Bevacizumab Biosimilars: Scientific Justification for Extrapolation of Indications

Abstract

The first biosimilar of bevacizumab was approved by the US FDA; other potential biosimilars of bevacizumab are in late-stage clinical development. Their availability offers opportunity for increased patient access across a number of oncologic indications. The regulatory pathway for biosimilar approval relies on the totality of evidence that includes a comprehensive analytical assessment, and a clinical comparability study in a relevant disease patient population. Extrapolation of indications for a biosimilar to other eligible indications held by the originator, in the absence of direct clinical comparison, frequently forms part of the regulatory judgment. Herein, we consider the evidence required to demonstrate biosimilarity for bevacizumab biosimilars, with particular focus on the rationale for extrapolation across oncologic indications. Bevacizumab (Avastin R ; Roche, Welwyn Garden City, UK; Genentech, CA, USA) is a monoclonal antibody directed against VEGF. It is approved in Europe and the USA for the treatment of a range of cancers, including metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC), metastatic renal cell carcinoma, metastatic colorectal cancer (CRC), cervical cancer, and platinum-resistant or platinum-sensitive recurrent epithelial ovarian, fallopian tube and primary peritoneal cancers [1,2]. In addition, in the USA, Japan, and many other countries, bevacizumab is indicated for the treatment of patients with glioblastoma. In Europe, it is also authorized for use in metastatic breast cancer and in combination with erlotinib for the first-line treatment of advanced, metastatic nonsquamous NSCLC with EGF receptor-activating mutations [3]. Randomized Phase III trials have shown that progression-free survival (PFS) and/or overall survival (OS) in patients with these cancers is prolonged with treatment combining bevacizumab with standard chemotherapy (Table 1) [4][5][6][7][8][9][10][11][12]. Nonetheless, patient access to bevacizumab may be limited.Barriers to bevacizumab use stem from factors such as insurance coverage and cost of treatment, manufacturing and supply and uncertainty as to its cost-effectiveness in some clinical settings [13][14][15]. A survey conducted by the European Society of Medical Oncology Consortium found budget constraints, affordability and issues related to the manufacture and assured supply of the product were cited most frequently as reasons for access to bevacizumab to be considered suboptimal [13]. Oncologists who were surveyed in the USA, Europe and in some emerging market countries (Brazil, Mexico and Turkey) stated the major barriers to prescribing bevacizumab were the high out-of-pocket costs for patients and a lack of reimbursement. These barriers were commonly cited as reasons for reducing the number of drug treatment cycles that were planned for patients [15].Protein-based biologics, such as bevacizumab, are produced in living cells rather than by chemical synthesis, and are large and structurally complex [16]. Their structure and activity are in...

NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 1.2020

“…Bevacizumab biosimilars may be used in any of the systemic therapy regimens containing bevacizumab (eg, ABCP) that are used for eligible patients with metastatic NSCLC based on clinical data and FDA approvals. [30][31][32][33][34] However, a specific bevacizumab biosimilar should be used for the entire regimen, including maintenance therapy, and should not be substituted in the middle of therapy.…”

A randomized, double-blind, single-dose study to evaluate the biosimilarity of QL1101 with bevacizumab in healthy male subjects

“…In addition, in January 2005, bevacizumab was approved in the EU [15] and later approved in China in February 2010. The first bevacizumab biosimilar (Mvasi ® ), developed by Amgen and Allergan, was approved by the FDA in September 2017 [16], and later approved in the EU in January 2018 [17].…”

Clinical and Regulatory Considerations for the Use of Bevacizumab Biosimilars in Metastatic Colorectal Cancer

“…1,3 Extrapolation, which can be carried out in parallel with the first approval of the biosimilar, is intended to avoid the conduct of unnecessary clinical trials and to shorten the biosimilar development process, providing additional treatment options and timely patient access to more affordable medicines. 59,60 Critically, extrapolation must be supported by the totality of evidence generated during all steps of the approval process (Figure 3). This is combined with a scientific justification based on knowledge of the RP, including historical reference data and/or clinical trials.…”