Bioequivalence assessment of BCD-022 (trastuzumab, manufactured by JSC BIOCAD, Russia) as compared with Herceptin® (F.Hoffmann-La Roche Ltd., Switzerland), used in combination with paclitaxel in HER2-positive metastatic breast cancer patients: findings of the international, double-blind phase III clinical study

Objective. Within the multi-center double-blind randomized clinical study, investigate the bioequivalence (immediate efficacy, safety and pharmacokinetics) of BCD-022 (trastuzumab, JSC BIOCAD, Russia), as compared with Herceptin® (trastuzumab, F.Hoffmann-La Roche, Switzerland), used in combination with paclitaxel in HER2-positive metastatic breast cancer (HER2(+) MBC) patients. Subjects and methods. The analysis included 126 HER2(+) MBC patients aged 18 to 75 years (65 in the BCD-022 group and 61 in the Herceptin® group). The treatment was provided by scheme BCD-022 or Herceptin® 8 mg/kg intravenous drip, paclitaxel 175 mg/m2 intravenous drip in day 1 of the three-week course, then by the same scheme with trastuzumab 6 mg/kg. The treatment was continued for 6 courses or until disease progression/development of intolerable toxicity effects. The groups were randomized at 1:1 ratio. The primary endpoint for the immediate efficacy evaluating was the overall response rate (complete response rate + partial response rate), for the safety evaluating - the adverse event (AE) rate. One of the primary endpoint for the pharmacokinetics evaluating was the area under concentration-time curve (AUC0-504) of trastuzumab after a single administration. Immediate efficacy was evaluated by CT with contrast using RECIST 1.1 criteria. The safety analysis included immunogenicity evaluating of the study drugs by the formation rate and titer of binding and neutralizing antibodies to trastuzumab. Findings. Out of 126 HER2(+) MBC patients, 110 were included in the immediate efficacy analysis: 56 in BCD-022 group and 54 in Herceptin® group. It was impossible to assess the effect in 16 patients due to the lack of the necessary data: 9 in BCD-022 group and 7 in Herceptin® group (p=0.9). Of these, 2/16 patients withdrew before the start of treatment and 4/16 patients withdrew prior to the first assessment of the effect for reasons not related to confirmed progression. One patient of 16 had disturbance of trastuzumab dosing regimen, and therefore the comparison of immediate efficacy would be incorrect. One patient of 16 showed nonconformity to the inclusion/non-inclusion criteria, and the patient was excluded from the study. In 8/16 patients, characteristics of lesions or their visualization technique did not allow an assessment in accordance with RECIST 1.1 criteria. These patients received treatment in the amount of 6 courses on the Protocol to the achievement of clinical efficacy. Overall response rate was recorded in 30/56 (53.6%) (95% CI 40.7-65.9%) and 29/54 (53.7%) (95% CI 40.6-66.3%) patients in BCD-022 group and Herceptin® group, respectively (p=0.9). No statistically significant differences were found when comparing the other parameters of immediate efficiency: complete response was observed in 3/56 (5.4%) and 2/54 (3.7%) patients, partial response in 27/56 (48.2%) and 27/54 (50.0%), stabilization in 14/56 (25.0%) and 14/54 (25.9%), progression in 12/56 (21.4%) and 11/54 (20.4%) patients in BCD-022 and Herceptin® group, respectively (p>0.05). Comparison by all the main pharmacokinetic parameters (AUC0-504, Cmax, Tmax, T1/2 and Ctrough) showed no statistically significant differences between the groups. Out of 126 patients, 124 were included in the safety analysis: 63 in BCD-022 group and 61 in Herceptin® group. Two patients withdrew from the study prior to treatment. AEs were registered in 62/63 (98.4%) and 60/61 (98.4%) patients in BCD-022 group and Herceptin® group, respectively. Statistically significant differences between the groups were not identified in any of the AEs. The most common AEs were hematologic toxicity, myalgia and arthralgia. Most reported AEs were mild to moderate by CTCAE 4.03. Serious adverse events (SAEs) were reported in 10 patients: in 4/63 (6.4%) patients in BCD-022 group and in 7/61 (11.5%) Herceptin® group (2 SAEs were reported in 1 patient in the Herceptin® group) (p=0.2). In most cases SAEs were due to concomitant diseases, exposure to chemotherapeutic agents or other non-study therapy causes. Trastuzumab-related SAEs were reported in 5 patients: in 1/63 (1.6%) in BCD-022 group and in 4/61 (6.5%) in Herceptin® (р=0.2) group. Immunogenicity study revealed the emergence of binding antibodies to trastuzumab in 3/63 (4.7%) patients in BCD-022 group and in 1/61 (1.6%) in Herceptin® group, of them neutralizing antibodies to trastuzumab were reported in 1 patient in BCD-022 group and in 1 in the control group (p=1.0). Conclusion. BCD-022 (trastuzumab, JSC BIOCAD, Russia) is non-inferior to the original trastuzumab drug Herceptin® (F.Hoffmann-La Roche Ltd., Switzerland) on the profile of immediate efficacy, safety and pharmacokinetic properties.