Clinical comparability between rituximab biosimilar RTXM83 and rituximab in diffuse large B-cell lymphoma patients Posted 13/09/2019

The arrival of biosimilars represents more affordable alternatives for patients in several countries, increasing their access to costly biological treatments [1]. The positive impact of biosimilars on the financial sustainability of healthcare systems has been recognized by several haemato-oncological societies.

The regulatory guidelines for biosimilars’ development consider the clinical comparability as confirmatory and the last step. Their recommendation is a head to-head comparison in a representative and sensitive subject population [5-7].

A proposed rituximab biosimilar (RTXM83) to the European Union (EU)-authorized originator (MabThera) was developed by mAbxience Research. A prospective, multicentre, double-blind, randomized clinical study (RTXM83-AC-01-11) was conducted to confirm comparable clinical performance (efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), safety and immunogenicity) of RTXM83 versus MabThera (NCT02268045), both in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as first-line treatment in Diffuse Large B Cell Lymphoma (DLBCL). Similar behaviour was anticipated in the clinical setting because the molecule has been shown to be structurally and functionally highly similar to the reference biological [5].

Rituximab is a chimeric anti-CD20 monoclonal antibody approved for the treatment of several types of non-Hodgkin’s lymphoma (NHL) and autoimmune diseases [8]. For these indications, a homogeneous population of DLBCL patients was chosen, as a sensitive indication that exhibits good clinical responses to rituximab [9, 10]. In this NHL subtype, rituximab is considered a standard of care for first-line treatment [9,11].

In total, 272 patients from 12 countries, <65 years of age and with a good prognosis, were randomized (1:1) to receive six cycles of either RTXM83 or MabThera (136 patients per treatment arm). All patients received at least one dose of the study treatment.

The primary efficacy endpoint was to compare the overall response rate (ORR) in each treatment arm after study treatment (cycle 6 or within 30 days after last administration of study treatment). This is considered a sensitive and appropriate indicator of activity by both European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidance [6, 7] for a biosimilar antibody such as rituximab, due to its treatment effect.

PK and PD profile, event-free survival (EFS), safety and immunogenicity profiles were assessed as secondary study endpoints.

Baseline demographic and clinical characteristics were comparable between treatment arms. The study met its primary endpoint by confirming the non-inferior efficacy (in terms of ORR) of RTXM83 to MabThera in the first-line treatment of DLBCL [12], with the lower boundary of the confidence interval (CI) of the treatment effect difference (-8.77%) not exceeding -13%. EFS was achieved in both treatment arms and was comparable. In addition, the Hazard Ratio (HR) was nearly 1 which indicates that the rate of events occurring in the biosimilar arm and the MabThera arm were nearly the same [12].

For the secondary endpoints, the results of the PK/PD assessment demonstrated a similar PK/PD profile for RTXM83 and MabThera [13]. The overall safety profile of RTXM83 was consistent with the known safety profile of rituximab plus CHOP in DLBCL [8], with haematological disorders, infections and infusion-related reactions as the most common reactions. Both treatments showed a comparable safety profile, with no differences in terms of the nature, frequency and severity of adverse events and no new safety signals identified in the study [12].

The rates of immunogenicity observed in the study [12, 13], were low (<4%) and similar in both treatment arms and raised no concern around the efficacy or safety compared to the MabThera safety profile [8].

Candelaria et al. conclude that RTXM83 has demonstrated biological activity comparable to MabThera and is expected to enhance treatment options, improving patient access [12].

Conflict of interest
The authors of the research paper [12] reported conflict of interest, including being an employee of mAbxience Research. They also reported that this work was supported by mAbxience Research. For full details of the authors’ conflict of interest, see the research paper [12].

Abstracted by Luis Pérez Díaz, Medical Advisor, 28 C/Manuel Pombo Angulo, 4th Floor. ES-28050 Madrid, Spain.

Editor’s comment
Readers interested to learn more about rituximab biosimilars are invited to visit to view the following manuscripts published in GaBI Journal:

Biosimilar rituximab in biological naïve rheumatoid arthritis patients

Phase I studies of infliximab and rituximab biosimilars demonstrate pharmacokinetic similarity

GaBI Journal is indexed in Embase, Scopus, Emerging Sources Citation Index and more.

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

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1. World Health Organization. Report on the expert consultation on improving access to and use of similar biotherapeutic products. Salle IV, International Labour Organization. WHO/EMP/RHT/TSN/2017.01. 2017 May 2 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
2. European Hematology Association. European Hematology Association Position paper. EU collaboration on pricing and reimbursement of innovative medicines. 2017 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
3. Tabernero J, Vyas M, Giuliani R, et al. Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. ESMO Open. 2017;1(6):e000142. 
4. Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology Statement: biosimilars in oncology. J Clin Oncol. 2018;36(12):1260-5. 
5. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev1. 18 Dec 2014 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
6. U.S. Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. December 2016 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
7. European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 2012 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
8. European Medicines Agency. EMEA/H/C/000165 - IB/0154. Mabthera: summary product characteristics. 2018 [homepage on the Internet]. [cited 2019 Sep 13]. Available from:
9. Rugo HS, Linton KM, Cervi P, et al. A clinician’s guide to biosimilars in oncology. Cancer Treat Rev. 2016;46:73-9.
10. Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):74-87.
11. Tilly H, Vitolo U, Walewski J, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii78-82. 
12. Candelaria M, González DE, Delamain MT, et al. Rituximab biosimilar RTXM83 versus reference rituximab in combination with CHOP as first-line treatment for diffuse large B-cell lymphoma: a randomized, double-blind study. Leuk Lymphoma. 2019:1-11. doi:10.1080/10428194.2019.1633632. [Epub ahead of print]
13. Candelaria M, Gonzalez D, Fernández Gómez FJ, et al. Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83TM, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach. Cancer Chemother Pharmacol. 2018;81(3):515–27.

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