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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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“Despite the availability of several treatment modalities for advanced stage HCC, such as transarterial chemotherapy (9), targeted therapy (10), and immunotherapy (11,12), the overall prognosis remains suboptimal.”
BackgroundSelf-citationDeng, L., Sun, Y.-Y., Wang, H., Liao, C., Li, D., Xu, G., & Yang, X. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s443779 · Cited by 9
“7,8 ICIs in combination with antiangiogenic drugs alter the tumor endothelium to enhance drug penetration and immune cell infiltration, which has shown promising prospects.”
BackgroundDong, R., Wang, T., Dong, W., Zhu, H., Liu, Q., Liang, H., Chen, X., Zhang, B., & Zhang, X. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116366 · Cited by 9
Self-citationThe State of Systematic Therapies in Clinic for Hepatobiliary Cancers
Chen, W., Hu, Z., Li, G., Zhang, L., & Li, T. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s454666 · Cited by 10
She, M., Wu, Y., Cheng, M., Feng, S., Li, G., & Rong, H. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1401139 · Cited by 9
Emerging Insights on Immunotherapy in Liver Cancer
Zhang, Y., Zhang, X., Kuang, M., & Yu, J. Q. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0047 · Cited by 9
“Moreover, a phase 2–3 clinical trial assessing sintilimab combined with IBI305 (a bevacizumab analogue) in first-line treatment for hepatitis B virus (HBV)-related HCC in China has been conducted and achieved good results (Ren et al, 2021).”
InfluentialLi, X., Jiang, Z., Wu, Y., Gong, W., Liao, X., & Li, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.935817 · Cited by 9
Chen, K., Luo, C., Ge, D.-X., Wang, K.-L., Luo, Q., Li, Y., You, X., Xiang, B., Li, L., Ma, L., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.946693 · Cited by 9
“In addition, ORIENT-32 study found that sintilimab plus bevacizumab showed a significant mPFS and mOS benefit versus sorafenib for patients with unresectable, HBV-associated HCC (10).”
BackgroundSalani, F., Genovesi, V., Vivaldi, C., Massa, V., Cesario, S., Bernardini, L., Caccese, M., Graziani, J., Berra, D., Fornaro, L., et al. (2022) · Cancers · doi:10.3390/cancers14194896 · Cited by 10
“Such rates appear to be consistent with the prevalent HBV-positive Chinese setting of ORIENT-32, where 27% PP was described on sintilimab/bevacizumab biosimilar therapy [32].”
ResultLi, X., Sun, W., Ding, X., Li, W., & Chen, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1060051 · Cited by 9
“9 months compared with mono-sorafenib (17, 18).”
Nanomaterial-Based Antivascular Therapy in the Multimodal Treatment of Cancer
Ma, X., Fang, W., Wang, D., Shao, N., Chen, J., Nie, T., Huang, C., Huang, Y., Luo, L., & Xiao, Z. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041207 · Cited by 10
“For example, both sorafenib and bevacizumab can be used as antivascular agents for combination immunotherapy, but bevacizumab has been shown to be superior to sorafenib in prolonging progression-free survival in a phase III clinical trial [160,161].”
BackgroundResearch progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma
Xie, S., Wang, M., Zeng, C., Ou, Y., Zhao, L., Wang, D., Chen, L.-W., Kong, F., & Yi, D. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1197698 · Cited by 9
The upward trend in the immunotherapy utilization for hepatobiliary cancers
Lan, X.-B., Papatheodoridis, G., Teng, Y., & Zhong, J. (2021) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn-21-342 · Cited by 9
“, pembrolizumab, nivolumab plus ipilimumab) in patients with advanced HCC (Table 1) (5-8).”
BackgroundLiu, W., Jiang, Q.-Y., Qi, Z., Zhang, F., Tang, W., Wang, H., & Dong, L. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s469529 · Cited by 8
Marsh‐Wakefield, F., Santhakumar, C., Ferguson, A. L., Ashhurst, T. M., Shin, J., Guan, F. H. X., Shields, N. J., Platt, B. J., Putri, G., Gupta, R., et al. (2024) · Hepatology Communications · doi:10.1097/hc9.0000000000000540 · Cited by 8
“[4] 7] Being the prototypical cancer of inflammatory origin, immune responses in HCC are implicated in both protumoral and antitumoral activities.”
