Shi Yinghong, Han Guohong, Zhou Jian, Shi Xuetao, Jia Weidong, Cheng Ying, Jin Yongdong, Hua Xiangdong, Wen Tianfu, Wu Jianbing, Gu Shanzhi, Bai Yuxian, Wang Xiangcai, Zhang Tao, Chen Zhiyu, Zhang Bixiang, Huang Ming, Liu Hongming, Mao Yilei, Zhou Ledu, Wang Rui, Shan Yunfeng, Zhang Wu, Song Tianqiang, Guo Yabing, Zhou Fuxiang, Shao Bingfeng, Zhang Mingjun, Liang Bo, Zheng Jinfang, Zhang Guoping, Shen Jie, Su Weiwen, Zhang Feng, He Yifu, Hu Sheng, Liu Rong, Zhang Chengwu, Shen Shunli, Zeng Hui, Wang Tsang-En, Guo Wenzhi, Shen Yan, Chen Yajin, Li Yong, Samol J, Hu Hongtao, Zhang Wenhua, Du Chengyou, Li Enxiao, Liu Chao, Pin Choo Su, Li Xun, Xu Hao, Huang Jee-Fu, Hao Chunyi, Lv Jing, Wang Wei, Xu Qian, Bai Aobing, Zhang Xiao, Liu Bifeng, Jin Chunlei, Fan Jia
Zhongshan Hospital, Fudan University, Shanghai, China.
Xi'an International Medical Center Hospital of Digestive Diseases, Xi'an, China.
Lancet Gastroenterol Hepatol. 2025 Jul;10(7):658-670. doi: 10.1016/S2468-1253(25)00059-7. Epub 2025 May 20.
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.
尽管几种程序性死亡受体1（PD-1）或程序性死亡配体1（PD-L1）抑制剂联合抗血管生成药物已被批准作为晚期肝细胞癌的一线治疗方案，但鉴于肝细胞癌的高发病率和死亡率，以及区域批准状况、医疗保险限制和成本等因素，治疗需求仍未得到满足。在这项3期HEPATORCH研究中，我们旨在比较托瑞帕利单抗联合贝伐珠单抗与索拉非尼在既往未接受过治疗的晚期肝细胞癌患者中的疗效和安全性。
我们在中国大陆、台湾和新加坡的57家医院进行了一项随机、开放标签的3期研究。使用中央交互式网络响应系统，将年龄在18-75岁、不可切除或转移性肝细胞癌的合格患者通过分层区组随机化方法随机分配（1:1），接受240mg托瑞帕利单抗（静脉注射，每3周一次）加15mg/kg贝伐珠单抗（静脉注射，每3周一次）或400mg索拉非尼（口服，每日两次）。随机化按大血管侵犯或肝外转移（存在与否）、东部肿瘤协作组（ECOG）体能状态评分（0 vs 1）和局部区域治疗史（是与否）进行分层。共同主要终点为无进展生存期（由独立评审委员会根据实体瘤疗效评价标准1.1版进行评估）和总生存期。在意向性治疗人群（即所有随机分配至治疗组的患者）中进行疗效分析。在所有接受至少一剂研究治疗的患者中评估安全性。该研究已在ClinicalTrials.gov注册，注册号为NCT04723004，且已完成。
2020年11月23日至2022年1月21日期间，545例患者被筛查纳入研究，其中219例不符合筛查标准。326例患者被随机分配接受干预：162例患者被分配至托瑞帕利单抗联合贝伐珠单抗组，164例患者被分配至索拉非尼组，中位年龄分别为58.0岁（四分位间距[IQR]50.0-66.0）和56.0岁（49.0-61.0）。所有326例患者均纳入意向性治疗人群和安全性人群。282例（87%）患者为男性，44例（14%）为女性。在无进展生存期的初步分析（数据截止于2022年8月10日）时，中位随访时间为9.4个月（IQR 7.0-12.0）。与索拉非尼相比，托瑞帕利单抗联合贝伐珠单抗显著延长了无进展生存期（中位5.8个月[95%置信区间（CI）4.6-7.2] vs 4.0个月[2.8-4.2]；风险比[HR]0.69[95%CI 0.53-0.91；p=0.0086]）。在总生存期的最终分析（2024年5月31日）时，中位随访时间为16.4个月（IQR 7.1-29.5）。与索拉非尼相比，托瑞帕利单抗联合贝伐珠单抗显著改善了总生存期（中位20.0个月[95%CI 15.3-23.4] vs 14.5个月[11.4-18.8]；HR 0.76[95%CI 0.58-0.99；p=0.039]）。托瑞帕利单抗联合贝伐珠单抗组102例（63%）患者发生3级或更高等级不良事件，索拉非尼组为100例（61%），托瑞帕利单抗联合贝伐珠单抗组21例（13.0%）参与者和索拉非尼组20例（12%）参与者因不良事件导致治疗中断。托瑞帕利单抗联合贝伐珠单抗组与索拉非尼组治疗相关致命不良事件的发生率相似（分别为2例[1%] vs 1例[1%]）。最常见的（托瑞帕利单抗联合贝伐珠单抗组发生率≥5%）3-4级不良事件为高血压（托瑞帕利单抗联合贝伐珠单抗组26例[16%] vs索拉非尼组19例[12%]）、血小板减少（16例[10%] vs 4例[2%]）、上消化道出血（10例[6%] vs 1例[1%]）、贫血（9例[6%] vs 7例[4%]）和肝功能异常（9例[6%] vs 5例[3%]）。最常见的（托瑞帕利单抗联合贝伐珠单抗组发生率≥2%）严重不良事件为上消化道出血（12例[7%] vs 1例[1%]）、肝功能异常（8例[5%] vs 5例[3%]）、腹水（6例[4%] vs 3例[2%]）和消化道出血（4例[2%] vs 3例[2%]）。
在既往未接受过治疗的晚期肝细胞癌患者中，托瑞帕利单抗联合贝伐珠单抗比索拉非尼显著延长了无进展生存期和总生存期，且安全性可接受。基于这些结果，该方案已获国家药品监督管理局批准在中国使用。
上海君实生物科技股份有限公司。
摘要的中文翻译见补充材料部分。
Zotero 插件