Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer

K Blackwell, P Gascon, C M Jones, A Nixon, A Krendyukov, R Nakov, Y Li, N Harbeck, K Blackwell, P Gascon, C M Jones, A Nixon, A Krendyukov, R Nakov, Y Li, N Harbeck

Abstract

Background: Following the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population.

Patients and methods: LA-EP2006 is a proposed biosimilar that has been developed for pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference pegfilgrastim with LA-EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor.

Results: A total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA-EP2006: n = 314; reference: n = 310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA-EP2006 and reference groups (1.05 ± 1.055 days versus 1.01 ± 0.958 days), with a treatment difference of - 0.04 days [95% confidence interval (CI): -0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of ±1 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference pegfilgrastim, and there were no reports of neutralizing antibodies.

Conclusions: This pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference pegfilgrastim in patients with breast cancer receiving TAC chemotherapy.

Clinical trial numbers: NCT01735175 and NCT01516736.

Keywords: biosimilar; breast cancer; granulocyte colony-stimulating factor; neutropenia; pegfilgrastim.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

References

    1. Bui LA, Hurst S, Finch GL. et al. Key considerations in the preclinical development of biosimilars. Drug Discov Today 2015; 20(Suppl 1): 3–15.
    1. Holzmann J, Balser S, Windisch J.. Totality of the evidence at work: the first U.S. biosimilar. Expert Opin Biol Ther 2016; 16(2): 137–142.
    1. Windisch J. Biosimilars versus original biologics. Similarities and differences from development to approval. Z Rheumatol 2015; 74(8): 672–681.
    1. European Medicines Agency. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies—Non-clinical and Clinical Issues. London, UK: Committee for Medicinal Products for Human Use; 2014.
    1. Federal Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015; (1 July 2016, date last accessed).
    1. Gabrilove JL. An analysis of current neutropenia therapies, including pegfilgrastim. Clin Cornerstone 2006; 8(Suppl 5): S19–S28.
    1. Mitchell S, Li X, Woods M. et al. Comparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: a systematic review. J Oncol Pharm Pract 2016; 22(5): 702–716.
    1. Kourlaba G, Dimopoulos MA, Pectasides D. et al. Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer. Support Care Cancer 2015; 23(7): 2045–2051.
    1. Blackwell K, Donskih R, Jones CM. et al. A comparison of proposed biosimilar LA-EP2006 and reference pegfilgrastim for the prevention of neutropenia in patients with early-stage breast cancer receiving myelosuppressive adjuvant or neoadjuvant chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a phase III, randomized, double-blind trial. Oncologist 2016; 21(7): 789–794.
    1. Harbeck N, Lipatov O, Frolova M. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 2016; 12(11): 1359–1367.
    1. Holmes FA, O'Shaughnessy JA, Vukelja S. et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002; 20: 727–731.
    1. Green MD, Koelbl H, Baselga J. et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003; 14: 29–35.
    1. Nabholtz JM, Mackey JR, Smylie M. et al. Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 2001; 19: 314–321.
    1. Mackey JR, Pieńkowski T, Crown J. et al.; Translational Research In Oncology (TRIO)/Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol 2016; 27: 1041–1047.
    1. Bondarenko I, Gladkov OA, Elsaesser R. et al. Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy. BMC Cancer 2013; 13: 386..
    1. Volovat C, Gladkov OA, Bondarenko IM. et al. Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer receiving chemotherapy. Clin Breast Cancer 2014; 14: 101–108.
    1. Holmes FA, Jones SE, O’Shaughnessy J. et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 2002; 13: 903–909.
    1. Masuda N, Tokuda Y, Nakamura S. et al. Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial. Support Care Cancer 2015; 23: 2891–2898.
    1. Yang BB, Morrow PK, Wu X. et al. Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe. Cancer Chemother Pharmacol 2015; 75(6): 1199–1206.
    1. Potosky AL, Malin JL, Kim B. et al. Use of colony-stimulating factors with chemotherapy: opportunities for cost savings and improved outcomes. J Natl Cancer Inst 2011; 103: 979–982.
    1. Weycker D, Hackett J, Edelsberg JS. et al. Are shorter courses of filgrastim prophylaxis associated with increased risk of hospitalization? Ann Pharmacother 2006; 40: 402–407.
    1. Naeim A, Henk HJ, Becker L. et al. Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF). BMC Cancer 2013; 13: 11..
    1. Almenar Cubells D, Bosch Riog C, Jiminez Orozco E. et al. Effectiveness of daily versus non-daily granulocyte colony-stimulating factors in patients with solid tumours undergoing chemotherapy: a multivariate analysis of data from current practice. Eur J Cancer Care (Engl) 2013; 22: 400–412.
    1. Aapro MS, Bohlius J, Cameron DA. et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011; 47: 8–32.
    1. Lyman GH. Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 2006; 20: 16–25.
    1. Aapro M, Cornes P, Abraham I.. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract 2012; 18(2): 171–179.
    1. Hadji P, Kostev K, Schröder-Bernhardi D. et al. Cost comparison of outpatient treatment with granulocyte colony-stimulating factors (G-CSF) in Germany. Int J Clin Pharmacol Ther 2012; 50(4): 281–289.
    1. Hirsch BR, Lyman GH.. Pharmacoeconomics of the myeloid growth factors: a critical and systematic review. Pharmacoeconomics 2012; 30(6): 497–511.

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