The First Hospital of Lanzhou University, Lanzhou, China. [51]The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. [52]Kaohsiung Medical University Chung Ho Memorial Hospital, Taiwan, China. [53]Beijing Cancer Hospital, Beijing, China. [54]The Affiliated Hospital of Qingdao University, Qingdao, China. [55]The First People's Hospital of Foshan, Foshan, China. [56]Shanghai Junshi Biosciences, Shanghai, China. [57]Zhongshan Hospital, Fudan University, Shanghai, China.

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Although several PD-1 or PD-L1 inhibitors combined with antiangiogenic agents have been approved as first-line treatment of advanced hepatocellular carcinoma, treatment needs remain unmet given the high incidence and mortality of hepatocellular carcinoma and due to factors such as regional approval status, medical insurance restrictions, and cost considerations. In this phase 3 HEPATORCH study, we aimed to compare the efficacy and safety of toripalimab plus bevacizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma.We did a randomised, open-label, phase 3 study in 57 hospitals across mainland China, Taiwan, and Singapore. Using a central interactive web response system, eligible patients aged 18-75 years with unresectable or metastatic hepatocellular carcinoma were randomly assigned (1:1) through a stratified block randomisation method to receive 240 mg toripalimab (intravenously, once every 3 weeks) plus 15 mg/kg bevacizumab (intravenously, once every 3 weeks) or 400 mg sorafenib (oral, twice daily). Randomisation was stratified by macrovascular invasion or extrahepatic spread (presence vs absence), ECOG performance status score (0 vs 1), and history of locoregional therapy (yes vs no). The co-primary endpoints were progression-free survival (assessed by the Independent Review Committee per Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Efficacy analysis was performed in the intention-to-treat population (ie, all patients randomly assigned to a treatment group). Safety was assessed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT04723004, and is completed.Between Nov 23, 2020, and Jan 21, 2022, 545 patients were screened for study inclusion, of whom 219 did not meet the screening criteria. 326 patients were randomly assigned to receive an intervention: 162 patients were assigned to the toripalimab plus bevacizumab group and 164 were assigned to the sorafenib group, with median age 58·0 years (IQR 50·0-66·0) and 56·0 years (49·0-61·0) years, respectively. All 326 patients were included in the intention-to-treat population and the safety population. 282 (87%) patients were male and 44 (14%) were female. At the primary analysis of progression-free survival (data cutoff Aug 10, 2022), median follow-up was 9·4 months (IQR 7·0-12·0). Toripalimab plus bevacizumab significantly prolonged progression-free survival compared with sorafenib (median 5·8 months [95% CI 4·6-7·2] vs 4·0 months [2·8-4·2]; hazard ratio [HR] 0·69 [95% CI 0·53-0·91; p=0·0086). At the final analysis of overall survival (May 31, 2024), median follow-up was 16·4 months (IQR 7·1-29·5). Toripalimab plus bevacizumab significantly improved overall survival compared with sorafenib (median 20·0 months [95% CI 15·3-23·4] vs 14·5 months [11·4-18·8]; HR 0·76 [95% CI 0·58-0·99; p=0·039). Grade 3 or higher adverse events occurred in 102 (63%) patients in the toripalimab plus bevacizumab group compared with 100 (61%) in the sorafenib group, and led to discontinuation of treatment in 21 (13·0%) participants in the toripalimab plus bevacizumab group and 20 (12%) participants in the sorafenib group. The incidence of treatment-related fatal adverse events (two [1%] vs one [1%]) was similar between the toripalimab plus bevacizumab and sorafenib groups. The most common (incidence ≥5% in the toripalimab plus bevacizumab group) grade 3-4 adverse events were hypertension (26 [16%] in the toripalimab plus bevacizumab group vs 19 [12%] in the sorafenib group), thrombocytopenia (16 [10%] vs four [2%]), upper gastrointestinal haemorrhage (ten [6%] vs one [1%]), anaemia (nine [6%] vs seven [4%]), and abnormal hepatic function (nine [6%] vs five [3%]). The most common (incidence ≥2% in the toripalimab plus bevacizumab group) serious adverse events were upper gastrointestinal haemorrhage (12 [7%] vs one [1%]), abnormal hepatic function (eight [5%] vs five [3%]), ascites (six [4%] vs three [2%]), and gastrointestinal haemorrhage (four [2%] vs three [2%]).Among patients with previously untreated advanced hepatocellular carcinoma, toripalimab plus bevacizumab resulted in significantly longer progression-free survival and overall survival than did sorafenib, with an acceptable safety profile. Based on these results, the regimen has been approved for use in China by the National Medical Products Administration.Shanghai Junshi Biosciences.For the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

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医学

小类 | 1 区胃肠肝病学

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第一作者机构： [1]Zhongshan Hospital, Fudan University, Shanghai, China.

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