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, camrelizumab plus apatinib, and toripalimab plus axitinib demonstrated potent antitumor effects in multiple types of cancers.
“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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Self-citationBreakthroughs in Hepatocellular Carcinoma Therapies
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Self-citationGlypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma
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“pembrolizumab or sintilimab combined with bevacizumab showed similar results (12, 13).”
ResultRecent advances in the management of hepatocellular carcinoma
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Self-citationImmune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice
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InfluentialImmune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy
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“This trial met its primary endpoint, showing that the combination provided better OS than sorafenib did (HR 0.57, 95% CI 0.43 – 0.75; p < 0.0001) [368].”
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“For example, combining ICIs and angiogenesis inhibitors incurred more serious adverse events than using angiogenesis inhibitors alone, such as high-grade hypertension, decreased platelet count, and proteinuria, and there were more bleeding events in the combined group leading to the withdrawal of treatment than angiog…”
BackgroundMethodInfluentialHepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy
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“6) 11 ORIENT-32 (54) Sintilimab, bevacizumab biosimilar (380) NR (NR-NR) 0.”
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“superiority to sorafenib when combined with the anti-PD-1 sintilimab [51].”
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“A subsequent phase III confirmatory study made clear that Sin/Bev greatly improved median OS and PFS in comparison to sorafenib [110].”
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“Similarly, the anti-PD-1 antibody sintilimab combined with a bevacizumab biosimilar (IBI305) has been reported to improve OS in Chinese patients with advanced-stage hepatitis B virus (HBV)-associated HCC relative to sorafenib [134].”
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“…atezolizumab (anti-PD-L1 antibody) and bevacizumab (anti-angiogenesis agent), the IMbrave150 study, and the combination of sintilimab (anti-PD-1 antibody) and a bevacizumab biosimilar, the ORIENT-32 trial, have successfully outper-formed sorafenib as the first-line therapy in advanced HCC [9, 10].”
BackgroundSelf-citationVerset, G., Borbath, I., Karwal, M., Verslype, C., Vlierberghe, H. V., Kardosh, A., Zagonel, V., Stal, P. I., Sarker, D., Palmer, D. H., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-3807 · Cited by 92 · see citing works
“…the ORIENT-32 study also demonstrated improved progression-free survival (PFS) and overall survival (OS) bene fi tswithsintilimab (aprogrammed death 1inhibitor)plusIBI305, a bevacizumab biosimilar, versus sorafenib as a fi rst-line treatment for unresectable hepatitis B virus – associated HCC (9).”
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“…2–3 clinical trials (ZGDH3, ORIENT-32, CARES-310 and Rationale-301) which led to the approval of donafenib, sintilimab plus bevacizumab biosimilar IBI305, camrelizumab plus rivoceranib and tislelizumab for uHCC, by the National Medical Products Administration (NMPA), China (Table 3) [18, 21–23].”
Self-citationClinically approved combination immunotherapy: Current status, limitations, and future perspective
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“The anti-PD-1 antibodies used in this study included pembrolizumab (200 mg q3w), nivolumab (3 mg/kg q2w), camrelizumab (200 mg q2w),(12) toripalimab (240 mg q3w), and sintilimab (200 mg q3w).(13) Because the preliminary efficacy and safety data for the lenvatinib/pembrolizumab combination was encouraging,(14) lenvatin…”
BackgroundSelf-citationRole of Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma
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Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges
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“Based on the ORIENT-32 trial, the National Medical Products Administration (NMPA) approved Sintilimab–IBI305 as a first-line treatment option in Chinese HCC patients [57].”
