Compatibility of Biosimilar Filgrastim with Cytotoxic Chemotherapy during the Treatment of Malignant Diseases (VENICE): A Prospective, Multicenter, Non-Interventional, Longitudinal Study

Introduction Febrile neutropenia (FN) is a serious and frequent complication of cytotoxic chemotherapy. Biosimilar filgrastim (Nivestim™, Hospira Inc, A Pfizer Company, Lake Forest, IL, USA) is a granulocyte-colony stimulating factor licensed for the treatment of neutropenia and FN induced by myelosuppressive chemotherapy. The primary goal of this VENICE study (ClinicalTrials.gov identifier, NCT01627990) was to observe the tolerability, safety and efficacy of biosimilar filgrastim in patients receiving cancer chemotherapy. Methods This was a prospective, multicenter, non-interventional, longitudinal study. Consenting adult patients with solid tumors or hematologic malignancies for whom cytotoxic chemotherapy and treatment with biosimilar filgrastim was planned were enrolled. Results Among the enrolled patients (N = 386), 81% were female, with a median age (range) of 61 (22–92) years, with 39% >65 years old. Most patients (n = 338; 88%) had solid tumors and the remainder (n = 49; 13%) had hematological malignancies. The majority of the patients (64%) received biosimilar filgrastim as primary prophylaxis and 36% as secondary prophylaxis. At the follow-up visits, for the majority of patients (95.6%) there had been no change in chemotherapy dose due to FN. For two patients (0.5%) the chemotherapy was discontinued due to FN and for four patients (1.0%) the chemotherapy dose was reduced due to FN. For the majority of patients (96.9%) the chemotherapy cycle following the first biosimilar filgrastim treatment was not delayed due to FN. For 3 patients (0.8%), the chemotherapy was delayed following the first biosimilar filgrastim treatment. Less than one-third (29.8%) of the patients experienced ≥1 adverse event that was at least potentially related to biosimilar filgrastim treatment. Conclusions Biosimilar filgrastim was effective and well-tolerated in both the primary and secondary prophylactic setting in patients undergoing chemotherapy for solid tumors and hematological malignancies. Trial Registration ClinicalTrials.gov identifier, NCT01627990. Funding Hospira Inc, A Pfizer Company, Lake Forest, IL, USA.

biosimilar filgrastim treatment. Less than one-third (29.8%) of the patients experienced C1 adverse event that was at least potentially related to biosimilar filgrastim treatment.
Conclusions: Biosimilar filgrastim was effective and well-tolerated in both the primary and secondary prophylactic setting in patients undergoing chemotherapy for solid tumors and hematological malignancies.

INTRODUCTION
Chemotherapy-induced neutropenia (CIN) is a common and serious complication of myelosuppressive chemotherapy [1].
Neutropenia is associated with life-threatening infections and may delay the chemotherapy schedule, having a negative impact on early and long-term outcomes [2]. It is associated with significant morbidity and mortality, and may increase the overall cost of providing cancer therapy [3]. The results of three large-scale studies demonstrated that primary prophylaxis with a granulocyte-colony stimulating factor (G-CSF) significantly reduces the incidence of febrile neutropenia (FN) resulting from cytotoxic chemotherapy [4][5][6]. Thus, G-CSF products reduce the risk of infectious complications and with it, the consequent loss of therapeutic options, which may result from neutropenia [7]. The use of a G-CSF plus antibiotics may reduce hospitalization time and improve the ability to achieve neutrophil recovery in individuals with chemotherapy-induced FN [8]. Several G-CSF biosimilar filgrastim products [Ratiograstim Ò (Ratiopharm, Ulm, Germany) Tevagrastim Ò (Teva, Petah Tikva, Israel), Biograstim Ò (CT Arzneimittel, Ulm, Germany) Zarzio Ò (Sandoz, Basel, Switzerland) Nivestim Ò (Hospira Inc, A Pfizer Company, Lake Forest, IL, USA)] [9] to the reference product Neupogen Ò (Amgen, Thousand Oaks, USA) have been approved in Europe [10]. All these products are manufactured in facilities with state-of-the-art technology and have passed the regulatory requirements for approval, mainly phase I and phase III trials, with the consequent pharmacodynamic/pharmacokinetic (PD/PK) evaluations and studies on efficacy and safety; however, there are still some unresolved questions regarding their long-term evaluation, in particular, the limited real-world experience at the time of approval of these products in terms of efficacy, safety and immunogenicity.
Biosimilar filgrastim (Nivestim) is a 175-amino acid protein recombinant methionyl human G-CSF, with a molecular weight of 18,800 Da, that is produced in Escherichia coli [11]. The active substance is non-glycosylated protein, containing an N-terminal methionyl extension. It stimulates the proliferation, differentiation and activation of late progenitor cells of the granulocyte lineage and enhances the activity of mature neutrophils.
Since the use of biosimilar filgrastim has not yet been sufficiently documented in the context of day-to-day medical practice, the goal of the VENICE study, (i.e., Compatibility of Nivestim with Cytotoxic Chemotherapy in the Treatment of Malignant Diseases) (ClinicalTrials.gov identifier, NCT01627990) was to assess the tolerability, safety and efficacy of prophylactic biosimilar filgrastim to reduce the duration of neutropenia and the incidence of FN in patients receiving cytotoxic cancer chemotherapy [12]. The VENICE study was a multicenter, prospective, longitudinal, observational study designed to evaluate the use of biosimilar filgrastim in 'real-world' clinical practice.

