Summary Basis of Decision for MVASI

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic and Pharmacodynamic Studies

MVASI is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor-A (VEGF). Vascular endothelial growth factor is a key mediator of angiogenesis (i.e., the process of new blood vessel growth). The binding of MVASI to VEGF results in the inhibition of the interactions between VEGF and its receptors, fetal liver kinase and kinase insert domain receptor on the surface of endothelial cells. The neutralizing activity of VEGF reduces the vascularization of tumours, thereby inhibiting tumour growth.

Study 20110216

Study 20110216 was a randomized, single-blind, single-dose, 3-arm, parallel group study conducted in healthy adult male volunteers. The primary objective of the study was to demonstrate the bioequivalence between MVASI and Avastin. The study was conducted at two sites, one in the United States and one in the United Kingdom, using United States and United Kingdom reference products respectively.

The study design consisted in the enrollment of 202 subjects, 18 to 45 years of age, who were randomized in a 1:1 ratio to MVASI or reference within each site and received either a single intravenous dose of 3 mg/kg MVASI, United Kingdom-sourced Avastin or United States-sourced Avastin. Subjects then returned periodically for safety evaluations, pharmacokinetic sample collections and anti-drug-antibodies tests until Day 85. Given the United Kingdom-sourced Avastin was designated as the official reference biologic drug in Canada, the results described below focus on the bioequivalence between MVASI and the United Kingdom-sourced Avastin (also referred to as Avastin).

The pharmacokinetic similarity was compared within the context of a bioequivalence analysis. The relative ratios of the area under the serum concentration-time curve from time 0 to time of last quantifiable concentration (AUC_last) suggests that an infusion of MVASI would deliver the same amount as Avastin within the clinical limits of ±20%.

Using a non-compartmental analysis method, the pharmacokinetic results showed that the 90% confidence interval (CI) for the ratio of least squares (LS) geometric mean (expressed as percentages) of MVASI to Avastin for AUC_last (92.0, 100.4) and the point estimate of maximum plasma concentration (103%) were within the acceptance margins of 80% to 125%.

Therefore, results obtained from Study 20110216 indicate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

For further details, please refer to the MVASI Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Efficacy and Safety

The clinical evidence supporting the similarity of MVASI to Avastin was based primarily on one Phase III, randomized, double-blind, multicentre study (Study 20120265) which compared MVASI to Avastin with respect to efficacy, safety, and immunogenicity in subjects with non-squamous non-small cell lung cancer (NSCLC).

In addition, one supportive comparative safety and immunogenicity study conducted in healthy subjects (Study 20110216 previously described above) was also included.

Efficacy Analysis

Study 2012065

Study 20120265 was a randomized, double-blind, active-controlled, multicentre study that compared the efficacy of MVASI and the reference biologic drug Avastin in adult patients with confirmed Stage 4 or recurrent metastatic non-squamous NSCLC. Patients were randomized 1:1 to receive either 15 mg/kg of MVASI or Avastin intravenously every 3 weeks (Q3W) for a total of 6 cycles in combination with carboplatin (target area under the concentration-time curve [AUC] 6) and paclitaxel (200 mg/m²) Q3W for at least 4 cycles and not more than 6 cycles. After the 6 cycles of treatment, no patients received MVASI or Avastin as a single agent in either arm. Patients were stratified by geographic region (Eastern Europe vs Western Europe vs Asia Pacific/Other vs North America), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and gender.

The primary efficacy endpoint was objective response rate (ORR) as determined by a central, independent, blinded radiologist according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. The primary analysis was tested using the 2-sided 95% confidence interval (CI) of the risk ratio in ORR between MVASI and Avastin with a pre-defined equivalence margin of (0.67, 1.5). Based on the intent-to-treat (ITT) set using a non-responder approach, patients in the MVASI arm achieved an ORR of 39.0% (Number of patients [n] = 128/328) and patients in the Avastin arm achieved an ORR of 41.7% (n = 131/314). The risk ratio in ORR was 0.93 (95% CI: 0.77, 1.12). The 2-sided 95% CI was entirely contained within the interval of 0.67 to 1.5. A secondary efficacy analysis also showed that the 95% CI of the risk difference in ORR (-2.90 [95% CI: -10.48, 4.67]) was entirely contained within the equivalence margin of ± 12.5%. These results demonstrated that there were no clinically meaningful differences in ORR between MVASI and Avastin.

Safety Analysis

The safety assessment was based on 324 patients in the MVASI arm and 309 patients in the Avastin arm who received at least one dose of MVASI or Avastin. The adverse event median follow-up time was 4.2 months (0.1 to 7.2 months) in the MVASI arm and 4.2 months (0.3 to 6.2 months) in the Avastin arm. It was stated by the sponsor that a longer follow-up was not necessary because most on-target toxicities including fatal events occurred early after treatment (first 2^nd and 3^rd cycles). A longer follow-up would have permitted the detection of potentially meaningful, less common adverse events, however given that a) no new safety signals were identified during the 6-cycle treatment period, b) patients did not receive any anti-cancer treatment after the 6-cycle treatment, and c) the two molecules were considered to be highly similar from the quality perspective, the follow-up time in the context of this submission was not considered to be an issue.

A total of 308 patients (95.1%) in the MVASI arm and 289 patients (93.5%) in the Avastin arm experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs observed in either arm (≥20%) were alopecia (43.2% in the MVASI arm vs 41.1% in the Avastin arm), nausea (25.6% vs 30.7%) and anemia (20.7% vs 20.7%). Grade ≥3 TEAEs occurred in 42.9% of the patients in the MVASI arm and 44.3% of the patients in the Avastin arm.

