A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers.

PURPOSE: MB02 is a biosimilar to bevacizumab that has demonstrated similar physicochemical and functional properties in in vitro studies to the reference bevacizumab (Avastin®). This study aims to assess the pharmacokinetic (PK) similarity of MB02 to the reference bevacizumab in Japanese population. METHODS: This double-blind, randomized, parallel-group, single-dose PK study, was performed in healthy Japanese male volunteers. Subjects were equally randomized (1:1) to receive a single (3 mg/kg) IV dose of MB02 or reference bevacizumab. PK assessments were done up to 70 days post-dose. Non-compartmental parameters were calculated. PK similarity was determined using predefined equivalence range (0.80-1.25) for the area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞). Immunogenicity samples were taken pre-dose and up to day 70. Safety was assessed throughout the study. RESULTS: In total, 48 subjects (24 in each treatment group) were dosed. Consequently to the observed similar PK profile, the 90% confidence interval for the geometric means ratio for the primary PK endpoint, AUC0-∞, was within the predefined equivalence range (0.981-1.11). Forty-seven treatment-emergent adverse events (TEAEs) were reported in 20 subjects (41.7%) with comparable incidence among MB02 and reference bevacizumab groups (22 and 25, respectively), none of them was severe or serious. Anti-drug antibodies incidence was low and similar between treatment groups. CONCLUSIONS: Pharmacokinetic similarity of MB02 to reference bevacizumab was evidenced in Japanese healthy subjects, with comparable safety and immunogenicity profile between treatments. This study supports the biosimilarity of MB02 to reference bevacizumab in Japanese population. ClinicalTrials.gov identifier: NCT04238650.

Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA).

BACKGROUND: MB02 (bevacizumab biosimilar) showed similar structural, functional, and pharmacokinetic properties to reference bevacizumab (Avastin®; EU-bevacizumab). OBJECTIVES: To confirm clinical similarity between MB02 and EU-bevacizumab, a comparability study was undertaken in the first-line treatment of stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This multinational, double-blind, randomized, phase III study (STELLA) compared MB02 or EU-bevacizumab (15 mg/kg) administered with chemotherapy (paclitaxel 200 mg/m2 and carboplatin AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18), followed by MB02/EU-bevacizumab in blinded monotherapy until disease progression, unacceptable toxicity, death, withdrawal of consent or end of study (Week 52). The primary efficacy endpoint was objective response rate (ORR) evaluated by an independent radiological review committee (IRC) at Week 18 (intent-to-treat population). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and immunogenicity. RESULTS: A total of 627 subjects were randomized 1:1 to MB02 (n = 315) or EU-bevacizumab (n = 312). ORR, assessed by the IRC at Week 18, was comparable in MB02 (40.3%) and EU-bevacizumab (44.6%) groups. ORR risk ratio of 0.910 (90% CI 0.780 to 1.060; 95% CI 0.758 to 1.092) and ORR risk difference of -4.02 (90% CI -10.51 to 2.47; 95% CI -11.76 to 3.71) were within the similarity predefined margins. There were no significant differences between MB02 and EU-bevacizumab groups in median PFS (36.0 vs 37.3 weeks, respectively; HR 1.187; 95% CI 0.98 to 1.44) and median OS (not achieved; HR 1.108; 95% CI: 0.83 to 1.49) at the end of study. The safety profile of MB02 and EU-bevacizumab regarding nature, frequency and severity of the adverse events (AE) was comparable. The most frequent grade ≥3 investigational-product-related AEs were hypertension and anemia, with a difference between treatment groups of <5%. Anti-drug antibodies (ADA) and neutralizing ADA (NAb) incidence were similar in both treatment groups. CONCLUSION: MB02 demonstrated similar efficacy to EU-bevacizumab, in combination with carboplatin and paclitaxel, in subjects with advanced non-squamous NSCLC, with comparable safety and immunogenicity profiles. CLINICAL TRIAL REGISTRATION: EudraCT No. 2017-001769-26; ClinicalTrials.gov: NCT03296163.

Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial.

