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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.

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BCD-020 (Acellbia, rituximab biosimilar candidate) was shown to be highly similar to innovator rituximab (MabThera®/Rituxan®) in terms of its quality characteristics, in vitro biological activity, as well as toxicology and PK/PD characteristics in non-human primates. International multicenter comparative randomized open-label clinical study was carried out in a period from 2011 to 2013 and involved over 30 centers in Russia, Ukraine and India. Its methodology and design complies with current EMA guidelines on similar biological products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010). 92 patients with follicular non-Hodgkin’s lymphoma, stage I-IV by Ann Arbor, or marginal zone lymphoma, stage I-IV by Ann Arbor, ECOG 0-2, who had at least 1 measurable lesion were enrolled. According to study protocol patients with secondary transformed B-cell lymphomas or with highly aggressive types of tumor, bulky disease, severe concomitant somatic disorders and some other conditions were excluded. If a patient had previous story of chemotherapy or radiation he could be included after at least 3 weeks post-treatment. Participation of patients who were previously treated with any kind of monoclonal antibodies was prohibited. After signing standard informed consent form and completion of 28-days screening period eligible patients underwent stratification in accordance to their prognostic risk (FLIPI or IPI) and previous treatment (naïve or pretreated). Subsequently patients were randomized (1:1) into 2 groups: 46 patients were included in the main group where Acellbia (rituximab biosimilar) was administered at a dose of 375 mg/m2 as a slow IV infusion on day 1, 8, 15 and 22; 46 patients were included in the reference group where MabThera was used at the same regimen. Use of any other medicines for the treatment of lymphoma was strictly prohibited. Efficacy was assessed on the basis of computed tomography and bone marrow evaluation which were performed 1 month after the completion of treatment. Median age of patients in each group was 57.5 years (main group [50.0-64.0], reference group [47.0-65.0]). Manageable comorbidities were reported in 50% of patients in the main group and 34.78% of patients in the reference group, p=0.2053. Comparative analysis of the prognostic risk factors confirmed the equivalence of study groups. The number of pretreated patients in both groups was equal – 8 individuals per group. Statistical analysis didn’t find any difference in overall response rate in general population of patients (39.52% patients in the main group vs. 36.57% patients in the reference group, p=0.8250), as well as in population of pretreated patients (28.6% vs 37.5% respectively, p=1.00) and in population of naïve patients (42.8% vs 39.4% respectively, p=1.00). The lower limit of the two-tailed 95% CI for difference in proportions of ORR was equal to -0.17 and exceeded the predefined non-inferiority margin -0.2, which confirmed non-inferiority of Acellbia to MabThera in terms of efficacy. Treatment-associated AE of any grade were reported in 21.74% patients in both arms, in the absence of statistically or clinically significant difference (p = 0.8005). There were 2 cases of CTCAE 4.03 grade 3-4 AEs in each group. PK and PD parameters were shown to be equivalent in both study groups. Thus, study results suggest that Acellbia has same efficacy and safety in patients with B-cell non-Hodgkin’s lymphoma. Disclosures Chernyaeva: JCS BIOCAD: Employment. Ivanov:JCS BIOCAD: Employment. Isaev:JCS BIOCAD: Employment.