Bi, X., Lu, Y., Chen, B., Yang, Z., Hong, Z., Wang, H., Sun, Y., Wang, X., Yuan, C., Zeng, D., et al. (2024) · Liver Cancer · doi:10.1159/000540857 · Cited by 12
Self-citationWang, C., Leng, B., You, R., Yu, Z., Ya, L., Diao, L., Jiang, H., Cheng, Y., Yin, G., & Xu, Q. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s480540 · Cited by 8
Self-citationGong, Y., Liu, Y., Jiang, F., & Wang, X. (2024) · Seminars in Ophthalmology · doi:10.1080/08820538.2024.2433636 · Cited by 8
Advancements in immunotherapy for hepatocellular carcinoma
Ascari, S., Chen, R., Vivaldi, C., Stefanini, B., Sinno, A. D., Dalbeni, A., Federico, P., & Tovoli, F. (2025) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2025.2461631 · Cited by 8
“The phase 2–3 ORIENT-32 trial with sintili-mab, an anti-PD1 monoclonal antibody, and a bevacizumab biosimilar (IBI305) showed comparable results [17].”
Möhring, C., Berger, M., Sadeghlar, F., Zhou, X., Zhou, T., Monin, M. B., Shmanko, K., Welland, S., Sinner, F., Schwacha-Eipper, B., et al. (2025) · Cancers · doi:10.3390/cancers17060972 · Cited by 9
“Concurrently, the ORIENT-32 study facilitated the approval in China of the sintilimab (PD-1 antibody) and IBI305 (a bevacizumab biosimilar) combination for first-line HCC treatment, showcasing significantly longer OS compared to sorafenib [11].”
Chen, X., Wu, X., Peng, W., Liu, L., Liu, X., Wan, X., Xu, H., Zheng, Y., Zhao, H., Mao, Y., et al. (2025) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s504016 · Cited by 8
Self-citationPan, Z., Liu, D., Cao, J., Fu, L., Zhang, X., Zhu, X., Pan, Y., Liu, J., Han, C., Jin, R., et al. (2025) · Liver Cancer · doi:10.1159/000545545 · Cited by 9
“The median PFS for the LEAP002 study [14] was 8.2 months, compared to 4.6 months in the ORIENT-32 study [28] and 6.8 months in the IMBRAVE-150 study [13].”
InfluentialSelf-citationFu, X., Guo, Y., Zhang, K., Cheng, Z., Liu, C., Ren, Y., Miao, L., Liu, W., Jiang, S., Zhou, C., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-97677-x · Cited by 8
Self-citationResponsive biomaterials for therapeutic strategies of hepatocellular carcinoma
Liao, X., Zhou, J., Feng, L., Wang, L., Wu, H., Li, J., Jia, Y., Wu, Q., & Shen, S. Y. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1673134 · Cited by 8
Rajak, D., Nema, P., Sahu, A., Vishwakarma, S., & Kashaw, S. K. (2025) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2025.111120 · Cited by 9
Gao, B., Wang, Y., Sun, Z., Tang, H., Cao, Y., Jiang, H., Zhang, W., Xu, Y., Hu, B., Liu, Z., et al. (2025) · Advanced Science · doi:10.1002/advs.202511152 · Cited by 8
Self-citationChen, J., Zhi-Cheng, J. I. N., Zhou, J.-W., Ding, R., Tie, J., Xin, Y., Zhang, L., Huang, M., Zhu, X.-L., Zhou, G.-H., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.103766 · Cited by 9
“These drugs were approved and available in China, with favorable therapeutic effect in HCC confirmed through several RCTs. 4,6,38 Finally, the study population consisted predominantly of Chinese patients with HBV-related HCC, and the response to immunotherapy in different etiologic populations…”
Self-citationGuiu, B., Bailly, C., Vibert, É., Tlili, G., Mariano‐Goulart, D., Edeline, J., Touchefeu, Y., Durand, E., Blanc, J. F., Chalaye, J., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.103884 · Cited by 8
Therapeutic Antibodies in Cancer Treatment in the UK
Eltarhoni, K., Kamel, F., Ihebunezie, K., Nisar, P. J., & Soloviev, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314589 · Cited by 8
Xiao, L., Liao, Y., Wang, J., Li, Q., Zhu, H., Hong, C., Li, R., He, J., Cui, H., Dong, H., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03417-3 · Cited by 8
“The proportion of older adults included in clinical trials evaluating ICI immunotherapy for liver cancer remains low [9, 10].”
