Abstract
BackgroundChemotherapy-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.Methods589 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.ResultsData 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.ConclusionsOverall, 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
Highlights
Chemotherapy-induced neutropenia is a common result of myelosuppressive chemotherapy treatment
Myelosuppressive chemotherapy treatment commonly results in chemotherapy-induced neutropenia (CIN), a complication associated with a high risk of morbidity, mortality, and hospitalization [1]
For the As Randomized population, the 95% confidence interval (CI) of the difference in mean duration of severe neutropenia (DSN) in Cycle 1 between the proposed pegfilgrastim biosimilar and United States (US)-licensed pegfilgrastim reference product was slightly outside the equivalence margin, but for the proposed pegfilgrastim biosimilar and European Union (EU)-approved pegfilgrastim reference product was contained within the pre-defined margin (Table 2)
Summary
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. After a course of chemotherapy, the duration of neutropenia and depth of the absolute neutrophil count (ANC) at nadir, correlates with the development of infections including febrile neutropenia (FN), sepsis and their morbidities [2, 3]. Pegfilgrastim retains the same biological activity as filgrastim and binds to the same G-CSF receptor. In both experimental animals and healthy human volunteers, pegfilgrastim showed decreased renal clearance and increased plasma half-life compared with unpegylated filgrastim, allowing pegfilgrastim a sustained pharmacological effect [6]. Patients receiving pegfilgrastim experienced a lower incidence of FN than patients receiving filgrastim [7]
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