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      A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma

      letter
      1 , , 2 , 1 , 3 , 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 34 , 34 , 34 , 34 , 34
      Journal of Hematology & Oncology
      BioMed Central
      Rituximab biosimilar, DLBCL, Efficacy equivalence

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          Abstract

          Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

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          CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.

          The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Hoffmann-La Roche. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®

            ABSTRACT Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China’s Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efficacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.
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              First analysis of the Completed Mabthera International (Mint) Trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favorable subgroup with IPI=O and no bulky disease

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                Author and article information

                Contributors
                syuankai@cicams.ac.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                16 April 2020
                16 April 2020
                2020
                : 13
                : 38
                Affiliations
                [1 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, , Chinese Academy of Medical Sciences & Peking Union Medical College, ; Beijing, China
                [2 ]GRID grid.414008.9, ISNI 0000 0004 1799 4638, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, ; Zhengzhou, China
                [3 ]GRID grid.412651.5, ISNI 0000 0004 1808 3502, Harbin Medical University Cancer Hospital, ; Harbin, China
                [4 ]GRID grid.452404.3, ISNI 0000 0004 1808 0942, Fudan University Shanghai Cancer Center, ; Shanghai, China
                [5 ]GRID grid.414048.d, ISNI 0000 0004 1799 2720, Daping Hospital, Third Affiliated Hospital of the Army Medical University, ; Chongqing, China
                [6 ]GRID grid.452451.3, The First Bethune Hospital of Jilin University, ; Changchun, China
                [7 ]GRID grid.452828.1, The Second Hospital of Dalian Medical University, ; Dalian, China
                [8 ]GRID grid.452509.f, ISNI 0000 0004 1764 4566, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, ; Nanjing, China
                [9 ]GRID grid.411525.6, ISNI 0000 0004 0369 1599, Changhai Hospital, ; Shanghai, China
                [10 ]GRID grid.411918.4, ISNI 0000 0004 1798 6427, Tianjin Medical University Cancer Institute & Hospital, ; Tianjin, China
                [11 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, Cancer Center of Guangzhou Medical University, ; Guangzhou, China
                [12 ]GRID grid.415110.0, ISNI 0000 0004 0605 1140, Fujian Provincial Cancer Hospital, ; Fuzhou, China
                [13 ]GRID grid.411176.4, ISNI 0000 0004 1758 0478, Fujian Medical University Union Hospital, ; Fuzhou, China
                [14 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Beijing Friendship Hospital, , Capital Medical University, ; Beijing, China
                [15 ]GRID grid.429222.d, The First Affiliated Hospital of Soochow University, ; Soochow, China
                [16 ]GRID grid.452349.d, ISNI 0000 0004 4648 0476, The 307th Hospital of Chinese People’s Liberation Army, ; Beijing, China
                [17 ]GRID grid.417031.0, ISNI 0000 0004 1799 2675, Tianjin People’s Hospital, ; Tianjin, China
                [18 ]GRID grid.417397.f, ISNI 0000 0004 1808 0985, Zhejiang Cancer Hospital, ; Hangzhou, China
                [19 ]GRID grid.413810.f, Shanghai Changzheng Hospital, ; Shanghai, China
                [20 ]GRID grid.412633.1, The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, China
                [21 ]GRID grid.412465.0, The Second Affiliated Hospital of Zhejiang University School of Medicine, ; Hangzhou, China
                [22 ]GRID grid.452222.1, Jinan Central Hospital Affiliated to Shandong University, ; Jinan, China
                [23 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Peking University Third Hospital, ; Beijing, China
                [24 ]GRID grid.460007.5, ISNI 0000 0004 1791 6584, Tangdu Hospital, Air Force Medical University, ; Xi’an, China
                [25 ]GRID grid.413606.6, ISNI 0000 0004 1758 2326, Hubei Cancer Hospital, ; Wuhan, China
                [26 ]GRID grid.412604.5, ISNI 0000 0004 1758 4073, The First Affiliated Hospital of Nanchang University, ; Nanchang, China
                [27 ]GRID grid.452829.0, The Second Hospital of Jilin University, ; Changchun, China
                [28 ]GRID grid.452661.2, ISNI 0000 0004 1803 6319, The First Affiliated Hospital, College of Medicine, Zhejiang University, ; Hangzhou, China
                [29 ]GRID grid.459742.9, ISNI 0000 0004 1798 5889, Liaoning Cancer Hospital & Institute, ; Shenyang, China
                [30 ]GRID grid.413405.7, ISNI 0000 0004 1808 0686, Guangdong Provincial People’s Hospital, ; Guangzhou, China
                [31 ]GRID grid.440230.1, Jilin Cancer Hospital, ; Changchun, China
                [32 ]GRID grid.410622.3, Hunan Cancer Hospital, ; Changsha, China
                [33 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Xiangya Hospital, Central South University, ; Changsha, China
                [34 ]Shanghai Henlius Biotech, Inc., Shanghai, China
                Article
                871
                10.1186/s13045-020-00871-9
                7164184
                32299513
                b1d1efb3-6b44-4902-a6d2-f2513a7877a4
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 11 February 2020
                : 1 April 2020
                Funding
                Funded by: Chinese National Major Project for New Drug Innovation
                Award ID: 2015ZX09501008, 2017ZX09304015
                Funded by: CAMS Innovation Fund for Medical Science
                Award ID: CAMS Innovation Fund for Medical Science
                Award Recipient :
                Categories
                Letter to the Editor
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                rituximab biosimilar,dlbcl,efficacy equivalence
                Oncology & Radiotherapy
                rituximab biosimilar, dlbcl, efficacy equivalence

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