Abstract P1-10-01: A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1)
Authors: Harbeck N , Zbarskaya I , Lipatov O , Frolova M , Udovitsa D , Topuzov E , Ganea-Motan DE , Nakov R , Singh P , Rudy A , Blackwell K 
Published: May 2016

Abstract
Background: An abbreviated pathway for biological products shown to be biosimilar to the reference product exists in Europe and the US. The randomized PROTECT1 trial compared the efficacy and safety of the proposed biosimilar pegfilgrastim with reference pegfilgrastim.
Methods: In this multinational, prospective, double-blind trial, chemotherapy-naïve women aged ≥18 years with histologically proven breast cancer received up to 6 cycles of (neo)-adjuvant TAC chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2). Patients were randomized to a single 6 mg SC injection of the proposed biosimilar pegfilgrastim (LA-EP2006) or the reference (Neulasta®) on day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) during Cycle 1, defined as number of consecutive days with an absolute neutrophil count (ANC) &lt;0.5 x 109/L. The study was powered at 90% and had a hierarchical testing procedure utilizing a ±1 day margin to test for equivalence (2-sided 95% confidence interval [CI]) and a subsequent −0.6 day non-inferiority margin (1-sided 97.5% CI) for DSN during Cycle 1. DSN was analyzed with an ANCOVA model adjusted for treatment, chemotherapy, region and baseline ANC. Secondary efficacy assessments were: time to ANC recovery, ANC nadir, incidence of febrile neutropenia, number of days of fever, frequency of infections and mortality due to infection. Safety was assessed at 4 weeks and 6 months after the last pegfilgrastim administration. Immunogenicity was assessed by testing for neutralizing anti-pegfilgrastim antibodies.
Results: A total of 316 patients were randomized and included in the full analysis set (LA-EP2006: n=159; reference: n=157). Baseline demographics were similar in both groups (mean±SD age: LA-EP2006 49.9±9.53, reference 50.5±10.87 years; breast cancer stage II-III: LA-EP2006 n=155 [97.5%], reference n=151 [96.2%]). Mean±SD DSN in Cycle 1 was 0.75±0.88 days with LA-EP2006 and 0.83±0.90 days with reference, with a treatment difference of 0.07 days (95% CI: −0.12, 0.26); LA-EP2006 was both equivalent and non-inferior to the reference. There were no clinically meaningful differences between LA-EP2006 and reference in incidence of febrile neutropenia (3.8% vs 7.0% in Cycle 1, 5.7% vs 7.6% across all cycles), days with fever, depth of ANC nadir in Cycle 1, time to ANC recovery in Cycle 1, or frequency of infections in Cycle 1 and across all cycles. Treatment-emergent adverse events (TEAEs) were similar across groups and consistent with the known safety profile of pegfilgrastim. Most frequently reported TEAEs related to treatment were musculoskeletal and connective tissue disorders (LA-EP2006 4.4%, reference 5.7%). Serious TEAEs were reported in 10.1% of LA-EP2006 and 13.4% of reference patients. No neutralizing anti-pegfilgrastim antibodies were detected.
Conclusions: Proposed biosimilar pegfilgrastim (LA-EP2006) met the primary endpoint demonstrating both equivalence and non-inferiority to the reference. LA-EP2006 and the reference are similar with no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving (neo)-adjuvant myelosuppressive chemotherapy.
Citation Format: Harbeck N, Zbarskaya I, Lipatov O, Frolova M, Udovitsa D, Topuzov E, Ganea-Motan DE, Nakov R, Singh P, Rudy A, Blackwell K. A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-01.