"Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study"

作者全名："Ren, Zhenggang; Xu, Jianming; Bai, Yuxian; Xu, Aibing; Cang, Shundong; Du, Chengyou; Li, Qiu; Lu, Yinying; Chen, Yajin; Guo, Yabing; Chen, Zhendong; Liu, Baorui; Jia, Weidong; Wu, Jian; Wang, Junye; Shao, Guoliang; Zhang, Bixiang; Shan, Yunfeng; Meng, Zhiqiang; Wu, Jianbing; Gu, Shanzhi; Yang, Wei; Liu, Chao; Shi, Xuetao; Gao, Zhenyuan; Yin, Tao; Cui, Jiuwei; Huang, Ming; Xing, Baocai; Mao, Yilei; Teng, Gaojun; Qin, Yanru; Wang, Jinhai; Xia, Feng; Yin, Guowen; Yang, Yong; Chen, Mingxia; Wang, Yan; Zhou, Hui; Fan, Jia"

作者地址："[Ren, Zhenggang] Fudan Univ, Liver Canc Inst, Zhongshan Hosp, Dept Hepat Oncol, Shanghai, Peoples R China; [Fan, Jia] Fudan Univ, Liver Canc Inst, Zhongshan Hosp, Dept Liver Surg & Transplantat, Shanghai 200030, Peoples R China; [Ren, Zhenggang; Fan, Jia] Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China; [Xu, Jianming] Peoples Liberat Army Gen Hosp, Med Ctr 5, Digest Oncol Dept, Beijing, Peoples R China; [Lu, Yinying] Peoples Liberat Army Gen Hosp, Med Ctr 5, Treatment & Res Ctr, Liver Canc Dept 2, Beijing, Peoples R China; [Bai, Yuxian] Harbin Med Univ, Dept Internal Med, Canc Hosp, Harbin, Peoples R China; [Xu, Aibing] Nantong Tumour Hosp, Dept Oncol Internal Med, Nantong, Peoples R China; [Cang, Shundong] Henan Prov Peoples Hosp, Dept Internal Med Oncol, Zhengzhou, Peoples R China; [Du, Chengyou] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Li, Qiu] Sichuan Univ, West China Hosp, Abdominal Tumour Dept, Chengdu, Peoples R China; [Chen, Yajin] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Hepatobiliary Surg, Guangzhou, Peoples R China; [Liu, Chao] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Pancreaticobiliary Surg, Guangzhou, Peoples R China; [Guo, Yabing] Nan Fang Hosp, Dept Tumours Liver, Guangzhou, Peoples R China; [Chen, Zhendong] Anhui Med Univ, Hosp 2, Oncol Dept, Hefei, Peoples R China; [Liu, Baorui] Nanjing Univ, Dept Oncol, Nanjing Drum Tower Hosp, Med Sch, Nanjing, Peoples R China; [Jia, Weidong] Anhui Prov Hosp, Gen Surg Dept, Hefei, Peoples R China; [Wu, Jian] Zhejiang Univ, Affiliated Hosp 1, Dept Hepatobiliary & Pancreat Surg, Hangzhou, Peoples R China; [Wang, Junye] Jining Med Univ, Dept Oncol, Affiliated Hosp, Jining, Peoples R China; [Shao, Guoliang] Zhejiang Canc Hosp, Dept Intervent Therapy, Hangzhou, Peoples R China; [Zhang, Bixiang] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Hepatobiliary Surg, Wuhan, Peoples R China; [Shan, Yunfeng] Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Wenzhou, Peoples R China; [Meng, Zhiqiang] Fudan Univ, Shanghai Canc Ctr, Dept Tradit Chinese Med Integrat Oncol, Shanghai, Peoples R China; [Wu, Jianbing] Nanchang Univ, Oncol Dept, Affiliated Hosp 2, Nanchang, Jiangxi, Peoples R China; [Gu, Shanzhi] Hunan Canc Hosp, Radioact Intervent Dept, Changsha, Peoples R China; [Yang, Wei] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Xian, Peoples R China; [Shi, Xuetao] Shandong Canc Hosp, Dept Hepatobiliary Surg, Jinan, Peoples R China; [Gao, Zhenyuan] Bengbu Med Coll, Affiliated Hosp 1, Med Oncol, Bengbu, Peoples R China; [Yin, Tao] Hubei Canc Hosp, Dept Hepatobiliary Surg, Wuhan, Peoples R China; [Cui, Jiuwei] Jilin Univ, Bethune Hosp 1, Oncol Dept, Changchun, Peoples R China; [Huang, Ming] Yunnan Canc Hosp, Dept Minimally Invas Intervent Med, Kunming, Yunnan, Peoples R China; [Xing, Baocai] Beijing Canc Hosp, Hepatobiliary Pancreat Surg 1, Beijing, Peoples R China; [Mao, Yilei] Peking Union Med Coll Hosp, Live Surg Ward, Beijing, Peoples R China; [Teng, Gaojun] Southeast Univ, Zhongda Hosp, Radiol Dept, Nanjing, Peoples R China; [Qin, Yanru] Zhengzhou Univ, Dept Internal Med Oncol, Affiliated Hosp 1, Zhengzhou, Peoples R China; [Wang, Jinhai] Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Gastroenterol, Xian, Peoples R China; [Xia, Feng] Southwest Hosp, Dept Hepatobiliary Surg, Hosp 1, AMU, Chongqing, Peoples R China; [Yin, Guowen] Jiangsu Canc Hosp, Intervent Dept, Nanjing, Peoples R China; [Yang, Yong; Wang, Yan; Zhou, Hui] Innovent Biol, Dept Med Sci & Strategy Oncol, Suzhou, Peoples R China; [Chen, Mingxia] Innovent Biol, Dept Biostat & Informat, Suzhou, Peoples R China"

通信作者："Fan, J (corresponding author), Fudan Univ, Liver Canc Inst, Zhongshan Hosp, Dept Liver Surg & Transplantat, Shanghai 200030, Peoples R China."

来源：LANCET ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000668269600043

JCR分区：Q1

影响因子：51.1

年份：2021

卷号：22

期号：7

开始页：977

结束页：990

文献类型：Article

关键词：　

摘要："Background China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. Methods This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline alpha-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Findings Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25 & middot;0% (95% CI 9 & middot;8-46 & middot;7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10 & middot;0 months (IQR 8 & middot;5-11 & middot;7) in the sintilimab-bevacizumab biosimilar group and 10 & middot;0 months (8 & middot;4-11 & middot;7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4 & middot;6 months [95% CI 4 & middot;1-5 & middot;7]) than did patients in the sorafenib group (2 & middot;8 months [2 & middot;7-3 & middot;2]; stratified hazard ratio [HR] 0 & middot;56, 95% CI 0 & middot;46-0 & middot;70; p<0 & middot;0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10 & middot;4 months [8 & middot;5-not reached]; HR 0 & middot;57, 95% CI 0 & middot;43-0 & middot;75; p<0 & middot;0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab- bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). Interpretation Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients."

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