Biosimilar Filgrastim Safety Confirmed in Analysis

Nadia Harbeck, MD, PhD

EP2006 (Zarxio; biosimilar filgrastim-sndz), a filgrastim (Neupogen) biosimilar, produced safety results equivalent to those observed with referent filgrastim in a combined analysis of 2 phase III breast cancer studies from the United States and Europe.

Mean duration of severe neutropenia (primary endpoint) was 1.04 (±1.51) days in cycle 1. The mean absolute neutrophil count (ANC) time course showed the expected increase at day 3 and subsequent decrease with nadir at days 7 to 8, with recovery from day 10.

“This combined analysis provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of G-CSF and is effective in the prevention of febrile neutropenia in patients with breast cancer undergoing myelosuppressive chemotherapy,” wrote Nadia Harbeck, MD, PhD, Brustzentrum der Universität München, Munich, Germany, and colleagues.

“These findings are in line with real-world evidence from the MONITOR-GCSF study, showing that the safety profile of biosimilar filgrastim is similar to historical safety data for reference filgrastim,” added Harbeck et al.

EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009, and in March 2015 became the first biosimilar approved by the FDA, when it was authorized for all 5 indications of its counterpart, the G-CSF analog filgrastim (Neupogen).

The treatment is indicated for patients with cancer who are receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, patients undergoing autologous peripheral blood progenitor cell collection and therapy, and those with severe chronic neutropenia.

In the current safety analysis, researchers reviewed combined data from the EP06-302 study in the United States and the EP06-301 study in Europe.

EP06-302 was a randomized, double-blind study comparing EP2006 with filgrastim in adult women with breast cancer who received neoadjuvant or adjuvant treatment with TAC chemotherapy (docetaxel 75 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m²). EP06-301 was a was a single-arm, open-label study of biosimilar filgrastim in adult women treated with 60 mg/m² of doxorubicin and 75 mg/m² docetaxel for breast cancer.

“Breast cancer treated by myelosuppressive chemotherapy is considered a sensitive indication in which similarity can be confirmed and any clinically meaningful differences between G-CSF products and their biosimilars can be resolved,” the investigators wrote.

Women in both studies were chemotherapy-naïve and had ECOG performance score ≤2. EP06-302 included patients between stages I and III, while EP06-301 included patients from stage II to IV. In both studies, patients received EP2006 as a subcutaneous bolus injection from day 2 of each cycle for up to 14 days or until ANC reached 10 x 10⁹/L after the expected nadir.

Patients in EP06-302 received 5 µg/kg of filgrastim per day. In EP06-301, the total daily dose of filgrastim was 300 µg for women weighing <60 kg and 480 µg for women weighing ≥60 kg.

The primary efficacy endpoint for this combined analysis was the mean duration of severe grade 4 neutropenia during cycle 1 of chemotherapy, defined as the number of consecutive days with an ANC <0.5 x 10⁹/L. Secondary efficacy endpoints included the number of patients who reported ≥1 fever episode, total number of days of fever, incidence of febrile neutropenia, and hospitalization due to febrile neutropenia.

A total of 277 patients across both studies received EP2006; 244 patients are included in this analysis. Mean age was 51.1 years (±10.8), and 78.7% of patients had stage II or III breast cancer.

In cycles 1 to 4 of treatment, 98.7% of patients receiving biosimilar filgrastim experienced treatment-emergent adverse events (TEAEs). Most TEAEs (96.9%) were related to chemotherapy including alopecia, nausea, asthenia, fatigue, neutropenia, and leukopenia. Investigators found that no serious TEAEs were associated with filgrastim.

About 10% of patients developed serious TEAEs, the most common being febrile neutropenia. Sixteen (7.2%) patients experienced serious febrile neutropenia in cycle 1. One patient died on day 6 of cycle 1 while receiving biosimilar filgrastim. This was not suspected to be related to study treatment.

Forty-six (20.6%) patients experienced TEAEs suspected to be related to EP2006, most frequently musculoskeletal and connective tissue disorders (15.2%), including bone pain (7.2%), myalgia (7.2%), musculoskeletal pain (1.8%), and arthralgia (1.8%). Other TEAEs related to study treatment included general disorders and administration site conditions (4.9%), blood and lymphatic system disorders (4.5%), and gastrointestinal disorders (1.8%).

Harbeck N, Gascón P, Krendyukov A, et al. Safety profile of biosimilar filgrastim (Zarzio/Zarxio): a combined analysis of phase III studies [published online January 9, 2018]. Oncologist. doi: 10.1634/theoncologist.2017-0348.