FormalPara Key Points
Table 1

1 Introduction

In 2006, the European Medicines Agency (EMA) approved the first biosimilar in Europe (Omnitrope®, Sandoz), followed in 2009 by approval of the granulocyte colony-stimulating factor (G-CSF), Sandoz biosimilar filgrastim (Zarzio®, Sandoz GmbH). Since then, the EMA has approved more than 50 other biosimilars [1, 2]. Sandoz biosimilar filgrastim was the first biosimilar approved by the US FDA in 2015, with 20 subsequent approvals of biosimilars to date [3, 4]. The increasing number of approved biosimilars in the oncology field, including bevacizumab, rituximab, and trastuzumab, may improve the sustainability of cancer care through expansion of available therapeutic options and the potential for reinvestment of funds [5,6,7,8]. For simplicity, we refer to Sandoz biosimilar filgrastim (Zarzio®/Zarxio®) as biosimilar filgrastim in this review.

Biosimilars are biologic medicines that have been shown to match an authorized reference biologic with regards to quality, primary and higher-order structure, biological activity and function, clinical efficacy, safety, and immunogenicity. Biosimilar approval by the EMA and FDA is highly regulated based on the concept of totality of evidence from evaluation of physicochemical and functional characteristics, pharmacokinetic/pharmacodynamic studies, and phase III confirmatory clinical studies [9]. Importantly, phase III confirmatory studies are required to be performed in an indication that is suitably sensitive in order to identify any potential differences in safety, efficacy, or immunogenicity between the biosimilar and reference biologic [9]. Once the safety and efficacy has been confirmed in a sensitive indication, a biosimilar may then be approved for all the licensed indications of the reference medicine without the need to perform clinical studies in each indication, a concept known as extrapolation [10, 11]. It is important that a biosimilar does not automatically receive approval for each indication of the reference medicine; each extrapolated indication must undergo a separate assessment and have solid scientific rationale and justification.

In this review, we discuss the clinical evidence for biosimilar filgrastim, including the phase III confirmatory studies assessing filgrastim as primary prophylaxis to reduce duration of chemotherapy-induced febrile neutropenia [12,13,14]. Following approval, clinical experience and real-world evidence have demonstrated the safety and efficacy of biosimilar filgrastim in patients with different tumor types undergoing myelosuppressive chemotherapy and in both autologous and allogeneic stem cell mobilization and severe chronic neutropenia. Evidence in these extrapolated indications is also included in this review.

2 Biosimilar Filgrastim Phase III Clinical Data

Biosimilar filgrastim was approved by the EMA in 2009 and by the FDA in 2015. The submission to the EMA included confirmatory clinical data from an open-label, single-arm, phase III study performed in patients with breast cancer undergoing myelosuppressive chemotherapy [13, 15, 16]. Other indications, including stem cell mobilization and severe chronic neutropenia, were approved on the basis of extrapolation [17], with no data available at the time of the regulatory review and approval. FDA authorization of biosimilar filgrastim was based on results from PIONEER, a randomized, double-blind, multicenter, phase III confirmatory study that compared biosimilar filgrastim with the US-marketed reference biologic. PIONEER was conducted between December 2011 and June 2013 and thus contributed to the post-EU-approval body of evidence for biosimilar filgrastim [12, 14,15,16].

2.1 EU Registration Study

The EU registration study was a phase III confirmatory study that evaluated biosimilar filgrastim as primary prophylaxis for neutropenia in 170 patients with breast cancer receiving cytotoxic chemotherapy (doxorubicin 60 mg/m2 and docetaxel 75 mg/m2) (Table 1) [13]. In this single-arm study, the primary endpoint, mean duration of severe neutropenia (DSN) in cycle 1 with biosimilar filgrastim (1.8 days) was comparable to previously published results for reference filgrastim (1.6‒1.8 days) [13, 18, 19]. Regarding safety, treatment-emergent adverse events that were considered to be treatment related were generally mild and in line with those historically known for G-CSF therapy [13]. No patient developed antidrug binding or neutralizing antibodies.

