Telpegfilgrastim for chemotherapy-induced neutropenia in breast cancer: A multicenter, randomized, phase 3 study

To the Editor: Chemotherapy is one of the mainstay therapies for patients with breast cancer (BC),[1,2] but it is often restricted by dose-limiting toxicities attributed to myelosuppression. Although recombinant human granulocyte colony-stimulating factors (rhG-CSF) are effective for treating and preventing chemotherapy-induced neutropenia, daily administration is inconvenient to patients.[3,4] Telpegfilgrastim (Peijin®, Xiamen Amoytop Biotech Co., Ltd, Xiamen, China) is a Y-shape branched pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF). In this multicenter, randomized, open-label, active drug-controlled, non-inferior, parallel-group, phase 3 study (ClinicalTrials.gov, No. NCT04466137), we evaluated the efficacy and safety of telpegfilgrastim in patients with BC for chemotherapy on the taxotere, adriamycin, and cyclophosphamide (TAC) regimen for the clinical management of neutropenia and febrile neutropenia (FN). The study was approved by the ethics committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (No. 19-120/1904) with written informed consent obtained from all patients before study entry. Considering the duration of grade 4 neutropenia as 1 day with a standard deviation of 1.5 days in cycle 1 of chemotherapy in telpegfilgrastim (2 mg fixed dose and 33 μg/kg) and control groups, using Power Analysis & Sample Size (PASS) version 15 with a predefined non-inferiority margin of 1 day at a power (1−β) of 0.9 and a one-sided test level of 0.025, the study required minimum sample size of 49 patients in each group. Furthermore, considering the drug exposure and potential dropout, the study enrolled a minimum of 85 patients in each group. Patients were included if they had histopathologically diagnosed BC, were ≥18 years, had a body weight ≥45 kg, a white blood cell count ≥3.5 × 109/L, a platelet count ≥100 × 109/L, an absolute neutrophil count (ANC) ≥1.5 × 109/L, and were suitable for chemotherapy. Patients who had received chemotherapy <2 months before screening, were scheduled for extensive radiotherapy (>25% of the total bone marrow), uncontrolled infections, antibiotics use ≤72 h before screening, or were allergic to rhG-CSF, were excluded. Patients were randomized in a 1:1:1 ratio based on gender (female and male patients with BC), age (≤65 years and >65 years), and history of previous chemotherapy; they received telpegfilgrastim 2 mg or 33 μg/kg or rhG-CSF (Topneuter®, Xiamen Amoytop Biotech Co., Ltd, Xiamen, China)/PEG-rhG-CSF (Xinruibai®, Qilu Pharmaceutical Co., Ltd, Jinan, China) using the Interactive Web Response System. Chemotherapy agents included an intravenous infusion of docetaxel 75 mg/m2 (Jiangsu Aosaikang Pharmaceutical Co. Ltd., Nanjing, China), doxorubicin 50 mg/m2 (Shenzhen Main Luck Pharmaceuticals Inc., Shenzhen, China), and cyclophosphamide 500 mg/m2 (Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang, China). A 21 day-cycle, which included 4 cycles of chemotherapy, was administered. The treatment group received either 2 mg or 33 μg/kg of telpegfilgrastim subcutaneously on the third day of each chemotherapy cycle (48 ± 12 h). In contrast, the control group received rhG-CSF (Topneuter®) 5 μg/kg once daily subcutaneously until ANC recovered to ≥5.0 × 109/L from the lowest value (usage not exceeding 14 days during cycle 1 of chemotherapy). During cycles 2–4 of chemotherapy, based on the patient’s choice, a single injection of PEG-rhG-CSF (Xinruibai®) 6 mg once in each chemotherapy cycle or rhG-CSF (Topneuter®) 5 μg/kg once daily was administered subcutaneously until ANC recovered to ≥5.0 × 109/L from the lowest value (usage not exceeding 14 days during each cycle of chemotherapy). The duration of grade 4 neutropenia in cycle 1 of chemotherapy was considered the primary endpoint, while the duration of grade 4 neutropenia in cycles 2–4 of chemotherapy, the incidence of grade 4 neutropenia across cycles 1–4 of chemotherapy, the duration and incidence of ≥grade 3 neutropenia, the incidence of FN, and a dynamic change in ANC from baseline were considered secondary endpoints. FN is defined as a single oral temperature measurement >101°F (>38.3°C) or a temperature ≥100.4°F (≥38.0°C) sustained for 1 h, with an ANC <0.5 × 109/L or an ANC between 0.5 × 109/L and 1.0 × 109/L that is expected to decrease to <0.5 × 109/L in the next 48 h. Safety was assessed in terms of adverse events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Continuous variables were presented as mean ± standard deviation (SD) and median ([minimum value, maximum value]/[Q1, Q3]), whereas categorical variables were expressed as N (%). Using the analysis of variance (ANOVA), differences in the duration of grade 4 neutropenia between the treatment groups were evaluated, and the least-squares mean, and 95% confidence interval (CI) were calculated using the analysis of covariance model (ANCOVA). The non-inferiority margin was set at ± 1 day. Multiple imputation method was used to impute missing data. The chi-squared test was used to analyze the difference in the incidence of neutropenia and FN between the groups. A two-sided test with a significance level of P <0.05 was considered statistically significant. SAS version 9.4 (SAS Institute, Cary, NC, USA) was used to perform all statistical analyses. Between October 16, 2020, and September 1, 2021, 265 patients were enrolled in this study. The patient disposition was presented in Supplementary Figure 1, https://links.lww.com/CM9/C275. The