Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy.
ABSTRACT: Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen(®), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC).A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1.The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments.This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment.NCT01519700.
Project description:Background:Chemotherapy-induced neutropenia is a common result of myelosuppressive chemotherapy treatment. Infections such as febrile neutropenia (FN) are sensitive to the duration of neutropenia as well as the depth of absolute neutrophil count (ANC) at nadir. Filgrastim, a granulocyte colony stimulating factor (G-CSF), can stimulate the function of mature neutrophils. Pegfilgrastim, a long-acting form of filgrastim, has been shown to reduce FN to a greater extent compared to filgrastim. G-CSF agents have been recommended for prophylactic administration with chemotherapy. Apotex developed a proposed pegfilgrastim biosimilar. This study was conducted to confirm that no clinically meaningful efficacy or safety differences exist between Apotex's proposed biosimilar and its reference product. Methods:589 breast cancer patients were randomized and dosed with the proposed pegfilgrastim biosimilar, US-licensed pegfilgrastim reference product, or EU-approved pegfilgrastim reference product. The primary endpoint assessed was the duration of severe neutropenia (DSN) and secondary endpoints included rate of FN and ANC nadir. Results:Data showed that the mean DSN, the primary endpoint measured, was comparable across all three treatments. The As Treated arm had a 95% confidence interval within the equivalence range for the proposed pegfilgrastim biosimilar with the US-licensed and EU-approved pegfilgrastim reference products. Secondary endpoints, which included depth and peak of ANC nadir, time to ANC recovery post-nadir and rates of FN, also showed similarity between the three different treatment groups. The adverse event incidence was similar across treatment arms and there were no unexpected safety events. Conclusions:Overall, these results show that the proposed pegfilgrastim biosimilar is similar to Amgen's US-licensed and EU-approved pegfilgrastim reference products with regard to the clinical efficacy and safety endpoints assessed.Trial registration EMA: European Union Clinical Trials Register: (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-002678-21) Eudract # 2011-002678-21 Registered: 01/10/2012.
Project description:Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2-21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10-14 days, while pegfilgrastim is administered once per cycle. When taken according to the guidelines, pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (<?7 days) and has been shown to be inferior to pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with pegfilgrastim might also aid patient adherence. The introduction of biosimilar pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar pegfilgrastim offers countries using biosimilar filgrastim opportunities to improve adherence and thus cancer survival, whilst offering economic benefits for countries using reference pegfilgrastim. These benefits can be realised in full if biosimilar pegfilgrastim becomes part of routine clinical practice supported by drug and therapeutic committees implementing guidelines with multidisciplinary support in the hospital.
Project description: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.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.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.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.ClinicalTrials.gov identifier, NCT01627990.Hospira Inc, A Pfizer Company, Lake Forest, IL, USA.
Project description:Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy.A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 × 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin.Baseline characteristics were well balanced. DSN was equivalent between groups at mean ± SD 1.36 ± 1.13 (LA-EP2006, n = 155) and 1.19 ± 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected.LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC.The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.
Project description:Neutropenia and febrile neutropenia (FN) are among the most common side effects/complications of chemotherapy. The aim of the present study was to evaluate the practice of the use of biosimilar filgrastim in the primary and secondary prevention of FN, and assess its efficacy and safety. A multi-center, non-interventional epidemiological study of 170 cancer patients aged 23-82 years was conducted. Data were collected via a questionnaire completed based on medical documentation and patient examination over five chemotherapy visits. The risk of FN related to the chemotherapy protocol used was in the range of 10-20% in >50% of the patients (53.5%) and a majority (74.7%) had additional FN risk factors. 60% of the patients received filgrastim as primary prevention of FN, and 40% received it as secondary prevention. In 40.6% of cases, six cycles of chemotherapy were used. More than 90% of patients continued chemotherapy according to the initial recommended dose. In majority of patients, no FN was observed following the final cycle of chemotherapy. Median neutrophil count at visit 1 was 2.2×103/µl and did not fall below that level. Majority of patients (>70%) performed self-injections of filgrastim, and 86.3% of patients were continuing therapy with this drug at the last visit. No treatment-related side effects were recorded. The use of biosimilar filgrastim in the primary and secondary prevention of FN allows to maintain initial chemotherapy dosage. Furthermore, the use of biosimilar filgrastim is safe and tolerable, and has a high acceptance by patients.