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Self-citationSystemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook
Fan, Y., Xue, H., & Zheng, H. (2022) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s358082 · Cited by 63 · see citing works
“The phase II/III ORIENT-32 trial conferred the combination of sintilimab (anti-PD-L1) and bevacizumab as the first-line treatment for unresectable HCC because this combination exhibited a better survival benefit than sorafenib.(23) In addition to the synergistic antitumor effect of anti-angiogenic therapy and immunoth…”
BackgroundAdvances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma
Chen, Y., Hu, H., Yuan, X., Fan, X., & Zhang, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.896752 · Cited by 61 · see citing works
Self-citationArterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations
Zhao, M. D., Guo, Z., Zou, Y., Li, X., Yan, Z.-P., Chen, M., Fan, W., Li, H.-L., Yang, J., Chen, X., et al. (2023) · Hepatology International · doi:10.1007/s12072-023-10599-6 · Cited by 61 · see citing works
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“Atezolizumab plus bevacizumab was approved as the first first-line combination therapy of unresectable HCC with positive results in the IMbrave150 trial [19], and other PD-1 inhibitors combined with TKIs, such as sintilimab plus bevacizumab biosimilar [20], pembrolizumab plus lenvatinib [21], camrelizumab plus apatini…”
ResultZhu, M., Liu, Z.-L., Chen, S., Luo, Z., Tu, J., Qiao, L., Wu, J., Fan, W., & Peng, Z. (2024) · Hepatology · doi:10.1097/hep.0000000000000776 · Cited by 60 · see citing works
“[3] The triple combination treatment of sintilimab, bevacizumab, and radiotherapy in this trial was expected to improve the ORR to 40%.”
Self-citationFulgenzi, C. A. M., D’Alessio, A., Airoldi, C. A., Scotti, L., Demirtaş, C. Ö., Gennari, A., Cortellini, A., & Pinato, D. J. (2022) · European Journal of Cancer · doi:10.1016/j.ejca.2022.06.058 · Cited by 60 · see citing works
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“(6) reported an ORR of 21% and a median progression-free survival (mPFS) of 4.”
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Self-citationImmunotherapy for hepatocellular carcinoma
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“Sintilimab+IBI305 (54) ORIENT 32 380 – 4.”
Ju, S., Zhou, C., Yang, C., Wang, C., Liu, J., Wang, Y., Huang, S., Li, T., Chen, Y., Bai, Y., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.835889 · Cited by 56 · see citing works
“Poor liver function and hepatitis B-associated HCC might have a poor prognosis after tumor treatment (27).”
BackgroundResultSelf-citationWu, H., Zheng, X., Pan, T., Yang, X., Chen, X., Zhang, B., Peng, L., & Xie, C. (2022) · International Journal of Cancer · doi:10.1002/ijc.34118 · Cited by 57 · see citing works
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“1) [55, 56], further validating VEGF blockade as a platform for ICIs efficacy across PD-1/ PD-L1 pathways.”
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“1 7 In particular, the prognoses of patients with HCC at the same clinical stage have been remarkably different, making it challenging to predict the outcomes.”
BackgroundSelf-citationXin, Y., Cao, F., Yang, H., Zhang, X., Chen, Y., Cao, X., Zhou, X., Li, X., & Zhou, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.929141 · Cited by 54 · see citing works
Self-citationFulgenzi, C. A. M., Scheiner, B., Korolewicz, J., Stikas, C., Gennari, A., Vincenzi, B., Openshaw, M. R., Silletta, M., Pinter, M., Cortellini, A., et al. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100702 · Cited by 54 · see citing works
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“Similar to the results of two extensive phase III studies, IMbrave150 and ORIENT-32 (15, 46), our findings reconfirmed the effectiveness of ICIs plus anti-VEGF antibody for the treatment of patients with advanced HCC.”
ResultSelf-citationYu, S. S., Yu, M., Keane, B., Mauro, D. M., Helft, P. R., Harris, W. P., Sanoff, H. K., Johnson, M. S., O’Neil, B. H., McRee, A. J., et al. (2024) · The Oncologist · doi:10.1093/oncolo/oyad331 · Cited by 54 · see citing works
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Self-citation
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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