Harbeck, N., Lipatov, O., Frolova, M., Udovitsa, D., Topuzov, E., Ganea-Motan, D.E., . . . Blackwell, K. (2016). Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncology, 12, 1359–1367.

The purpose of the PROTECT-1 study was to confirm efficacy and safety of the biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim (Neulasta^®) in the reduction of duration of severe neutropenia (DSN) in patients with breast cancer receiving myelosuppressive chemotherapy.

1:1 stratified randomization of adult (aged 18 years or older) women with breast cancer (stratified by Europe, Asia, or European region and receipt of adjuvant or neoadjuvant myelosuppressive TAC regimen chemotherapy [docetaxel 75 mg/m², doxorubicin 50 mg/m², and cyclosphosphamide 500 mg/m²]) into a one of two groups to receive either LA-EP2006 or Neulasta. TAC was administered on day 1 of each cycle and then every 3 weeks up to 6 cycles. Patients could remain in the study if they had a 25% reduction in chemotherapy due to a grade 3-4 nonhematologic toxicity, grade 4 thrombocytopenia, or febrile neutropenia. A 6 mg subcutaneous injection of LA-EP2006 or Neulasta was administered on day 2 of each cycle (24 hours or longer following the end of chemotherapy). Patients were followed for 6 months following the last dose of LA-EP2006 or Neulasta.

• N = 316   
• AGE: Mean = 50.2 years (range = 40.4-61.4)
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage I-IV breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: ECOG performance status of 2 or lower; ANC of 1.5 x10⁹/L or greater; platelet count 100 x 10⁹/L or greater; hemoglobin 10 g/dl or greater; normal total bilirubin; AST and ALT 2 x upper limit of normal (ULN) or less; liver-derived alkaline phosphatase 3x ULN or less; creatinine 1.5 x ULN or less; and a negative pregnancy test within seven days of randomization and use of effective birth control for women of childbearing potential. Women were excluded if they had a history of previous or current malignancies and/or hematologic disorders (myelodysplastic syndrome, sickle cell disease, CML) and any current medical condition and concurrent or prior treatment for breast cancer.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 42 sites across cancer centers in Europe, Asia, and America

PHASE OF CARE: Active anti-tumor treatment

Randomized, double-blind study

Outcomes of mean duration of severe neutropenia–number of consecutive days of grade IV neutropenia: ANC 0.5x10⁹/L or less during cycle 1, depth of ANC nadir, time to ANC recover (nadir to ANC 2 x 10⁹/L or greater in cycle 1; incidence of febrile neutropenia (PO temp 38.3^oC or greater with ANC 0.5 x 10⁹ or less) or neutropenic sepsis (FN/NS) by cycle and across cycles; number of patients with fever(PO temp 38.3^oC or greater) per cycle; number of patients with infections per cycle and across cycles; and infection-related mortality. Safety was also measured through the incidence, occurrence, and severity of treatment-emergent adverse events (TEAEs) using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. FNs were reported as AEs. ELISA testing was used to validate immunogenicity of LA-EP2006 or Neulasta.

RESULTS: There were no demographic differences between groups. 159 patients were in the LA-EP2006 group and 157 were in the neulasta group. 19 and 7 discontinued treatment in the LA-EP2006 and neulasta groups, respectively. 2 patients in the neulasta group died from infections; 4 patients in the LA-EP2006 group died (cause of death not disclosed). In cycle 1, the DSN was 0.75 (SD = 0.88) days with LA-EP2006 and 0.83 (SD = 0.9) days with Neulasta. The difference between the groups was 0.07 days (90% CI [-0.09, 0.23]; 95% CI [-0.12, 0.26]).Similar findings in the per protocol analysis No clinically meaningful differences were found between groups for depth of ANC nadir, mean days to ANC recovery,  and time course of mean ANC. Frequency of infections (cycle 1: 4.4%, n = 7 versus 2.5%, n = 4; across cycles: 13.8%, n = 22 versus 15.3%, n = 24). No differences between groups were found for safety (TEAE 1 or greater 88.1% LA-EP2006 and 82.8% neulasta) or neutralizing antibodies.

LA-EP2006 was found to be as effective and safe as neulasta. Use of biosimilar pegfilgrastim can potentially increase the availability of patients receiving prophylactic pegfrilgrastim for improved outcomes while undergoing chemotherapy treatment for cancer.

Infections were not defined and the causes of death of the four patients in the LA-EP2006 arm were not disclosed.

Nurses being aware of biosimilars for pegfilgratim can help guide practice for use of prophylactic pegfilgrastim when standard pegfilgrastim (neulasta) is not available. In addition, nurses can assess patients for risks of adverse events related to chemotherapy treatments.