demographic characteristics of patients were shown in Supplementary Table 1, https://links.lww.com/CM9/C275. The mean duration of grade 4 neutropenia during cycle 1 of chemotherapy was 0.58 ± 1.09, 0.74 ± 1.59, and 0.48 ± 0.92 days in the telpegfilgrastim 2 mg group, telpegfilgrastim 33 μg/kg group, and control (rhG-CSF) group, respectively. The least-squares mean difference between the telpegfilgrastim (2 mg and 33 μg/kg) groups and control (rhG-CSF) group was 0.10 (95% CI: −0.19, 0.38; P = 0.51) and 0.22 (95% CI: −0.09, 0.52; P = 0.17), respectively, 95% CI were within the prespecified margin of ±1 day, confirming the non-inferiority of both telpegfilgrastim groups compared to the control (rhG-CSF) group [Supplementary Table 2, https://links.lww.com/CM9/C275]. In cycles 2–4 of chemotherapy, no significant differences in the mean duration of grade 4 neutropenia (P >0.05) between the telpegfilgrastim groups and the control (PEG-rhG-CSF or rhG-CSF) group. No significant differences in the incidence of grade 4 neutropenia across cycles 1–4 of chemotherapy between the telpegfilgrastim groups and the control (rhG-CSF or PEG-rhG-CSF) group. No significant differences in the duration of ≥grade 3 neutropenia, the incidence of grade 3/4 neutropenia, and the FN rates between telpegfilgrastim and control groups across cycles 1–4 of chemotherapy. ANC showed a double-peak pattern [Supplementary Figure 2, https://links.lww.com/CM9/C275], and the stratification analysis based on age or previous chemotherapy is shown in the Supplementary Tables 3 and 4, https://links.lww.com/CM9/C275. All patients in this study experienced at least one AE, with similar incidence, type, and severity across the three groups. Grade ≥3 treatment-emergent adverse events (TEAEs) were 59.6% for the telpegfilgrastim 2 mg group, 70.5% for the telpegfilgrastim 33 μg/kg group, and 62.5% for the control group. TEAEs leading to study discontinuation occurred in 1.1% of patients in each group. Serious adverse events (SAEs) were 5.6% in the telpegfilgrastim 2 mg group, 6.8% in the telpegfilgrastim 33 μg/kg group, and 6.8% in the control group. No study-drug-related deaths were reported [Supplementary Table 5, https://links.lww.com/CM9/C275]. TEAEs related to the study drugs are detailed in Supplementary Table 6, https://links.lww.com/CM9/C275. In a phase 3 study on patients with BC receiving epirubicin and docetaxel, the mean duration of grade 4 neutropenia in cycle 1 was 0.54 days and 0.61 days with 6 mg and 100 μg/kg of mecapegfilgrastim, respectively, and 1.02 days with filgrastim.[5] The duration of grade 4 neutropenia was 1.7 days with pegfilgrastim and 1.8 days with filgrastim, confirming the non-inferiority between the agents.[6] In this study, the duration of grade 4 neutropenia during cycle 1 of chemotherapy was 0.58 days with telpegfilgrastim 2 mg, 0.74 days with telpegfilgrastim 33 μg/kg, and 0.48 days with rhG-CSF. This study also demonstrated the non-inferiority of telpegfilgrastim in the duration of grade 4 neutropenia compared with rhG-CSF in cycle 1 of chemotherapy. The incidence of FN was 4.5% in mecapegfilgrastim 100 μg/kg and 1.82% in the filgrastim group in cycle 1 of chemotherapy in patients with BC. No significant difference was observed between the mecapegfilgrastim and filgrastim groups.[5] In this study, in the telpegfilgrastim 2 mg group, FN only occurred in cycle 1 of chemotherapy, the incidence of FN was 2.2%; the incidence of FN for telpegfilgrastim 33 μg/kg group was 3.4% in cycle 1, 1.2% in cycle 2, and 1.4% in cycle 4 of chemotherapy; and the incidence of FN in the control group was 3.4% in cycle 1 and 1.2% in cycle 2 of chemotherapy. No statistically significant difference was observed in the incidence of FN among the telpegfilgrastim 2 mg, telpegfilgrastim 33 μg/kg, and control groups. The results showed that the efficacy of telpegfilgrastim was equal to that of rhG-CSF and PEG-rhG-CSF. The incidence, type, and severity of AEs were similar among these three groups. The incidence of TEAEs was comparable between the telpegfilgrastim groups and the control group. This study has limitations. It only included Chinese patients with BC for chemotherapy on the TAC regimen, which may not represent all chemotherapy regimens used in clinical practice. There was no long-term follow-up of patients in this study, and only 4 cycles of chemotherapy were observed for safety, potentially introducing bias.[7] In conclusion, this study demonstrated that telpegfilgrastim had a similar efficacy and safety profile compared to rhG-CSF and PEG-rhG-CSF for the prevention of chemotherapy-induced neutropenia. A fixed dose of telpegfilgrastim 2 mg is more convenient and recommended for patients weighing ≥45 kg, while telpegfilgrastim 33 μg/kg may be a better option for patients with low body weight, particularly those weighing <45 kg. Acknowledgments The authors acknowledge Dr. Satya Lavanya Jakki and Dr. Ramandeep Singh (Indegene, Bangalore, India) for medical writing, editorial assistance, which was funded by Fosun Pharma. We also thank Dr. Zucheng Xie and Dr. Xinrui Chen (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing China) for the editorial assistance. Funding This study was funded by Xiamen Amoytop Biotech Co., LTD and partly supported by the National Science and Technology Major Project for Key New Drug Development (No. 2017ZX09304015). Conflicts of interest The authors declare that there are no conflict of interests. This study was funded by Xiamen Amoytop Biotech Co., LTD, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.