Table 1 Summary of phase III and representative post-approval data for EU-approved biosimilars of filgrastim

2.2 US Registration Study

The US registration study was PIONEER, a randomized, double-blind, multicenter, phase III confirmatory study performed in patients with breast cancer (n = 218) receiving up to six cycles of chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 [TAC regimen]) (Table 1) [12]. Biosimilar filgrastim was considered non-inferior to the reference filgrastim, since the mean treatment difference for DSN was 0.02 days, with a lower limit of the 97.5% confidence interval of − 0.27 days, which was entirely above the predefined margin of − 1 day [12]. There were also no clinically meaningful differences in safety and immunogenicity between biosimilar filgrastim and the reference filgrastim [12].

PIONEER also provided the first published clinical evidence in oncology patients regarding repeated switching between a reference biologic and a biosimilar [12, 14, 20]. The results showed no clinically meaningful differences regarding efficacy, safety, or immunogenicity when patients were switched from reference to biosimilar filgrastim, or vice versa [14].

3 Biosimilar Filgrastim Post-Approval Evidence

3.1 Chemotherapy-Induced Neutropenia

Clinical experience in the use of biosimilar filgrastim since the original EU approval has provided further evidence of its efficacy and safety profile [17]. Real-world evidence is available from the MONITOR-GCSF study, a multicenter, prospective, observational study performed in 12 European countries describing the treatment patterns and clinical outcomes of patients with cancer (n = 1447) who received biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia (Table 1) [21]. The real-world data from MONITOR-GCSF showed that biosimilar filgrastim was effective, with a safety profile consistent with historical data for the reference filgrastim and with what is expected for biosimilar filgrastim based on the totality of evidence. In addition, several non-interventional clinical studies with biosimilar filgrastim, conducted post-approval, showed outcomes in accordance with the MONITOR-GCSF study [21], confirming the efficacy and safety of biosimilar filgrastim in real-world clinical practice [22,23,24,25,26,27].

Subanalyses of MONITOR-GCSF have provided evidence for the efficacy and safety profile of biosimilar filgrastim in hematological and solid malignancies [17]. The study enrolled patients with different tumor types, including diffuse large B-cell lymphoma (n = 245) [28], non-small-cell lung cancer (n = 345) [29], and breast cancer (n = 466) [30]. Overall, the results from these subgroup analyses showed that, in real-world clinical practice in these tumor types, biosimilar filgrastim demonstrated similar  efficacy and safety to published data for reference filgrastim, expanding on the evidence for the efficacy, safety, and tolerability from the clinical development program.

3.2 Stem Cell Mobilization

3.2.1 Autologous Stem Cell Mobilization

Beyond the wealth of available data in chemotherapy-induced neutropenia, a large body of evidence is also available from clinical studies for stem cell mobilization in both the autologous and the allogeneic settings [31, 32]. A recent systematic review reported data from 1019 patients undergoing autologous transplantation in a total of 27 studies [33]. Generally, data from studies of stem cell mobilization in the autologous setting demonstrated that the efficacy and safety of biosimilar filgrastim were consistent with the known profile of reference filgrastim. Furthermore, similar results were observed when reference filgrastim was included as a comparator [34,35,36,37,38,39,40,41,42,43,44]. Representative studies of autologous stem cell mobilization with biosimilar filgrastim are summarized in Table 1.

3.2.2 Allogeneic Stem Cell Mobilization

Importantly, although most data in stem cell mobilization are in the autologous setting, evidence is also emerging in allogeneic stem cell mobilization. A recent systematic review discussed the evidence for biosimilar filgrastim in the allogeneic setting, including 331 patients in eight studies [33, 45,46,47,48,49,50]. This included real-world evidence, including data from the largest healthy volunteer donor cohort (n = 244) of allogeneic stem cell mobilization reported to date [51], a long-term ongoing safety surveillance study with a planned duration of 10 years. An interim data analysis from a mean follow-up of 433 days (range 2–1528) showed that the safety profile and the efficacy of biosimilar filgrastim in allogeneic stem cell mobilization were consistent with previously reported data for biosimilar filgrastim [51]. A full analysis will be performed at the completion of the 10-year planned study duration period. Representative studies of allogeneic stem cell mobilization with biosimilar filgrastim are summarized in Table 1. Based on the comprehensive evidence for the safety and efficacy of biosimilars of filgrastim, the World Marrow Donor Association recently recommended their use in healthy donors [52].

