Efficacy and safety of BCD-017, a novel pegylated filgrastim: Results of open-label controlled phase II study in patients with breast cancer receiving myelosuppressive chemotherapy.

Abstract

e20593 Background: Pegfilgrastim (conjugate of filgrastim and 20 kDa polyethylene glycol (PEG) is approved for treatment of chemotherapy-associated neutropenia. BCD-017 (empegfilgrastim) is a covalent conjugate of filgrastim with 30 kDa PEG. Increased molecular weight of PEG molecule may provide additional benefits compared to pegfilgrastim. Methods: To compare efficacy and safety of filgrastim and BCD-017 at 3 mg and 6 mg doses an open-label, randomized, active-comparator, non-inferiority trial was conducted. 60 patients with histologically or cytologically confirmed breast cancer were randomly assigned to receive either subcutaneous (s.c.) injection of 3 mg BCD-017 (n=21), 6 mg BCD-017 (n = 20), or 5 mg/kg s.c. injections of filgrastim (n=19) administered daily until ANC ≥ 10x109 cells/L (maximum of 14 days) after chemotherapy (doxorubicin 60 mg/m2 and docetaxel 75 mg/m2) with stratification for weight and prior chemotherapy exposure. The primary efficacy endpoint was the incidence of severe neutropenia (ANC < 1.0x109 cells/L) during the first cycle of chemotherapy. Results: Incidence of severe neutropenia during the first chemotherapy cycle was 85,7%, 65,0% and 61,1% in BCD-017 3 mg, BCD-017 6 mg and filgrastim groups, respectively. Differences between BCD-017 groups and filgrastim group were not significant. Mean duration of grade 4 neutropenia in cycle 1 was 0,43, 0,40 and 0,33 days, accordingly (95% CI for difference between BCD-017 3 mg and filgrastim groups -0.22 to 0.41; 95% CI for difference between BCD-017 6 mg and filgrastim groups -0.25 to 0.38). Febrile neutropenia was observed only in BCD-017 3 mg and BCD-017 6 mg groups (one case in each group). A single administration of BCD-017 at the doses of 3 mg and 6 mg was as safe and well tolerated as standard daily filgrastim administration. There were no unexpected adverse events in all groups. Conclusions: The results of this study support comparable efficacy of single s.c. injection of 6 mg BCD-017 versus daily 5 mg/kg s.c. injections of filgrastim. Further phase III study of BCD-017 for treatment and prophylaxis of neutropenia in patients receiving chemotherapy is necessary. Clinical trial information: NCT01569087.

Systematic Review and Meta-analysis of Short- versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia

“…Seventeen publications reported RCT data: five congress abstracts [ 34 , 42 , 47 – 49 , 60 ], four full foreign language publications with an English abstract [ 52 , 56 , 58 , 59 ], and eight full English language publications [ 33 , 35 , 36 , 45 , 51 , 53 , 55 , 57 ]. Publications reported data from RCTs conducted in China ( n = 6) [ 51 , 52 , 56 – 59 ], multiple countries worldwide ( n = 3) [ 35 , 36 , 53 ], Russia ( n = 2) [ 34 , 48 , 60 ], India ( n = 2) [ 47 , 49 ], Europe ( n = 1) [ 42 ], Korea ( n = 1) [ 45 ], Italy ( n = 1) [ 33 ], and the United States ( n = 1) [ 55 ]. Studies compared pegfilgrastim with filgrastim ( n = 10) [ 33 , 35 , 36 , 42 , 45 , 49 , 51 , 53 , 55 , 57 ], the long-acting G-CSF empegfilgrastim with filgrastim ( n = 2) [ 34 , 48 , 60 ], and a pegylated G-CSF with an unpegylated daily dose G-CSF (drug name not provided; n = 5) [ 47 , 52 , 56 , 58 , 59 ].…”

“…Eleven RCTs assessed the incidence of FN with short- and long-acting G-CSFs (Supplementary Appendix Table S8) [ 33 – 36 , 45 , 48 , 49 , 51 – 53 , 57 , 60 ]. Of these, nine studies included patients by specific cancer type [ 33 – 36 , 45 , 48 , 49 , 53 , 57 , 60 ] and two included patients across cancer types [ 51 , 52 ].…”

“…Eleven RCTs assessed the incidence of FN with short- and long-acting G-CSFs (Supplementary Appendix Table S8) [ 33 – 36 , 45 , 48 , 49 , 51 – 53 , 57 , 60 ]. Of these, nine studies included patients by specific cancer type [ 33 – 36 , 45 , 48 , 49 , 53 , 57 , 60 ] and two included patients across cancer types [ 51 , 52 ]. None of the RCTs reported a statistically significant difference in the incidence of FN between short- and long-acting G-CSFs [ 33 – 36 , 45 , 48 , 49 , 51 – 53 , 57 , 60 ].…”

“…Furthermore, an observational study reported lower adherence to treatment guidelines and recommendations for timing of G-CSF initiation with use of filgrastim/lenograstim versus pegfilgrastim [ 65 ]. Among the studies identified in this SLR, few non-RCTs (2 of 24) and nearly all RCTs (11 of 12) indicated that short-acting G-CSF was administered for ≥ 7 days [ 6 , 27 – 31 , 34 – 36 , 42 , 45 , 48 , 49 , 51 – 53 , 57 , 60 ]. This observation supports other evidence of under-dosing of short-acting G-CSFs in real-world clinical practice and that compliance is likely to be lower in routine clinical practice compared with RCTs.…”

“…Most (11 of 17) RCTs included in this meta-analysis were described as open-label [ 36 , 42 , 45 , 47 , 48 , 51 , 52 , 55 , 57 – 59 ]. The absence of blinding in open-label studies may increase the risk of performance and detection bias.…”