Despite Concerns Over Extrapolation, Bevacizumab Biosimilars Are Widely Used in mCRC

A review article in Future Medicine discussed the scientific justification of extrapolation of the bevacizumab biosimilar SB8 (Samsung Bioepis) to all indications of the reference product (Avastin). Overall, despite any remaining concerns about extrapolation of biosimilars among health care providers and patients, the reviewers reported that bevacizumab biosimilars including SB8 have been integrated into clinical practice.

The phase 3 trial that led to the approval of SB8 was conducted in non-small cell lung cancer (NSCLC). As of 2022, the authors said, 9 bevacizumab biosimilars were approved in the European Union and 4 in the US, all of which were investigated in NSCLC. Their review provided an overview of the totality of evidence supporting the effectiveness and safety of SB8 and the real-world use of bevacizumab biosimilars, especially in metastatic colorectal cancer (mCRC).

Bevacizumab inhibits the interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR), inhibiting downstream signaling and consequently tumor angiogenesis. The reference product was originally approved in 2004 by the European Medicines Agency (EMA), and 2005 by the FDA, for mCRC. It is now approved for several other solid tumor types.

Although biosimilars must demonstrate similarity to their reference products in a “stringent regulatory process,” the reviewers said some health care providers remained concerned, in particular about extrapolation. They added, “These concerns are mainly due to poor understanding of the development and regulatory approval process of biosimilars including the concept of extrapolation…consequently, educational efforts are advised to address these concerns.”

Totality of Evidence: Each Step Addresses Residual Uncertainties

The reviewers explained that authorization of a biosimilar is based on the totality of evidence demonstrating similarity, which includes in vitro, nonclinical, and clinical comparisons to establish similarity to the reference product in structure, biological activity, post-translational modifications, pharmacokinetics, pharmacodynamics, efficacy, and safety. Each step in the process is designed to “dispel any residual uncertainty” from previous steps, they wrote. Since efficacy and safety have already been established for the reference product once a biosimilar has been proposed, the aim of studies on a proposed biosimilar is to “exclude any clinically meaningful differences between the proposed biosimilar and its reference product.”

The totality of evidence on SB8, the authors said, demonstrates biosimilarity to the reference bevacizumab.

Justification of Extrapolation

After a proposed biosimilar has demonstrated biosimilarity to the reference product, the authors noted FDA and EMA will grant approval for additional indications via extrapolation, without additional comparability trials, if there is scientific justification that the mechanism of action of the reference product does not differ across its approved indications and the totality of evidence supports that there are no clinically meaningful differences between the biosimilar and reference product. In the case of bevacizumab, the authors noted the proposed mode of action, inhibition of binding of VEGF to its receptor, “is considered to be identical across all approved indications.”

Furthermore, in an analysis of 8 phase 1 to 3 clinical studies on the reference product in patients with colorectal cancers, hormone refractory prostate cancer, metastatic breast cancer, and NSCLC, pharmacokinetic parameters were comparable across all types of tumors. Phase 2 and 3 studies on the reference product for treatment of mCRC, metastatic breast cancer, NSCLC, and multiple other solid tumors consistently found “significant clinical benefit” that resulted in the approval of bevacizumab for treating each of these indications. Although the incidence of adverse events in studies of the reference product varied by indication, they are “predictable within the different indications and are thus expected to be comparable with bevacizumab biosimilars.”

Since the mechanism of action, pharmacokinetics, efficacy, safety, and immunogenicity of the bevacizumab originator are comparable across indications, the authors said, extrapolation of biosimilars to all indications of reference bevacizumab “is scientifically justified.”

Use of Bevacizumab Biosimilars in mCRC

The reviewers said that bevacizumab treatment has been “instrumental” in improving the overall survival of patients with a number of solid tumors including mCRC. Despite any hesitation expressed by health care professionals regarding extrapolation, the reviewers said bevacizumab biosimilars have successfully been incorporated into clinical practice. Although all the currently approved bevacizumab biosimilars were evaluated in clinical trials in patients with NSCLC, they said more than half (56%) of both reference and biosimilar bevacizumab products in Europe are used in colorectal cancers.

Citing drug usage data from IQVIA, they said SB8 is used at similar levels to the reference product in France, Germany, Italy, Spain, and the United Kingdom. In these 4 countries, biosimilars now make up 87% of sold bevacizumab vials. Since bevacizumab biosimilars were introduced in 2019, the number of vials sold has increased while the total sales value has decreased, “emphasizing that indeed biosimilars facilitate patient access to treatment and lower the average price per unit.”

Finally, the reviewers discussed studies on the stability of SB8 and other bevacizumab biosimilars after dilution. Since monoclonal antibodies such as bevacizumab are usually packaged in single-use vials that require dilution prior to administration, they said the stability of the molecule when diluted affects its efficacy. Studies showed that after dilution, SB8 was stable after storage at 2°C to 8°C for 45 days followed by 28°C to 32°C for 3 days. These stability data “can support the definition of increased shelf-life which may eventually reduce drug waste…the prolonged stability of SB8 adds another benefit to the use of SB8 among bevacizumab and its biosimilars.”

Reference

Peeters M, Lipp HP, Park M, Yoon YC, Arnold D. SB8, an approved bevacizumab biosimilar based on totality of evidence: scientific justification of extrapolation. Future Oncol. Published online March 8, 2023. Accessed April 30, 2023. doi: 10.2217/fon-2022-1273.