3.3 Severe Chronic Neutropenia

As a part of the EMA post-approval commitment to address potential safety concerns for biosimilar filgrastim (e.g., osteoporosis, severe splenomegaly/splenic rupture, acute respiratory distress syndrome, cutaneous vasculitis), a study was performed in patients with severe chronic neutropenia, a group of very rare hematological disorders that may present at birth or later in life. Patients with severe chronic neutropenia have blood neutrophil counts of < 500/μL, lasting for months or years, whereas other blood cell counts remain normal or close to normal. The European Branch of the Severe Chronic Neutropenia International Registry (SCNIR) includes patients in 26 European countries, Israel, Russia, and Turkey. This study included data that had been collected by SCNIR since 1994 on the long-term follow-up of patients with severe chronic neutropenia. Patients who received biosimilar filgrastim between 1 July 2011 and 31 March 2018 were separately analyzed as follow-up of a Sandoz study. Final analysis is ongoing, but no serious adverse events have been reported so far in patients receiving biosimilar filgrastim [53]. The number of treated patients was small because of the rarity of this disease, but the absence of any significant safety findings in this registry analysis led to the EMA’s decision to remove this surveillance activity from the pharmacovigilance plan, indicating that the major safety concerns in this indication with biosimilar filgrastim had been addressed.

4 Extrapolation in Clinical Practice

The experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure and 10 years of real-world clinical evidence, indicating successful extrapolation. Together, this experience can help reassure clinicians, other healthcare professionals (HCPs), and patients that the concept of extrapolation is based on strong scientific evidence and principles. Furthermore, other biosimilars of filgrastim are available and, alongside biosimilars of epoetin alfa and recently approved biosimilars of pegfilgrastim, offer HCPs and patients several options for improved sustainability of supportive cancer care. Table 1 highlights the abundance of data available for these biosimilars of filgrastim, with phase III confirmatory studies performed in patients undergoing cytotoxic chemotherapy receiving G-CSF for prevention of neutropenia. The availability of clinical data is just one approach to provide reassurance about biosimilars and must be complemented by patient education, clinical practice recommendations, regulatory guidance, and positioning statements such as those recently published by the American Society of Clinical Oncology and the European Society for Medical Oncology [54, 55], if the full potential of biosimilars in oncology is to be realized.

A total of 14 types of biosimilars approved in the EU, and nine types approved in the USA, indicates the level of uptake of biosimilars. Acceptance of biosimilars is also reflected by the inclusion of biosimilars of filgrastim and biosimilars of epoetin in international clinical practice guidelines [79,80,81,82]. This adoption of biosimilars has been driven by several factors, including the experience with established biosimilars such as filgrastim and epoetin alfa, which has in turn improved understanding of the biosimilar concept and totality of evidence and confidence in the extrapolation concept [83]. A recent survey by the European Society for Medical Oncology assessed oncology specialists’ level of understanding and comfort with using biosimilars [84]. The survey reported that nearly half of responding prescribers used biosimilars in their clinical oncology practice, and ~ 80% reported an average to very high level of biosimilar knowledge [84], showing an encouraging level of understanding of biosimilars and comfort in their use in oncology. However, switching was identified as an area in which prescribers were less confident at the time of survey. Nonetheless, the latest publication of switching studies in oncology [12, 14, 20] and other therapeutic areas [85,86,87,88] has contributed to acceptance of biosimilars, including those more recently approved. In addition, a recent systematic review assessed whether switching could lead to altered clinical outcomes. It included data from 90 studies that enrolled 14,225 subjects and reported that the vast majority of studies did not show differences in efficacy or safety after multiple switches [89]. Systematic reviews such as this, and publication of real-world evidence, will help further reassure physicians and drive acceptance of biosimilars. Finally, the efforts of international medical oncology societies in providing guidance on using biosimilars [54, 55] have also paved the way for acceptance of newer biosimilars, allowing more patients to benefit. This support must be continued to maintain clinical confidence in biosimilars in oncology.

5 Conclusion

The stringent processes for biosimilar development, including the totality of evidence approach based on solid scientific evidence, and the review and approval by regulatory bodies such as the EMA and FDA, should reassure HCPs and patients that approved biosimilars are efficacious and safe. Biosimilar filgrastim provides a practical example of how a decade of clinical experience can reassure HCPs regarding the extrapolation concept and the safety and efficacy of biosimilars in different indications.