Pooled Analysis on the Effectiveness and Safety of Lipegfilgrastim in Patients With Urological Malignancies in the Real-World Setting

Lipegfilgrastim is a long-acting glycopegylated granulocyte-colony stimulating factor (G-CSF) approved for the management of chemotherapy-induced neutropenia. In general, there is little information on the use of any G-CSFs specifically in patients with urological malignancies receiving chemotherapy. This report combines information from two prospective non-interventional studies on the prophylactic use of lipegfilgrastim in urological cancer patients receiving chemotherapy in the real-world setting. Data were derived from two phase IV studies (NADIR and LEOS) with similar protocols conducted in nine European countries. Analysis included 228 patients (142 prostate, 50 testicular, 27 bladder, and 9 other urological cancers). Chemotherapy-induced febrile neutropenia risk was classified as high (43.0%), intermediate (49.1%), or low (7.5%). Lipegfilgrastim was administered as primary (n=180, 78.9%) or secondary (n=29, 12.7%) prophylaxis. The incidence of febrile neutropenia over all chemotherapy cycles (n=998) and first cycles (n=228) for which lipegfilgrastim was administered for prophylaxis was 2.6% and 1.3%, respectively. Corresponding results for Grade 3/4 neutropenia were 2.2% and 0.9%, respectively. Adverse drug reactions occurred in 24 patients (10.5%): those in more than one patient were bone pain (n=6, 2.6%) and pyrexia (n=3, 1.3%). The use of lipegfilgrastim for the prophylaxis of chemotherapy-induced neutropenia was effective and well tolerated in patients with urological malignancies in the real-world setting.


INTRODUCTION
Chemotherapy-induced neutropenia is a common, and the most serious, hematological adverse event (AE) in cancer patients treated with myelosuppressive chemotherapies (1,2). It frequently results in chemotherapy-dose delay or reduction, which can reduce dose intensity sufficiently to compromise optimal treatment response and survival (1,3). Fever is frequently the first symptom of infection in cancer patients with chemotherapy-induced neutropenia and patients exhibiting febrile neutropenia usually require aggressive treatment including systemic antimicrobial treatment that necessitates hospitalization (1). Risk factors for the development of febrile neutropenia include intensive chemotherapy regimens and patient-related factors such as advanced age, advanced disease stage, previous episodes of febrile neutropenia, and comorbid conditions (4,5).
Recombinant N-methionyl human granulocyte-colony stimulating factors (r-metHuG-CSFs, hereafter G-CSFs) are effective agents in cancer patients, reducing the duration and incidence of chemotherapy-induced neutropenia and febrile neutropenia by stimulating the release of neutrophils and neutrophil proliferation from bone marrow (6,7). G-CSFs should be instituted for the prophylactic prevention of febrile neutropenia in high-risk patients (≥20% risk), and those at intermediate risk (10-20%) in the presence of other factors such as advanced age, advanced disease, previous febrile neutropenia, and no antimicrobial prophylaxis according to current treatment guidelines (4,5,8,9).
G-CSFs have undergone considerable development and refinement since their initial introduction more than 25 years ago. The first agent to become available, filgrastim, has a relatively short half-life, which necessitated repeated daily subcutaneous administration for a mean of 10-11 days (10,11) and up to 14 days per chemotherapy cycle (6,7) to provide adequate absolute neutrophil count (ANC) recovery in clinical trials. However, a recent review of real-world observational studies showed that the mean duration of filgrastim treatment was considerably shorter at 3.7-7.5 days (12). This, combined with a delay in starting filgrastim in clinical practice, appears to contribute to reduced efficacy (13)(14)(15)(16)(17). The half-life of filgrastim was prolonged sufficiently by pegylation to allow the effective administration of a fixed dose of pegfilgrastim once per chemotherapy cycle (18). Single-dose pegfilgrastim was as effective as filgrastim administered daily for 10-14 days per cycle for prophylaxis of febrile neutropenia according to metaanalyses of randomized controlled trials (16,17,19,20). However, observational studies suggest pegfilgrastim is more effective for the prevention of severe neutropenia and febrile neutropenia than filgrastim in a real-world setting (14,(21)(22)(23) and more convenient to administer.
Lipegfilgrastim (Lonquex ® , Teva Pharmaceuticals Industries Ltd, Petach Tikva, Israel) is approved by the European Medicines Agency for the management of chemotherapy-induced neutropenia (24). It is a glycopegylated G-CSF with a prolonged half-life compared with the same dose of pegfilgrastim and produces a more sustained ANC increase (25)(26)(27). Lipegfilgrastim was at least as effective and as well tolerated compared to the same dose of pegfilgrastim in a phase III clinical trial among breast cancer patients receiving doxorubicin/docetaxel (28); subsequent analysis of secondary endpoints revealed a favorable response with lipegfilgrastim for some endpoints (e.g. time to ANC recovery, incidence of severe neutropenia, depth of ANC nadir) (26,29). Glycopegylation as applied for lipegfilgrastim is the most specific pegylation method available to date, selectively adding one molecule of methoxyPEG (mPEG) to a sugar-activated threonine (threonine 134 ) in filgrastim. In addition to this defined glycopegylation pattern, the position of the methoxypegylation site is also worthy of mention and could be the basis for hypothesis generation, as one particular aspect of the PEG modification in lipegfilgrastim is shielding the protein from enzymatic degradation and protection from recognition by the immune system. A centrally positioned mPEG-chain, as in lipegfilgrastim, might be favorable over an N-terminal-positioned PEG-chain as in pegfilgrastim (26).
There are no published reports on the effectiveness or safety of lipegfilgrastim specifically in patients with urological malignancies such as prostate, testicular, kidney, or bladder cancer. Patients with testicular cancer are usually young and are treated with highly myelosuppressive chemotherapy regimens where the goal is to cure the disease and, consequently, it is highly important to maintain dose intensity. Here, we report pooled data from two non-interventional studies of lipegfilgrastim conducted in urological cancer patients with chemotherapy-induced neutropenia.