METHODS
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was not required from patients as this was a non-interventional observational trial.

Patient Population
The study enrolled children and adults of either gender with solid or malignant hematological tumors who were scheduled to undergo prophylactic treatment with biosimilar filgrastim (Nivestim) to shorten the duration of a neutropenia, or to prevent the occurrence of chemotherapy-induced FN. Reasons for exclusion from the study included chronic myeloid leukemia or myelodysplastic syndrome, hypersensitivity to any component of the biosimilar filgrastim product, not undergoing chemotherapy, or being treated curatively with G-CSF.

Primary Outcome Measures
The primary objective was to assess the tolerability, safety and efficacy of prophylactic treatment using biosimilar filgrastim in patients receiving cytotoxic chemotherapy for cancer, with an emphasis on patients undergoing in-patient treatment.

Secondary Outcome Measures
The secondary objectives were to describe the characteristics of patients being treated with biosimilar filgrastim; the treatment modalities using biosimilar filgrastim; and the characteristics of participating physicians and their prescribing practices with regard to G-CSF.   Other tumor types are summarized in Table 4. Based on the TNM classification system, the majority of solid tumors were small, low-grade cancers with no metastasis, although they ranged from Stage I to Stage IV.

Chemotherapy
The goal of chemotherapy for all patients at enrollment was adjuvant (49%) or curative (31.9%) (

Hematologic Laboratory Values
Median hemoglobin and thrombocyte values in all tumor subgroups remained relatively 3.2 9 10 9 /L, increasing to 4.1 9 10 9 /L before the last chemotherapy cycle (Table 8). For patients with breast cancer, the median leukocyte value was 4.3 9 10 9 /L, increasing to 5.3 9 10 9 /L, while the median leukocyte value

Adverse Events
In the course of the study, 29.8% of patients experienced C1 AE that was at least potentially related to biosimilar filgrastim treatment ( Table 9). The treatment related AEs reported most frequently were musculoskeletal and connective tissue disorders (12.3%) with the preferred term (PT) bone pain (7.6%); general   Less than one percent (0.8%) of patients had a delay in their chemotherapy due to FN after the first biosimilar filgrastim treatment and for 4.7% of patients, the chemotherapy in any subsequent cycle was delayed because of neutropenia. Reduction of the chemotherapy dose after first biosimilar filgrastim treatment due to FN was reported for 1% of patients and reduction of the chemotherapy dose in any subsequent cycle due to neutropenia was reported for 4.7% of patients.

Patient-Reported Data
The majority of patients administered the biosimilar filgrastim injection themselves at both treatment visits (77.7% at first visit and 68.6% at last visit). On a scale of very difficult to very easy, most of the self-applicators reported that the application was easy or very easy. On a scale of 0 (no pain) to 10 (extreme pain) most patients perceived the pain of the biosimilar filgrastim injection as mild (median score 1.0).