Treatment patterns and outcomes in patients with non‐small cell lung cancer receiving biosimilar filgrastim for prophylaxis of chemotherapy‐induced/febrile neutropaenia: Results from the MONITOR‐GCSF study

Abstract Objective Real‐world evidence data on the use of granulocyte colony‐stimulating factor (G‐CSF) in patients with non‐small cell lung cancer (NSCLC) are limited. MONITOR‐GCSF is a pan‐European, multicentre, prospective, non‐interventional study designed to describe patient characteristics, treatment patterns and clinical outcomes in patients receiving biosimilar filgrastim in the prophylaxis of chemotherapy‐induced neutropaenia (CIN) and febrile neutropaenia (FN). Methods In this subanalysis, patient characteristics, treatment patterns, and outcomes are described for 345 patients with stage 3 or 4 NSCLC, receiving up to six chemotherapy cycles. Patients were treated with biosimilar filgrastim as per their treating physician's best judgement. Results CIN (any grade) occurred in 13.6% of patients in Cycle 1 and in 36.5% of patients in all cycles. FN occurred in 1.4% of patients in Cycle 1 and in 5.2% of patients in all cycles. Grade 3–4 FN occurred in 1.2% of patients in Cycle 1 and in 3.8% of patients in all cycles. Conclusion Results show that in real‐life practice in patients with NSCLC, biosimilar filgrastim has similar effectiveness and safety to the known effectiveness and safety profile of reference filgrastim, supporting the use of biosimilar filgrastim for the real‐world treatment of neutropaenia in patients with NSCLC.

Platinum-based chemotherapy is the standard of care for NSCLC. Platinum doublets chemotherapy is recommended for adjuvant chemotherapy in stage II (A/B) and stage III (A/B) NSCLC (Postmus et al., 2018). Cisplatin-based regimens (e.g., cisplatin/ etoposide or cisplatin/vinorelbine) in conjunction with radiotherapy are also recommended in the treatment of locally advanced stage III NSCLC (Vansteenkiste et al., 2013). For advanced NSCLC, the current standard of care for first-line treatment of stage IV epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-negative disease comprises platinum doublets, with carboplatin-based doublet chemotherapy recommended for elderly patients (Planchard et al., 2018). For tumours with an activating EGFR mutation, first-line treatment with an EGFR tyrosine kinase inhibitor (gefitinib, erlotinib, afatinib, dacomitinib, and orosimertinib) is recommended, with ALK inhibitors (crizotinib, alectinib, ceritinib, and brigatinib) preferred for patients with ALKrearranged NSCLC (NCCN, 2018;Planchard et al., 2018). Survival in patients with NSCLC remains poor, with 5-year survival rates estimated at 10%-20% (Davies et al., 2017). Platinum-induced myelosuppression is a complication associated with chemotherapy in NSCLC patients (Cao et al., 2016). Some regimens (i.e., carboplatin/docetaxel, cisplatin/etoposide and cisplatin/vinorelbine/ cetuximab) are associated with a high risk of chemotherapy-induced neutropaenia (CIN)/febrile neutropaenia (FN) Crawford, Caserta, & Roila, 2010). This can result in dose reductions and/or delays to chemotherapy, which can impact on treatment success . Prophylactic prevention of CIN/FN is therefore warranted to ensure cytotoxic chemotherapy is delivered on time and at efficacious doses (Rivera, Haim Erder, & Fridman, 2003). International guidelines recommend primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs), such as filgrastim or pegfilgrastim, for patients with a 20% or greater risk of CIN/FN (i.e., those receiving a high-risk chemotherapy regimen, or those with risk factors that may increase the overall CIN/FN risk) Crawford, Caserta, & Roila, 2010;Smith et al., 2006Smith et al., , 2015. Filgrastims have demonstrated efficacy in decreasing the incidence, severity and duration of CIN/ FN episodes, and reducing the risk of dose reduction, discontinuation or delays to chemotherapy .
The use of G-CSF prophylaxis varies widely in real-life clinical practice, both in the timing of therapy and the type of patients who use it . Furthermore, G-CSF prophylaxis is often not used in line with guideline recommendations (Krzemieniecki et al., 2014). Further data on the efficacy and safety of G-CSF prophylaxis and its use in a real-world setting are needed.
MONITOR-GCSF is an international, multicentre, prospective, open-label, non-interventional study of cancer patients treated with myelosuppressive chemotherapy regimens whose treating physicians prescribed CIN/FN prophylaxis with Sandoz biosimilar filgrastim (Zarzio ® /Zarxio ® /EP2006; Hexal AG/Sandoz International GmbH). Treatment patterns and outcomes associated with CIN/FN prophylaxis with biosimilar filgrastim in 1,447 patients with solid or haematologic malignancies have previously been reported . In this paper, we describe patient characteristics, treatment patterns, and outcomes for the cohort of patients with NSCLC from MONITOR-GCSF who received primary or secondary prophylaxis with biosimilar filgrastim as part of routine clinical practice.

