Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab

Abstract

Background: BCD-022 is a trastuzumab biosimilar which was shown to be equivalent to reference trastuzumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to comparatively assess efficacy and safety of BCD-022 and reference trastuzumab in combination with paclitaxel used as the therapy of metastatic HER2(+) breast cancer. Pharmacokinetics and immunogenicity were also studied. Methods: Patients with no previous treatment for metastatic HER2(+) breast cancer were randomly assigned 1:1 to BCD-022 or reference trastuzumab and were treated with trastuzumab + paclitaxel. Therapy continued for 6 cycles of therapy (every 3 weeks), until progression of the disease or unbearable toxicity. Primary study endpoint was overall response rate. Study goal was to prove equivalent efficacy of BCD-022 and reference trastuzumab. Equivalence margins for 95% CI for difference in overall response rates were set at [− 20%; 20%]. Results: In total 225 patients were enrolled into the study, 115 in BCD-022 arm and 110 in reference trastuzumab arm. Overall response rate was 49.6% in BCD-022 arm and 43.6% in reference trastuzumab arm. Limits of 95% CI for difference of overall response rates between arms were [(− 8.05)-19.89%], thus, they lied within predetermined equivalence margins [− 20%; 20%]. Profile of adverse events was similar between groups (any AEs were reported in 93.81% of patients in BCD-022 arm and 94.55% of patients in reference arm). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding antibody occurrence rate (either BAb or NAb) was found between BCD-022 (n = 3; 2.65%) and comparator (n = 4; 3.64%). Both drug products are characterized with low occurrence rate and short life of anti-trastuzumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures: AUC 0-504 , С mах , Т max , T 1/2. Analysis of C trough did not reveal any significant inter-group differences as well.

Characteristics of Clinical Trials Evaluating Biosimilars in the Treatment of Cancer

“…After applying our exclusion criteria, we identified 42 studies, and 11 were excluded after final review, leaving 31 studies involving 12 310 patients for detailed analysis (Figure 1; eTable 1 in the Supplement). Twenty-one studies presented an overall low risk of bias, 2 had a high risk of bias, and for 2 trials, the risk of bias was unclear (eTable 2 in the Supplement). All trials were preregistered.…”

Systematic Review on the Use of Biosimilars of Trastuzumab in HER2+ Breast Cancer

“…In addition, no statistically significant differences were found in the incidence of antibodies development between BCD-022 ( n = 3, 2.6%) and the reference drug ( n = 4, 3.6%). Evaluation of pharmacokinetics after the first and sixth injections of the drug also showed equivalent parameters (AUC0-504, Сmах, Тmax, T1/2, C trough) [ 58 ].…”

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

“…Early breast cancer (EBC) might represent a more sensitive and homogeneous population with fewer confounding factors such as prior therapies, location of metastases and disease severity in comparison with metastatic breast cancer. However, developers as Accord Healthcare (HLX02), Biocad (BCD-022) and Mylan (MYL-1401O) decided to conduct their comparative trials in patients with MBC in combination with paclitaxel or docetaxel [59,62,63] whereas Amgen (ABP 980) and Samsung Bioepis (SB3) evaluated their candidates with combination chemotherapy in the neoadjuvant setting in EBC patients [58,66]. Celltrion Healthcare (CT-P6) and Pfizer (PF-05280014) compared their biosimilars candidates with the RMP in both patient settings [60,61,64,92].…”

“…In the case of TRA biosimilars, the chosen primary end point varied as a function of the type of study population assessed. Thereby, when a biosimilar candidate was evaluated in patients with MBC, the primary end point was ORR as it happened with BCD-022 (Biocad), CT-P6 (Celltrion Healthcare), HLX02 (Accord Healthcare), MYL-1401O (Mylan) and PF-05280014 (Pfizer) [59,61,63,64]. The selected end point in the EBC population setting was, in most cases, the total pCR defined as the absence of residual invasive disease in the breast and axillary lymph nodes at the completion of neoadjuvant treatment.…”