METHODS
Data were derived from two (NADIR and LEOS) prospective, multicenter, phase IV, observational cohort studies with similar protocols, which were conducted from 8 January 2014 to 16 January 2017 in nine European countries (Austria, Belgium, Czech Republic, Germany, Italy, Poland, Slovakia, Spain, and The Netherlands). Neither study had any influence on an individual's course of treatment. The study protocols were approved by ethical review boards at all their respective study centers and written informed consent was obtained from patients prior to inclusion. The studies followed the principles of the Declaration of Helsinki and guidelines of the International Conference on Harmonization of Good Clinical Practice. Full details of the methods and results of NADIR have been published for all 2,489 evaluable patients with various cancers (37). Interim results of the LEOS study have been reported for 621 patients with various cancers (38).

Patients and Treatment
Patients were male or female adults (≥18 years) with solid urological tumors receiving cytotoxic chemotherapy in whom their treating physician had decided to institute lipegfilgrastim for primary or secondary prophylaxis of neutropenia. Pregnant or lactating women were excluded.
The treating physician determined the cancer therapy appropriate for each patient, which followed the standard clinical practice for the relevant country. Lipegfilgrastim 6 mg was administered subcutaneously approximately 24 h after cytotoxic chemotherapy and continued for up to six cycles according to standard clinical practice and within approved marketing authorization (37).

Assessments
The following baseline demographic and clinical characteristics were recorded during screening: age, gender, height, weight, ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status score, primary disease/tumor history, nutritional deficiency, details of previous and current chemotherapy, history of febrile neutropenia, concurrent diseases and medications, and blood counts. Baseline individual patient-related risk factors for febrile neutropenia (4) and intended use of lipegfilgrastim (primary or secondary prophylaxis) were determined. Patients were followed from initiation of lipegfilgrastim until 6-8 weeks after the last dose of lipegfilgrastim. Efficacy endpoints included incidence of severe (Grade 3/4) neutropenia, febrile neutropenia, use of antimicrobial agents, hospitalization, and chemotherapy dose modifications.

