Proposed rituximab biosimilar BCD‐020 versus reference rituximab for treatment of patients with indolent non‐Hodgkin lymphomas: An international multicenter randomized trial

Abstract

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo.International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied.Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m 2 for 4 weeks.Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity.One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy.Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported.Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold.Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages.In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile,

Current State and Comparison of the Clinical Development of Bevacizumab, Rituximab and Trastuzumab Biosimilars

“…It should be noted that the prespecified bioequivalence margin does denote that both sides of the 90% CI must be fully contained within this equivalence margin to meet the standard for bioequivalence [32]. The reported data from all the biosimilar candidates confirmed their bioequivalence to the corresponding RMP with 90% CI for PK values within the prespecified standard equivalence margin [50,51,[68][69][70][71][72][74][75][76][77][78][79][80][81][82][83]85,88], as it is the case of the RTX candidate RXTM83 (mAbxience) that demonstrated PK similarity with its RMP in DLBCL patients with ratios of geometric least-square means of 0.992 (0.936-1.05) for AUC and 0.996 (0.939-1.05) for C max [75].…”

“…In the case of RTX, the PK assessments were carried on a sensitive patient population [67]. Biocad (BCD-020) and mAbxience (RTXM83) conducted the PK assessment trial in the same population that the study of efficacy, safety and immunogenicity: patients diagnosed with DLBCL [50,74,75]. Other RTX biosimilar developers, including Henlius (HLX01), Pfizer (PF-05280586) and Sandoz (GP2013) chose to study the PK profile of their candidates in a nononcologic indication, RA [76][77][78].…”

“…ABP798, the candidate of Amgen was evaluated in patients with grade I, II or IIIa FL and low tumor burden [49]. The RTX biosimilar candidate of AryoGen Pharmed (Zytux™) was compared with the RMP in patients with CLL [57] and BCD-020 (Biocad) in grade I/II FL patients, despite it is not an approved indication for RMP in Europe [50]. Biocad chose this population following the European Society for Medical Oncology guidelines.…”

“…Comparative efficacy trials: study design According to the EMA guidelines, the similarity between the biosimilar candidate and its RMP should be demonstrated in adequately powered, randomized, parallel-group comparative clinical trial and preferably doubleblind [20,67]. All the comparative efficacy clinical trials of proposed biosimilars were designed as randomized, parallel-group comparative, double-blind trials in multiple centers except Biocad that conducted an open-label trial for its RTX candidate, BCD-020 [50].…”

A Clinical Review of Biosimilars Approved in Oncology

“…Other rituximab biosimilars have been developed (eg, MK-8808, BI 695500), but the manufacturers have since terminated development and are no longer listing the rituximab biosimilars as part of their product pipeline. 56-59…”