BACKGROUND: BEVZ92 is a proposed biosimilar to bevacizumab. The two molecules have similar physicochemical and functional properties in in-vitro and preclinical studies. In this clinical study, we compared the pharmacokinetic profile, efficacy, safety, and immunogenicity of BEVZ92 with reference bevacizumab as a first-line treatment in patients with metastatic colorectal cancer. METHODS: We did a randomised, open-label trial at 15 centres in Argentina, Brazil, India, Spain, and Ukraine. Eligible patients were aged 18 years or older, had metastatic colorectal cancer with at least one measurable non-irradiated lesion for which first-line chemotherapy was indicated and Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, had not received previous treatment for advanced disease, and whose bone marrow, hepatic, renal, and coagulation markers were all within normal ranges. Patients were randomly assigned (1:1) to either BEVZ92 or reference bevacizumab (5 mg/kg on day 1 of each cycle every 2 weeks) in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI). Randomisation was done via a web service based on a stochastic minimisation algorithm and was stratified by chemotherapy regimen (FOLFOX vs FOLFIRI), previous adjuvant therapy (yes vs no), ECOG performance status (0-1 vs 2), and study site. The primary endpoint was the area under the concentration-versus-time curve after a single infusion (AUC0-336h) and at steady state (AUCss)-ie, at cycle 7-in the assessable population, which comprised all treated patients for whom serum concentration measurements were available during the first seven cycles. Bioequivalence was established if the 90% CIs for the ratio of BEVZ92 to reference bevacizumab of the geometric means for AUC0-336h and AUCss were within the acceptance interval of 80-125%. Secondary endpoints included objective response, clinical benefit, and progression-free survival in the intention-to-treat population and immunogenicity and safety profiles in all treated patients. This trial is registered with ClinicalTrials.gov, number NCT02069704, and is closed to new participants, with follow-up completed. FINDINGS: 142 patients were randomly assigned, 71 to the BEVZ92 group and 71 to the reference bevacizumab group. Two participants assigned to BEVZ92 did not receive treatment (one withdrew consent, the other had a serious intestinal obstruction before starting treatment); therefore, the treated population comprised 69 patients in the BEVZ92 group and 71 in the reference bevacizumab group. The geometric mean ratio of AUC0-336h in the BEVZ92 versus the control group was 99·4% (90% CI 90·5-109·0) and of AUCss was 100·0% (90·2-112·0). Objective response (35 [49%] of 71 vs 40 [56%] of 71), clinical benefit (62 [87%] vs 65 [92%]), and progression-free survival (median 10·8 months [95% CI 7·4-11·5] vs 11·1 months [95% CI 8·0-12·8]) were similar in the BEVZ92 and reference bevacizumab groups. No relevant differences were noted between the safety profiles of the two study treatments. Neutropenia was the most common grade 3 or 4 adverse event reported in the BEVZ92 (14 [20%] of 69 patients) and reference bevacizumab (19 [27%] of 71 patients) groups. Serious adverse events occurred in 19 (28%) patients in the BEVZ92 group and 21 (30%) in the reference bevacizumab group. Two patients died because of bevacizumab-related serious adverse events: a sudden death in the BEVZ92 group and a serious large intestinal perforation in the reference bevacizumab group. The occurrence of anti-drug antibodies was low and similar in both treatment groups (two patients in the BEVZ92 group and one in the reference bevacizumab group). INTERPRETATION: Our results suggest that BEVZ92 and reference bevacizumab are pharmacokinetically bioequivalent and have no appreciable differences in efficacy, immunogenicity, and safety profiles as first-line treatment in combination with FOLFOX or FOLFIRI in patients with metastatic colorectal cancer. FUNDING: mAbxience Research SL.

Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83™, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach.

PURPOSE: The main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and Cmax) between RTXM83, a proposed rituximab biosimilar, and its reference product, using a population PK model approach. METHODS: Rituximab PK and PD data were obtained from a randomized, double-blind, phase III clinical study (RTXM83-AC-01-11) in patients with diffuse large B-cell lymphoma (DLBCL) that received 375 mg/m2 intravenous RTXM83 or its reference product with CHOP regimen, every 3 weeks, for six cycles. Rituximab levels were quantified by Meso Scale Discovery assay. PK analysis was performed using NONMEM 7.3.0. The effect of disease and patient covariates on RXTM83 PK was investigated. Model was evaluated using visual predictive check and non-parametric bootstrap. RESULTS: In total, 251 DLBCL patients (127 and 124 in RXTM83-CHOP and rituximab-CHOP arms, respectively) and 5341 serum concentrations (2703 for RXTM83 and 2638 for rituximab, respectively) were available for the population PK analysis. The volume of distribution of the central compartment (V1) and clearance of RXTM83 were estimated at 3.19 L and 12.5 mL/h, respectively. Body surface area allowed to explain the interindividual variability for V1. A statistical analysis showed that systemic exposure (AUC and Cmax) of RTXM83 was similar to rituximab. The 90% confidence intervals for all pairwise comparisons were within the predefined bioequivalence interval of 0.80-1.25. PD similarity of B-cell depletion and recovery was also observed. CONCLUSIONS: The time course of RTXM83 was well characterized by the model developed. The systemic exposure of RTXM83 and its associated variability were similar to those for rituximab reference in DLBCL patients, demonstrating PK similarity. The PD similarity of RTXM83 and rituximab reference product was also demonstrated.