Safety
AEs and adverse drug reactions (ADRs) potentially related to lipegfilgrastim (yes/no) were coded by Medical Dictionary for Regulatory Affairs v20.0 and graded by National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Serious AEs and serious ADRs were reported in an expedited manner and coded/graded in the same manner. Highly prevalent chemotherapy-derived AEs (e.g., nausea, vomiting) were excluded from being recorded in one study (LEOS).

Statistics
Data are reported using descriptive statistics with continuous variables as mean ± standard deviation (SD) and median (range), and different categories of discrete variables as frequencies (%). Statistical analyses were performed using IBM ® SPSS Statistics (v21.0 or higher) and StatXact ® (v6.0), with missing values not being replaced or extrapolated.

Demographics and Clinical Characteristics
The study included a total of 228 patients who had received ≥2 cycles of chemotherapy with at least one dose of lipegfilgrastim, which constituted the safety and efficacy populations. The demographic and clinical characteristics of the entire study population (N=228) as well as the three major subpopulations with prostate (n=142), testicular (n=50), and bladder (n=27) cancer are summarized in Table 1. Age and tumor stage were lower in the subpopulation with testicular cancer.

Effectiveness
The incidence of febrile neutropenia over all cycles (n=998) and first cycles (n=228) that lipegfilgrastim was administered for prophylaxis was 2.6% and 1.3%, respectively ( Table 4). The incidence of febrile neutropenia over all cycles and first cycles, respectively, was lower among those who received primary prophylaxis (1.7% and 0.6%) compared to those who received secondary prophylaxis (6.9% and 3.4%). The incidence of Grade 3/4 neutropenia over all cycles and first cycles of lipegfilgrastim was 2.2% and 1.3%, respectively, with lower incidences during primary prophylaxis (2.2% and 1.1%, respectively) compared to secondary prophylaxis (3.4% and 3.4%, respectively).

Safety
Fifty ADRs (12.5%) occurred in 24 patients (10.5%). The most frequent ADRs (occurring in >1% of patients) were bone pain (n=6, 2.6%) and pyrexia (n=3, 1.3%). The full list of ADRs is    reported in Table 5. Lipegfilgrastim was discontinued because of an ADR in one patient (0.4%). Fourteen serious ADRs (6.1%) were recorded in nine patients (3.9%). The most frequent serious ADRs (occurring in >1 patient) were fever and hematuria (each n=2, 0.9%). Overall, 12 serious AEs were categorized as deaths occurring in nine patients (3.95%), none of which were considered related to lipegfilgrastim. The events leading to death in the nine patients were reported as prostate cancer with metastasis and general physical health deterioration, sepsis, general physical health deterioration and neoplasm, general physical health deterioration and anemia, renal failure, Clostridium difficile colitis, neoplasm recurrence, pneumonia, and death.