| Design
The background and methodology of MONITOR-GCSF have previously been described (Gascón, Aapro, Ludwig, Rosencher, Boccadoro et al., 2011;. In brief, MONITOR-GCSF was a European-wide, prospective, non-interventional, multi-level, pharmaco-epidemiological study of chemotherapy-treated cancer patients who started treatment with Sandoz biosimilar filgrastim for the prophylaxis of CIN/FN as per their prescribing physician's best clinical judgment. Male or female adults (aged ≥18 years) diagnosed with stage III or IV breast cancer, bladder cancer, NSCLC, or diffuse large B-cell lymphoma, or metastatic prostate cancer were eligible for inclusion if they were scheduled to receive their first of at least four cycles of chemotherapy and received treatment with biosimilar filgrastim as indicated.
The study was approved by the ethical review committees of participating centres in accordance with national laws and regulations.
Patients provided written informed consent.

| Data collection
Patients were observed for up to six cycles of chemotherapy. All available data were recorded. Descriptive data on demographics, clinical status, medical history, concomitant comorbid conditions and current status of disease, and prior and concomitant medications were collected at enrolment. Data on chemotherapy regimen, including any changes, were collected at every visit. Outcomes of interest included the incidence of CIN/FN, antibiotic prophylaxis, biosimilar filgrastim prophylaxis, and adverse events (AEs).
Data were summarised overall and according to age ≥65 years and ≥70 years at baseline. Here we present results for patients with NSCLC only.

| Prophylaxis
Data on biosimilar filgrastim prophylaxis were available for 341 patients with NSCLC, including 142 aged ≥65 years and 81 aged ≥70 years (Table 2). Changes to the chemotherapy regimen are detailed in Table 3.

| D ISCUSS I ON
Evidence suggests that G-CSF is frequently not used according to international recommendations in daily clinical practice, highlighting a need for further data from observational studies to help guide optimal use of G-CSF. This may be particularly important in older patients who are at high risk of CIN/FN. This subanalysis described patient characteristics, treatment patterns, and clinical outcomes for patients with NSCLC who received primary or secondary prophylaxis with biosimilar filgrastim as part of routine clinical practice in the MONITOR-GCSF observational study.
Of the patients with NSCLC included in MONITOR-GCSF, patients had a mean age of 62.9 years, with 41% of patients aged ≥65 years and 24% of patients aged ≥70 years. The most commonly  (Font et al., 1999). Data are not available in the literature regarding the risk of FN in patients with NSCLC receiving carboplatin/ etoposide.
A large proportion of patients (≥80%) experienced changes to their chemotherapy regimens-in addition to reasons such as lack of efficacy, tolerability concerns, and disease progression, chemoresistance may have been responsible for this finding since this is a widely reported limitation of cisplatin (Brabec, Kasparkova, Kostrhunova, & Farrell,2016 ). This highlights a need for improved understanding of the molecular mechanisms of cisplatin resistance and of identifying markers of resistance (Fennell et al., 2016).
Clinical outcomes for patients with NSCLC were generally consistent with those reported for the overall population of 1,447 patients, and for different patient populations included in MONITOR-GCSF such as DLBCL and breast cancer, supporting clinical extrapolation (Aapro, Krendyukov, Krivtsova, & Gascón, 2018;Gascón et al., 2016;Gascón, Krendyukov, Höbel, & Aapro, 2018). Regarding CIN, 36.5% of NSCLC patients experienced one or more episode of any grade throughout the study, compared with 34.8% in the overall study population. In MONITOR-GCSF, the percentage of patients experiencing FN (any grade) in patients with NSCLC (5.2%) was comparable to the overall population (5.9%). In Cycle 1, FN was reported in 1.4% patients with NSCLC, a similar level to the overall population in the HEXAFIL study (1.8%), an observational study assessing use of biosimilar filgrastim in routine clinical practice in Germany (Tesch et al., 2015). IMPACT Solid was a large prospective observational study designed to describe FN incidence and adherence to G-CSF guidelines in patients with solid tumours with a FN risk of ≥20%. In Cycle 1, FN was reported in 4% of the 224 patients with NSCLC included in the study (Krzemieniecki et al., 2014). A retrospective analysis, including patients with breast cancer, colorectal cancer, and NSCLC receiv-  Adverse events were reported in five patients with NSCLC and included arthralgia, bone pain, cough, gastroenteritis, and myalgia (each in one patient, 0.3%). This is a lower level than in the overall population where 53.7% of patients experienced AEs . The reasons for this are unclear and are worthy of further investigation. AEs for the NSCLC patients were not reported in the IMPACT Solid study. It should be noted that collection of AE data in non-interventional studies is a widely recognised challenge since patients appear less likely to report well-known side effects in this setting (Gascón et al., 2013).
The findings from this subanalysis of patients with NSCLC demonstrate that the efficacy and safety of biosimilar filgrastim in real-life practice are similar to the known efficacy and safety profile of reference filgrastim. This supports the use of filgrastim biosimilar in patients with NSCLC in a real-world setting and extends the efficacy and safety from its clinical development programme. The large percentage of patients aged ≥65 years included in the study adds to the body of evidence on how to best treat older patients with NSCLC receiving myelosuppressive chemotherapy.