The incidence of serious adverse events was similar between the MVASI arm (26.2%) and the Avastin arm (23.0%). Serious adverse events reported at an incidence ≥1% in the MVASI arm vs Avastin arm were: febrile neutropenia (3.4% vs 2.6%), neutropenia (1.9% vs 1.0%), pneumonia (1.9% vs 1.6%), pulmonary embolism (1.5% vs 1.9%), anemia (0.9% vs 1.9%), dyspnea (0.9% vs 1.3%) and hemoptysis (0.9% vs 1.6%), respectively. The numerical differences observed between the two treatment arms are considered to be not clinically meaningful.

As with Avastin, the major identified safety concerns include gastrointestinal perforations, hemorrhage (including pulmonary hemorrhage/hemoptysis which is more common in NSCLC patients), atrial thromboembolism, non-gastrointestinal fistula, hypertensive crises, posterior reversible encephalopathy syndrome, neutropenia and infections, nephrotic syndrome, and congestive heart failure. A Serious Warnings and Precautions box describing serious warnings and precautions has been included in the Product Monograph for MVASI for gastrointestinal perforations, hemorrhage and wound healing complications. These warnings are also found in the Product Monograph for Avastin.

Also included in the Serious Warnings and Precautions box is a warning that MVASI is not formulated and has not been authorized for intravitreal use. Local and systemic adverse events have been reported in the post-market setting with unauthorized intravitreal use.

Appropriate warnings and precautions are in place in the approved MVASI Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Avastin.

Overall, the safety profile of MVASI is considered to be comparable to that which has been established for the reference biologic drug Avastin. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the MVASI Product Monograph, as they are in the Product Monograph for Avastin.

For more information, refer to the MVASI Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Immunogenicity

As with all therapeutic proteins, there is a potential to develop an immune response to bevacizumab (the medicinal ingredient in MVASI). In Study 20120265 (for details see Clinical Efficacy), immunogenicity was evaluated at Baseline, Week 7, Week 13, and Week 19, and 6 months after the end of treatment at Week 19 if the subject was still on study. An electrochemiluminescent (ECL) immunoassay was used to detect antibodies capable of binding MVASI or Avastin.

Based on Study 20120265, of the 627 patients with evaluable anti-drug-antibodies samples, 3 patients (1.0%) in the Avastin arm tested positive for pre-existing non neutralizing anti-drug-antibodies. Four patients (1.4%) in the MVASI arm and 7 patients (2.5%) in the Avastin arm had post-baseline positive anti-drug-antibodies. None of these patients developed neutralizing antibodies.

One major limitation of the immunogenicity assay was that about 50% of the overall samples relying on either the screening or confirmatory test had drug levels greater than the drug tolerance limit of 50 µg/mL. It is considered that high drug concentrations detected in the majority of the serum samples may interfere with the sensitivity of the assay and prevent an accurate detection of anti-drug-antibodies in most cases. However, given that a) bevacizumab (the medical ingredient in MVASI) is known to have low immunogenicity, b) despite the high drug levels present in both arms, consistently low incidences of anti-drug-antibodies were detected in both the MVASI and the Avastin arms, and c) the Chemistry and Manufacturing (Quality) review team did not identify any quality concerns that could explain any differences in immunogenicity, the immunogenicity profile between MVASI and Avastin is considered comparable.

Immunogenicity testing in the clinical study was conducted in patients who received MVASI in combination with the immunosuppressant dexamethasone and chemotherapy. It is unclear whether immunogenicity could have been hampered by the use of dexamethasone and chemotherapy, and thus precluded the detection of a clinically meaningful difference between the two products in the monotherapy setting (i.e., indication for recurrent glioblastoma (rGBM]). In addition, while no anti-drug-antibodies were detected in the pharmacokinetic single-dose (3 mg/kg) study, the immunogenicity results are limited due to the short length of the study with only one post-dose anti-drug-antibodies sample collection. There are also no published bevacizumab immunogenicity data in the literature for the rGBM indication and thus the data related to the reference biologic drug was not considered to be sufficient and adequate from the regulatory perspective. For these reasons, the benefit-risk balance of MVASI in the recurrent rGBM indication could not be adequately assessed. (see Question 2. Why was MVASI approved?).

Indications

MVASI is considered to be biosimilar to Avastin, the reference biologic drug. Avastin is authorized and marketed in Canada for several indications and clinical uses.

Within this drug submission, the sponsor requested the authorization of MVASI for indications that are currently authorized for Avastin, including: Metastatic Colorectal Cancer, Locally Advanced, Metastatic or Recurrent Non-small Cell Lung Cancer, and Malignant Glioma (WHO Grade IV) - Glioblastoma (Notice of Compliance with Conditions [NOC/c] authorization). Based on the assessment of all the relevant data provided in the submission, MVASI was considered to have a risk-benefit profile that is favourable for the treatment of mCRC and non-squamous NSCLC patients. However, the clinical knowledge of the reference biologic drug bevacizumab in the context of glioblastoma remains uncertain and thus the data related to the reference biologic drug was not considered to be sufficient and adequate from the regulatory perspective. For these reasons, the benefit-risk balance of MVASI in the recurrent GBM indication could not be adequately assessed. Therefore, market authorization of the rGBM indication was not granted for MVASI.

Based on the totality of evidence derived from the comparative structural, analytical and functional, non-clinical, pharmacokinetic and clinical data, similarity between MVASI and Avastin has been demonstrated and therefore Health Canada approved MVASI for the following two indications:

• Metastatic Colorectal Cancer (mCRC)

  MVASI, in combination with fluoropyrimidine based chemotherapy, is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

  Consideration should be given to current standard of care guidelines for colorectal cancer.

• Locally Advanced, Metastatic or Recurrent Non-small Cell Lung Cancer (NSCLC)

  MVASI, in combination with carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.