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Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study
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.
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“Combination therapies such as sintilimab plus anlotinib, sintilimab plus IBI305 (bevacizumab biosimilar), camrelizumab plus apatinib, and toripalimab plus axitinib demonstrated potent antitumor effects in multiple types of cancers [22, 114–120].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [119]
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“In addition, in a recent phase III trial, the combination of sintilimab (antiPD1 antibody) plus a bevacizumab-biosimilar agent obtained similar results in China (1,3).”
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“These AEs were consistent with the known safety profiles of tisle and len and the established tolerability of HAIC in advanced HCC. 4,6,19 The modified FOLFOX regimen (oxaliplatin and 5-fluorouracil) used in HAIC could cause myelosuppression, potentially leading to leukopenia and thrombocytopenia.”
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Cirrhosis, portal hypertension and hepatocellular carcinoma: a stage-based approach
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“…therapy is combined with immunotherapy, such as lenvatinib combined with pembrolizumab, bevacizumab combined with atezolizumab, bevacizumab analogs combined with sintilimab, or apatinib combined with camrelizumab, ORRs greater than 20% are observed in the treatment of unresectable HCC [81–83] .”
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“Finally, sintilimab plus a bevacizumab biosimilar (IBI305) was evaluated in the ORIENT-32 trial and met the primary endpoint of improved OS and response versus sorafenib (21).”
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“10 One possible explanation for this discrepancy is that HAIC can deliver stable high concentrations of chemotherapeutic agents directly to the tumor site and can be administered repeatedly, leading to significant tumor shrinkage.”
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InfluentialSelf-citation
Metadata
- Authors
- Ren, Z., Xu, J., Bai, Y., Xu, A., Cang, S., Du, C., Li, Q., Lu, Y., Chen, Y., Guo, Y., Chen, Z., Liu, B., Jia, W., Wu, J., Wang, J., Shao, G., Zhang, B., Shan, Y., Meng, Z., Wu, J., Gu, S., Yang, W., Liu, C., Shi, X., Gao, Z., Yin, T., Cui, J., Huang, M., Xing, B., Mao, Y., Teng, G., Qin, Y., Wang, J., Xia, F., Yin, G., Yang, Y., Chen, M., Wang, Y., Zhou, H., & Fan, J.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Chinese PLA General Hospital (CN)
- Third Affiliated Hospital of Harbin Medical University (CN)
- Nantong University (CN)
- Henan Provincial People's Hospital (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Sichuan University (CN)
- Sun Yat-sen University (CN)
- Nanfang Hospital (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Nanjing Drum Tower Hospital (CN)
- Anhui Provincial Hospital (CN)
- Second Affiliated Hospital of Nanchang University (CN)
- Second Affiliated Hospital of Xi'an Jiaotong University (CN)
- Zhejiang Cancer Hospital (CN)
- Huazhong University of Science and Technology (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Fudan University (CN)
- Hunan Cancer Hospital (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Shandong Tumor Hospital (CN)
- First Affiliated Hospital of Bengbu Medical College (CN)
- Hubei Cancer Hospital (CN)
- First Hospital of Jilin University (CN)
- Peking Union Medical College Hospital (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Southwest Hospital (CN)
- Jiangsu Cancer Hospital (CN)
- Innovent Biologics (China) (CN)
- Corresponding author
- Fan, Jia
- ORCID
- 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
- Gao, Zhenyuan
- Yin, Tao
- Cui, Jiuwei
- Huang, Ming
- Mao, Yilei
- Qin, Yanru
- Wang, Jinhai
- Yin, Guowen
- Yang, Yong
- Chen, Mingxia
- Zhou, Hui
- Fan, Jia
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 22
- Issue
- 7
- Pages
- 977-990
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W3166753505
- Cited by
- 1,124
- References
- 30
- Citations by year
- 2026: 162 · 2025: 241 · 2024: 273 · 2023: 247 · 2022: 178 · 2021: 21
- FWCI
- 100.04
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-08-01)
- Open access
- closed
- Licence
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- sintilimab, bevacizumab biosimilar, sorafenib, hepatocellular carcinoma, PD-1 inhibitors, first-line therapy, unresectable liver cancer, hepatitis B virus, overall survival, progression-free survival, combination immunotherapy, anti-angiogenic therapy, China, safety and tolerability, macrovascular invasion
- MeSH terms
- Bevacizumab, Sorafenib, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, China, Female, Hepatitis B, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Time Factors, Disease Progression, Young Adult, Biosimilar Pharmaceuticals, Antibodies, Monoclonal, Humanized
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