Project description:Background:The granulocyte-colony stimulating factor (G-CSF) biosimilar filgrastim (Nivestim™) reduces the duration and severity of neutropenia and the frequency of occurrence of febrile neutropenia (FN). Administration of this biosimilar filgrastim and the patient population receiving it at home have not been sufficiently documented in day-to-day medical practice. Insight into home administration may help optimize the management of FN in this setting, potentially at a reduced cost and patient burden vs hospital administration. Materials and methods:This was a prospective, non-interventional, non-comparative, multisite study involving 171 patients across 29 sites treated with at least one dose of filgrastim. Mean age was 59.3 years, and most patients were female and G-CSF-naïve. The data collected originated from paper-based patient questionnaires and routine documentation by the treating physicians. The primary endpoint was the characterization of patients treated with filgrastim. Secondary endpoints were satisfaction with filgrastim, effectiveness, safety and tolerability, and compliance with prescription. Results:Most patients had solid tumors (95.9%), mainly located in the breast, while 4.7% had malignant hematological disease. Solid tumors were recorded as grade 1 (7.9%), grade 2 (28.0%), grade 3 (45.7%), and grade 4 (3.0%), and the majority of patients classified at TNM Stages I and II. Many patients (71.0%) could self-inject filgrastim and 72.2% found the handling instructions "extremely straightforward and easy to understand" at least once. Nearly all (99.4%) patients found the syringes "easy to use" at least once and 91.7% were willing to continue home administration. The mean patient satisfaction score for home administration was 1.9±0.9, ranging from 1 (very satisfied) to 6 (absolutely dissatisfied). No cases of neutropenia were observed and only one event of FN occurred. Conclusion:Home-based prophylaxis for FN with filgrastim was found to be effective, well tolerated, and well received by patients (ClinicalTrials.gov Identifier: NCT02956967).
Project description:The study aims to assess the relative efficacy of granulocyte colony-stimulating factor (G-CSF) products administered as primary prophylaxis (PP) to patients with cancer receiving myelosuppressive chemotherapy.A systematic literature review identified publications (January 1990 to September 2013) of randomized controlled trials evaluating PP with filgrastim, pegfilgrastim, lenograstim, or lipegfilgrastim in adults receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma. Direct, indirect, and mixed-treatment comparison (MTC) were used to estimate the odds ratio and 95 % credible interval of febrile neutropenia (FN) during cycle 1 and all cycles of chemotherapy combined without adjusting for differences in relative dose intensity (RDI) between study treatment arms.Twenty-seven publications representing 30 randomized controlled trials were included. Using MTC over all chemotherapy cycles, PP with filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. FN risk was also significantly reduced with pegfilgrastim PP versus filgrastim PP. Over all chemotherapy cycles, there was a numerical but statistically nonsignificant increase in the FN risk for lipegfilgrastim PP versus pegfilgrastim PP. Using MTC in cycle 1, PP with filgrastim, pegfilgrastim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk.In this meta-analysis, using MTC without adjustment for RDI, PP with all G-CSFs evaluated reduced the FN risk in patients receiving myelosuppressive chemotherapy. Future studies are needed to assess the influence of RDI on FN outcomes and to eliminate potential bias between G-CSF arms receiving more intensive chemotherapy than control arms.
Project description:Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.
Project description:AIM:This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1). PATIENTS & METHODS:Women (≥18 years) were randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin. RESULTS:For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26). CONCLUSION:LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.
Project description:BACKGROUND:Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. METHODS:Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n?=?121) and the reference product (n?=?118). All patients received up to 6?cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6?mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC?<?0.5?×?109/L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2-4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. RESULTS:The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6?days (reference), with a difference (LS Mean) of 0.1?days (95% CI -0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1?day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified. CONCLUSIONS:Treatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated. TRIAL REGISTRATION:The trial was registered prospectively, prior to study initiation. EudraCT number ( 2013-003166-14 ). The date of registration was 12 July, 2013.