FDA Approves Second Filgrastim Biosimilar

The FDA approved filgrastim-aafi (Nivestym), a filgrastim (Neupogen) biosimilar, to prevent and treat side effects associated with cancer treatment, including febrile neutropenia and severe neutropenia.

Pfizer, the maker of filgrastim-aafi, issued a press release July 20 announcing the agency’s decision.

“The FDA approval of Nivestym marks an important step in helping expand access to critical treatment options for patients with neutropenia, many of whom have cancer and can be hospitalized for potentially life-threatening side effects stemming from chemotherapy,” Berk Gurdogan, US Institutions president for Pfizer Essential Health, said in a statement. “We believe biosimilars, like Nivestym, are essential in helping to address evolving healthcare needs and may provide more affordable medicines to patients.”

Filgrastim-aafi is indicated to reduce the incidence and duration of neutropenia and neutropenia-related clinical sequelae in:

• Patients with nonmyeloid malignancies undergoing myelosuppressive therapy
• Patients with acute myeloid leukemia following induction or consolidation chemotherapy
• Patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation
• Patients with chronic congenital, cyclic, or idiopathic neutropenia
• Patients undergoing autologous hematopoietic progenitor cell collection and treatment

Filgrastim-aafi is the second filgrastim biosimilar approved for use in the United States following the 2015 approval of EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz).

In results from a combined analysis of the phase III PROTECT-1 (NCT01735175) and PIONEER (NCT01519700) trials published in March, EP2006 produced safety results equivalent to those observed with referent filgrastim. The mean duration of severe neutropenia was 1.04 (±1.51) days in cycle 1, meeting the primary endpoint. 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.

PROTECT-1 was a single-arm, open-label European study of biosimilar filgrastim in adult women treated with 60 mg/m² of doxorubicin and 75 mg/m² docetaxel for breast cancer. PIONEER was a randomized, double-blind study comparing EP2006 with filgrastim in adult women with breast cancer in the United States who received neoadjuvant or adjuvant treatment with TAC chemotherapy (docetaxel 75 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m²).

Women in both studies were chemotherapy-naïve and had ECOG performance score ≤2. PIONEER included patients in stages I to III, while PROTECT-1 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 PIONEER received 5 µg/kg of filgrastim per day. In PROTECT-1, 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 no serious TEAEs 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, but that death was not believed to be related to the 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%).

In its Biosimilars Action Plan issued earlier this month, the FDA said that there are 68 programs enrolled in the agency’s Biosimilar Product Development (BPD) Program as of July 1. The BPD is designed to “facilitate the rapid development of biosimilar and interchangeable products.”

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. 2018;23(4):403-409. doi: 10.1634/theoncologist.2017-0348.