Zhenggang Ren1, Jianming Xu2, Yuxian Bai3, Aibing Xu4, Shundong Cang5, Chengyou Du6, Qiu Li7, Yinying Lu8, Yajin Chen9, Yabing Guo10, Zhendong Chen11, Baorui Liu12, Weidong Jia13, Jian Wu14, Junye Wang15, Guoliang Shao16, Bixiang Zhang17, Yunfeng Shan18, Zhiqiang Meng19, Jianbing Wu20, Shanzhi Gu21, Wei Yang22, Chao Liu23, Xuetao Shi24, Zhenyuan Gao25, Tao Yin26, Jiuwei Cui27, Ming Huang28, Baocai Xing29, Yilei Mao30, Gaojun Teng31, Yanru Qin32, Jinhai Wang33, Feng Xia34, Guowen Yin35, Yong Yang36, Mingxia Chen37, Yan Wang36, Hui Zhou36, Jia Fan38. 1. Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. 2. Digestive Oncology Department, The Fifth Medical Centre of PLA General Hospital, Beijing, China. 3. Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, China. 4. Department of Oncological Internal Medicine, Nantong Tumour Hospital, Nantong, China. 5. Department of Internal Medicine-Oncology, Henan Provincial People's Hospital, Zhengzhou, China. 6. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 7. Abdominal Tumour Department, West China Hospital, Sichuan University, Chengdu, China. 8. Treatment and Research Centre for Liver Cancer Department 2, The Fifth Medical Centre of PLA General Hospital, Beijing, China. 9. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 10. Department of Tumours of Liver, Nan Fang Hospital, Guangzhou, China. 11. Oncology Department, The Second Hospital of Anhui Medical University, Hefei, China. 12. Department of Oncology, Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 13. General Surgery Department, Anhui Provincial Hospital, Hefei, China. 14. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China. 15. Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, China. 16. Department of Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou, China. 17. Department of Hepatobiliary Surgery, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. 18. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 19. Department of Traditional Chinese Medicine/Integrative Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China. 20. Oncology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, China. 21. Radioactive Interventional Department, Hunan Cancer Hospital, Changsha, China. 22. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China. 23. Department of Pancreaticobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 24. Department of Hepatobiliary Surgery, Shandong Cancer Hospital, Jinan, China. 25. Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China. 26. Department of Hepatobiliary Surgery, Hubei Cancer Hospital, Wuhan, China. 27. Oncology Department, Bethune First Hospital of Jilin University, Changchun, China. 28. Department of Minimally Invasive Interventional Medicine, Yunnan Cancer Hospital, Kunming, China. 29. Hepatobiliary Pancreatic Surgery 1, Beijing Cancer Hospital, Beijing, China. 30. Live Surgery Ward, Peking Union Medical College Hospital, Beijing, China. 31. Radiology Department, Zhongda Hospital Southeast University, Nanjing, China. 32. Department of Internal Medicine Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 33. Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China. 34. Department of Hepatobiliary Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China. 35. Intervention Department, Jiangsu Cancer Hospital, Nanjing, China. 36. Department of Medical Science and Strategy Oncology, Innovent Biologics, Suzhou, China. 37. Department of Biostatistics and Information, Innovent Biologics, Suzhou, China. 38. Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. Electronic address: fan.jia@zs-hospital.sh.cn.
Abstract
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 α-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 25·0% (95% CI 9·8-46·7). 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 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). 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 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). 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. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
RCT Entities:
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 α-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 25·0% (95% CI 9·8-46·7). 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 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). 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 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). 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. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.