Proposed Biosimilar Pegfilgrastim (LA-EP2006) and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients with Breast Cancer: A Randomized, Double-Blind Trial. Protect 2: Pegfilgrastim Randomized Oncology (supportive care) Trial to Evaluate Comparative Treatment Results
Authors: Blackwell Kimberley , Paltuev Ruslan , Donskih Roman , Burdaeva Olga , Bit-Sava Elena , Maksud Tanveer , Jones Michael , Nixon Allen , Vidal Maria J , Nakov Roumen , Singh Pritba , Schaffer Gregor , Gascon Pere , Harbeck Nadia 
Published: October 2019

Abstract
Background: Approval of a biosimilar is based on it being highly similar with regard to safety, purity, and potency and with no clinically meaningful differences when compared with a reference product.The first biosimilar, filgrastim (EP-2006), was recently approved in US.LA-EP2006 is a proposed biosimilar to the reference product pegfilgrastim (Neulasta®).
Methods: This was a prospective, randomized, double-blind trial conducted in the US, Latin America, Asia and Europe. Patients with histologically proven breast cancer receiving (neo)-adjuvant TAC chemotherapy (docetaxel 75mg/m2, doxorubicin 50mg/m2, cyclophosphamide 500mg/m2) over six cycles were treated with a single 6mg SC injection of LA-EP2006 or reference pegfilgrastim on day 2 of each cycle. Primary endpoint was the duration of severe neutropenia (DSN) during Cycle 1 defined as number of consecutive days with an absolute neutrophil count (ANC) <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 (two-sided 95% confidence interval [CI]) and then a -0.6 day non-inferiority margin (one-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, depth of ANC nadir, incidence of febrile neutropenia, number of days of fever, infection frequency and mortality due to infection. Safety and immunogenicity were assessed until 4 weeks after last study drug administration.
Results: A total of 308 patients were randomized and included in the full analysis set (LA-EP2006: n=155; reference: n=153). Baseline characteristics were similar in both groups (mean±SD age: LA-EP2006 48.8±10.50, reference 49.1±10.07 years; breast cancer stage II-III: LA-EP2006 n=148 (95.5%), reference n=139 (90.8%). Mean±SD DSN in Cycle 1 was 1.36 ± 1.13 days in the LA-EP2006 group versus 1.19 ± 0.98 days in the reference group (treatment difference −0.16 days; 95% CI: −0.40, 0.08). LA-EP2006 was thus both equivalent and non-inferior to reference pegfilgrastim as the 95% CI was within the defined margin of ±1 day and the lower bound of the 95% CI was entirely above −0.6 days. There were no clinically meaningful differences between LA-EP2006 and reference in incidence of febrile neutropenia (7.7% vs 9.8% in Cycle 1, 10.3% vs 13.1% across all cycles), days with fever, depth of ANC nadir in Cycle 1, time to ANC recovery in Cycle 1, or frequency of infections. Treatment-emergent adverse events (TEAEs) were similar across groups and consistent with the known safety profile of pegfilgrastim. The most frequent TEAEs related to treatment were musculoskeletal and connective tissue disorders (LA-EP2006 16.1%, reference 13.7%). Serious TEAEs were reported in: LA-EP2006 18.7%, reference 20.9%). No neutralizing anti-pegfilgrastim antibodies were detected.
Conclusions: Proposed biosimilar pegfilgrastim (LA-EP2006) met the primary endpoint demonstrating it to be both equivalent and non-inferior 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.
Acknowledgment: The authors acknowledge the other investigators who participated in the PROTECT2 study.

Disclosures
Blackwell: Celgene: Consultancy, Research Funding; GE Healthcare: Consultancy; Genentech: Consultancy, Research Funding; Hospira: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Roche: Consultancy; Sandoz: Consultancy; Pfizer: Research Funding; Genomic Health: Speakers Bureau; Boehringer Ingelheim: Consultancy; Amgen: Consultancy. Nakov:Sandoz: Employment. Singh:Sandoz: Employment. Schaffer:Sandoz: Employment. Gascon:Sandoz: Honoraria, Speakers Bureau. Harbeck:Sandoz: Other: Chair of Data and Safety Monitoring Board (DSMB) on trials sponsored by Sandoz.