BackgroundSelf-citationLi, Q.-M., Sun, Q., Jian, Y., He, J., Zhu, H.-B., Hong, C., Zeng, L., Li, R.-N., Wang, J.-R., Li, Y., et al. (2023) · Discover Oncology · doi:10.1007/s12672-023-00708-0 · Cited by 8
“In clinical trials, the combination of antiangiogenic drugs and ICIs has achieved significant clinical efficacy, with higher ORR and better survival results than monotherapy [10, 19, 36–38].”
BackgroundSelf-citationJeschke, M., Ludwig, J. M., Leyh, C., Pabst, K. M., Weber, M., Theysohn, J. M., Lange, C. M., Herrmann, K., Schmidt, H., & Jochheim, L. S. (2023) · Cancers · doi:10.3390/cancers15174274 · Cited by 8
Qu, S., Wu, D., & Hu, Z. (2023) · Technology in Cancer Research & Treatment · doi:10.1177/15330338231206704 · Cited by 8
“4,5,28,29 Similarly, a great ORR of 75.7% to 84.2% has also been revealed for uHCC patients with this combination in many studies.”
BackgroundInfluentialCharacteristics of clinical trials of new oncology drugs approved in China
Yang, J., Ji, Y., & Yuanjia, H. (2023) · Cancer · doi:10.1002/cncr.35106 · Cited by 8
“36 Also, camrelizumab and toripalimab have been approved for naso-pharyngeal cancer, 32,34 which was not covered by nivolumab or pembrolizumab.”
BackgroundYang, Y., Li, L., Xü, Y., Ouyang, J., Zhou, Y., Ye, F., Huang, Z., Zhang, W., Zhou, A., Zhao, X., et al. (2024) · La radiologia medica · doi:10.1007/s11547-023-01753-z · Cited by 8
Self-citationProgress in the treatment of advanced hepatocellular carcinoma with immune combination therapy
Pan, D., Liu, H., Qu, P.-F., Ma, X., Ma, L., Chen, X., Wang, Y., Qin, X., & Han, Z. (2024) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v16.i2.273 · Cited by 8
Self-citationHuang, Z., Han, X., Wang, J., Gu, L., Tang, L., Wu, S.-Y., Di, T., Hou, Y., Lau, W. Y., Jiang, Y., et al. (2024) · Liver Cancer · doi:10.1159/000536518 · Cited by 8
“In addition, the recently published CARES-310 study using low-dose TKIs showed the longest median survival time among 5 phase 3 clinical trials of patients with advanced-stage HCC [19 – 23].”
MethodResultSelf-citationYuan, G., Li, W., Zang, M., Li, R., Li, Q., Hu, X., Zhang, Q., Huang, W., Ruan, J., Pang, H., et al. (2024) · Discover Oncology · doi:10.1007/s12672-024-00917-1 · Cited by 8
Self-citationZhao, Y., Bai, J. Y., Wang, X., Zhang, Y., Yan, X., Qi, J., Xia, X., Feng, Y., & Duan, B. (2024) · Journal of Cancer · doi:10.7150/jca.93885 · Cited by 9
“Compared with TKI mono-therapy, combination therapy based on ICIs has become the first-line and new standard treatment for unresectable HCC [79,80].”
BackgroundMohammadnezhad, G., Esmaily, H., Talebi, M., & Jafari, M. (2024) · Journal of Gastrointestinal Cancer · doi:10.1007/s12029-024-01038-2 · Cited by 8
“In three studies, ORIENT-32 results were used to calculate the utility of BVC + sintilimab [25, 27, 29, 33], Checkmate-459 trial results were used for nivolumab [26, 29, 34], ZGDH-3 trial results were used for donafenib [27, 29, 35], and REFLECT clinical trial was used for lenvatinib [27, 36].”
Du, J., Zhang, E., & Huang, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1358306 · Cited by 8
SEOM-GEMCAD-TTD clinical guidelines for the management of hepatocarcinoma patients (2023)
López, C., Calvo, M., Cámara, J. C., García-Paredes, B., Gómez-Martín, C., López, A. M., Pazo-Cid, R., Sastre, J., Yayá, R., & Feliú, J. (2024) · Clinical & Translational Oncology · doi:10.1007/s12094-024-03568-4 · Cited by 8
“…comparing the PD-1 inhibitor sintilimab (200 mg) plus bevacizumab biosimilar (15 mg/Kg) every 3 weeks versus sorafenib confirmed the advantage of these types of combinations (HR 0.57, p 0.0001) for OS, as well as for PFS (HR 0.56, p 0.001) and time to deterioration in quality of life [49].”
BackgroundInfluential
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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