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

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.

在这项III期HEPATORCH研究中，我们旨在比较toripalimab联合bevacizumab与索拉非尼在先前未经治疗的晚期肝细胞癌患者中的疗效和安全性。

Methods

We did a randomised, open-label, phase 3 study in 57 hospitals across mainland China, Taiwan, and Singapore.

我们在大陆、台湾和新加坡的57家医院开展了一项随机、开放标签、第三阶段研究。

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).

通过中央互动网络响应系统，年龄在18-75岁之间、患有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（1:1）被随机分配接受240毫克的托瑞利单抗（静脉注射，每3周一次）加15毫克/公斤贝伐单抗（静脉注射，每3周一次）或400毫克的索拉非尼（口服，每日两次）。

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).

随机分组根据大血管侵犯或肝外扩散（存在与否）、ECOG表现状态评分（0 vs 1）以及局部区域治疗史（有与否）进行分层。

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-treatpopulation (ie, all patients randomly assigned to a treatment group).

共同主要终点是无进展生存期（由独立评审委员会根据实体瘤反应评估标准第1.1版评估）和总生存期。疗效分析在意向治疗人群中进行（即，所有被随机分配到治疗组的患者）。

Safety was assessed in all patients who received at least one dose of study treatment.

所有接受至少一次研究治疗的患者均进行了安全性评估。

The study is registered with ClinicalTrials.gov, NCT04723004, and is completed.

该研究已在ClinicalTrials.gov注册，注册号为NCT04723004，并已完成。

Results

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.

在2020年11月23日至2022年1月21日期间，共有545名患者被筛查以纳入研究，其中219名患者未满足筛查标准。326名患者被随机分配接受干预：162名患者被分配至toripalimab联合bevacizumab组，另外164名被分配至sorafenib组，中位年龄分别为58.0岁（四分位数间距50.0-66.0岁）和56.0岁（四分位数间距49.0-61.0岁）。

All 326 patients were included in the intention-to-treatpopulation and the safety population. 282 (87%) patients were male and 44 (14%) were female.

所有326名患者均被纳入意向治疗人群和安全性人群。其中282名（87%）为男性，44名（14%）为女性。

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).

在主要的无进展生存期分析中（数据截止日期为2022年8月10日），中位随访时间为9.4个月（四分位数间距7.0-12.0个月）。

Toripalimab plus bevacizumab significantly prolonged progression-free survivalcompared 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).

托珠单抗联合贝伐珠单抗显著延长了无进展生存期，与索拉非尼相比（中位数5.8个月 [95% CI 4.6-7.2] 对比 4.0个月 [2.8-4.2]；风险比 [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).

在总生存期的最终分析中（截至2024年5月31日），中位随访时间为16.4个月（四分位数间距7.1-29.5个月）。

Toripalimab plus bevacizumab significantly improved overall survivalcompared 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).

托珠单抗联合贝伐珠单抗显著改善了总生存期，与索拉非尼相比（中位生存期20.0个月 [95% 置信区间 15.3-23.4] 对比 14.5个月 [11.4-18.8]；风险比0.76 [95% 置信区间 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.

在托珠单抗联合贝伐珠单抗组中，有102名（63%）患者出现3级或更高级别的不良事件，而在索拉非尼组中有100名（61%）患者出现此类不良事件，导致托珠单抗联合贝伐珠单抗组中有21名（13.0%）参与者和索拉非尼组中有20名（12%）参与者停药。

The incidenceof treatment-related fatal adverse events (two [1%] vs one [1%]) was similar between the toripalimab plus bevacizumab and sorafenib groups.

托珠单抗联合贝伐珠单抗组和索拉非尼组之间治疗相关致命不良事件的发生率相似（分别为两例[1%]对比一例[1%]）。

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%]).

在托瑞利珠单抗联合贝伐珠单抗组中，发生率≥5%的最常见3-4级不良事件包括高血压（托瑞利珠单抗联合贝伐珠单抗组26例[16%]，索拉非尼组19例[12%]）、血小板减少症（16例[10%]对比4例[2%]）、上消化道出血（10例[6%]对比1例[1%]）、贫血（9例[6%]对比7例[4%]）和肝功能异常（9例[6%]对比5例[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%]).

在托瑞利珠单抗联合贝伐珠单抗组中，发生率≥2%的最常见严重不良事件包括上消化道出血（12例[7%]对比1例[1%]）、肝功能异常（8例[5%]对比5例[3%]）、腹水（6例[4%]对比3例[2%]）和胃肠道出血（4例[2%]对比3例[2%]）。

interpretation

Among patients with previously untreated advanced hepatocellular carcinoma, toripalimab plus bevacizumab resulted in significantly longer progression-free survivaland overall survivalthan did sorafenib, with an acceptable safety profile.

在先前未经治疗的晚期肝细胞癌患者中，托瑞利珠单抗联合贝伐珠单抗相较于索拉非尼，显著延长了无进展生存期和总生存期，并具有可接受的安全性特征。

Based on these results, the regimen has been approved for use in China by the National Medical Products Administration.

基于这些结果，该方案已获得中国国家药品监督管理局的批准用于临床应用。

funding

Shanghai Junshi Biosciences.

上海君实生物科技股份有限公司。

translation

For the Chinese translation of the abstract see Supplementary Materials section.

摘要的中文翻译请参见补充材料部分。