DISCUSSION
The incidence of febrile neutropenia and Grade 3/4 neutropenia was 2.6% and 2.2%, respectively, over all cycles (n=998) of chemotherapy when lipegfilgrastim was administered as prophylaxis for neutropenia in a cohort of 228 patients with various urological malignancies (predominantly prostate, testicular, and bladder cancers). The corresponding incidence of febrile neutropenia and Grade 3/4 neutropenia was 1.3% and 0.9%, respectively, when analysis was restricted to the first cycle of chemotherapy. The incidence of febrile neutropenia was lower at 1.7% over all cycles, and even lower at 0.6% over the first cycle, when analysis was restricted to those patients who received lipegfilgrastim as primary prophylaxis. Final results from the full NADIR study using lipegfilgrastim in~2500 patients with a range of cancers (predominantly breast cancer, lung cancer, and non-Hodgkin lymphoma) showed an almost identical incidence of febrile neutropenia (2.7%), while the incidence of Grade 3/4 neutropenia was considerably higher at 26.8% (37). Lipegfilgrastim and pegfilgrastim (each 6 mg per cycle) have been compared directly in a prospective, randomized, controlled trial in 188 patients with breast cancer receiving up to 4 cycles of high-risk chemotherapy (28). None of the lipegfilgrastim recipients experienced febrile neutropenia during cycle 1 compared with 3.2% of pegfilgrastim recipients and the incidence of severe (Grade 4) neutropenia was 43.6% and 51.1% (p=0.3409), respectively, during cycle 1. Lipegfilgrastim 6 mg and placebo have also been compared in a prospective, randomized, controlled trial in~375 patients with non-small cell lung cancer receiving up to 4 cycles of high-risk chemotherapy (51). The incidence of febrile neutropenia was 2.4% and 5.6% with lipegfilgrastim and placebo, respectively, during cycle 1. The incidence of febrile neutropenia has been reported in a number of observational studies of pegfilgrastim: 3% (52), 4.4% (51, 52), 5.7% (53), and 5.6-6.3% (54). These observational studies rarely included any patients with urological malignancies and none reported results specifically in this subpopulation. Pegfilgrastim and filgrastim have been compared in many observational studies but such studies did not include patients with urological malignancies and several did not report the incidence of febrile neutropenia or severe neutropenia. Morrison and colleagues (21) reported a lower incidence of febrile neutropenia comparing pegfilgrastim and filgrastim in 2,863 US patients (4.7% vs 6.5%, p=0.044), and Almenar Cubells and colleagues (14) reported respective incidences for febrile neutropenia (6.7% vs 13.3%) and Grade 3/4 neutropenia (28.3% vs 49.3%) among 391 Spanish patients. A recent review of real-world comparative effectiveness studies found that the risk of febrile neutropenia was generally lower for prophylaxis with pegfilgrastim compared with that with short-acting G-CSFs (12).
It should be noted that 43.0% of the study population of patients with urological malignancies had a high risk (>20%) of febrile neutropenia from the chemotherapy compared to 49.1% with an intermediate risk (10-20%) and 7.5% with a low risk (<10%). Almost 80% of patients received lipegfilgrastim as primary prophylaxis. This would generally appear to be in line with current treatment guidelines which recommend primary G-CSF prophylaxis should be given to patients at high risk and to those at intermediate risk in the presence of other risk factors such as advanced age, advanced disease stage, prior febrile neutropenia, and/or concurrent comorbid conditions (4,5,8,9). Most patients had additional risk factors [including age >65 years (59.6%), prior febrile neutropenia (50.9%), and hemoglobin >12 g/dL (18.4%)], at least one comorbidity (59.0%), and stage III/IV disease (69.6%), which would account for the use of lipegfilgrastim in those patients who received intermediate-or low-risk chemotherapy regimens.
With respect to safety, any grade ADRs occurred in 15.4% of patients, with bone pain (2.6%) and pyrexia (1.3%) occurring in >1% of patients. The ADR profile was similar to that previously reported for lipegfilgrastim in other cancers and compared to other long-and short-acting G-CSFs (28,55).
The study was limited by the relatively low numbers of patients evaluated, although this is the first study to our knowledge that has specifically examined the efficacy and safety of lipegfilgrastim in patients with urological malignancies. The number of patients receiving lipegfilgrastim as secondary prophylaxis in the study was too low to allow any meaningful or reliable conclusions with respect to effectiveness. The study was, furthermore, limited by the relatively large proportion of patients with missing data. Another limitation of the investigation is the use of reduced Cabazitaxel dose to 20 mg/ kg, which is mainly carried out in the USA. However, in real-life clinical scenarios Cabazitaxel is also often dose reduced so that there are fewer side effects whilst maintaining similar efficacy, as shown in recent publications (56).

CONCLUSION
In conclusion, lipegfilgrastim was effective and well tolerated for the prophylaxis of chemotherapy-induced neutropenia in patients with urological malignancies in the real-world setting. The use of lipegfilgrastim in these patients generally appeared to comply with current treatment recommendations and guidelines.