Safety and efficacy of mecapegfilgrastim in preventing neutropenia in patients with head and neck cancer: a multicenter, prospective, observational, real-world study

Introduction

In 2020, head and neck cancer was ranked as the sixth most prevalent cancer type, with 870,000 new cases and 440,000 deaths worldwide (1). The management of patients with head and neck cancer necessitates aggressive multimodal approaches, such as chemoradiotherapy alone or surgery followed by either radiotherapy alone or chemoradiotherapy (2,3). Combining chemotherapeutic agents with radiotherapy has shown significant effectiveness in achieving local control and improving patient survival rates (4). For patients with recurrent or metastatic tumors, available treatment options include immune checkpoint inhibitors, platinum-based compounds, and fluorouracil (5). However, compared to radiotherapy alone, concurrent chemotherapy is linked with a substantial escalation in acute—and at times life-threatening—toxicity (6-9). Myelosuppression is a prevalent adverse effect of cytotoxic chemotherapy. Within the subcategories of myelosuppression, neutropenia is regarded as having the most severe toxicity, as it compromises the immune system and increases patient vulnerability to infections. Neutropenia frequently results in treatment delays, dose reductions, or even discontinuations, leading to diminished efficacy, prolonged hospitalizations, and increased treatment costs (10,11). Additionally, patients who experience neutropenia may not exhibit typical signs of infection, with fever often being the sole indicator. The concurrent presence of neutropenia and fever constitutes febrile neutropenia (FN), a condition that can lead to serious infections and life-threatening situations (12,13). Therefore, it is important to find effective therapies for the prevention or treatment of neutropenia in patients with head and neck cancer.

Granulocyte colony-stimulating factor (G-CSF) is widely used to prevent chemotherapy-induced neutropenia and FN. Common options included short-acting recombinant human G-CSF (rhG-CSF) and long-acting pegylated recombinant human G-CSF (PEG-rhG-CSF). both of which have shown significant efficacy in reducing grade 3/4 neutropenia and FN (14,15). Compared to short-acting rhG-CSF, which requires daily injections, long-acting PEG-rhG-CSF has an extended half-life, allowing for a single injection per chemotherapy cycle, making it more convenient and improving patient compliance. Furthermore, a study in breast cancer patients have indicated that PEG-rhG-CSF is more cost-effective and associated with lower toxicity (16). Mecapegfilgrastim, a PEG-rhG-CSF, is administered subcutaneously once per chemotherapy cycle as a preventive measure (17,18). In 2018, the Chinese National Medical Products Administration (NMPA) approved the use of mecapegfilgrastim to decrease the risk of infection, especially for FN. In patients with non-myeloid malignancies receiving myelosuppressive anticancer treatment associated with a clinically significant incidence of FN (17-19). In addition, a multicenter, randomized, phase III study of patients with breast cancer receiving myelosuppressive chemotherapy revealed that mecapegfilgrastim demonstrated efficacy comparable to that of short-acting G-CSF (filgrastim) and superior performance in lowering the frequency and duration of severe neutropenia. Additionally, its tolerability and safety profiles were similar to those of filgrastim (20). In real-world settings, mecapegfilgrastim administration for preventing neutropenia in patients with non-myeloid malignancies has only been reported in our prospective, multicenter, noninterventional study for a midterm analysis (cutoff date: November 2020) (19). The findings of this study indicated that patients with different cancer types tolerated mecapegfilgrastim well. Neutropenia occurrence after primary administration was less frequent compared to that of secondary administrations, and continuous use contributed to sustaining a lower neutropenia incidence rate.

Both radiotherapy and immunotherapy are widely used in the treatment of head and neck cancer. Therefore, we conducted this multicenter, prospective, observational, real-world study to evaluate the efficacy of mecapegfilgrastim for preventing neutropenia in patients with head and neck cancer undergoing chemotherapy, with a specific focus on patients who also underwent radiotherapy or combined immunotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2035/rc).

Methods

Study design and patients

We conducted a prospective, observational study in real-world settings across 66 sites in China. This study was registered at the Chinese Clinical Trial Registry Centre (No. ChiCTR2000031768). Approximately 3,000 patients diagnosed with non-myeloid malignancies were enrolled from May 2019 to November 2021. A midterm analysis, conducted with data cutoff in November 2020, assessed the safety and efficacy of prophylactic use of mecapegfilgrastim for neutropenia in 638 patients. The findings of this analysis were published in December 2021 (19). Our focus within this study was a subgroup of 197 patients with head and neck cancer enrolled from 24 sites across China.

Prior to the commencement of the study, written informed consent was obtained from all participants. The study received approval by the ethics committee of the Harbin Institute of Hematology and Oncology (No. 2019-006). All participating hospitals/institutions were informed and agreed with this study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Data collection was conducted using a commercial electronic data capture (EDC) system, with subsequent verification of source documents being completed. Inclusion and exclusion criteria remained consistent with those detailed in a prior real-world study (19). Eligible patients were aged ≥18 years, with a pathologically or cytohistologically confirmed diagnosis of head and neck cancer, and were deemed acceptable for mecapegfilgrastim administration by the investigator. Exclusion criteria mainly included pregnant or lactating women, as well as individuals with allergies to mecapegfilgrastim, PEG-rhG-CSF, rhG-CSF or other Escherichia coli-expressed preparations.

Treatment

This real-world study aimed to assess the safety and efficacy of mecapegfilgrastim across a variety of dosing regimens. It was structured to accommodate prescription choices made by investigators, while also honoring patient preferences, without prescribing specific administration timings for mecapegfilgrastim. Patients received mecapegfilgrastim subcutaneously, either as a fixed dose (6 mg) or a weight-based dose (100 µg/kg), administered 24 hours after chemotherapy. Investigators were advised to adhere to the National Comprehensive Cancer Network (NCCN) guidelines for hematopoietic growth factors (version 2019.V1) to ensure safe drug utilization. Baseline patient characteristics were collected after enrollment, including age, sex, body weight, history of chemotherapy-induced FN or neutrophil reduction, history radiotherapy or immunotherapy, tumor metastasis, and baseline values for neutrophils, white blood cells, platelets, and hemoglobin. Complete blood counts (CBCs) were conducted on the days 7 to 9 and on day 14±2 of each treatment cycle. A maximum of four chemotherapy cycles were observed in this study, with end-of-trial follow-up conducted 30±2 days after the last dose of mecapegfilgrastim. For adverse events that had not resolved by the end of the trial, treatment and follow-up continued until recovery to baseline or complete resolution.

Outcomes

The primary outcome was the occurrence of adverse events after the administration of mecapegfilgrastim, as assessed by investigators. This included monitoring for changes in clinical laboratory parameters, physical examinations, and vital signs. The secondary outcomes included the incidence of grade ≥3 and grade 4 neutropenia [absolute neutrophil count (ANC) <1.0×10⁹/L and ANC <0.5×10⁹/L, respectively, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0], the incidence of FN, and the rate of infection throughout all cycles of chemotherapy in patients treated with mecapegfilgrastim.

Statistical analysis

The full analysis set (FAS) for baseline and prophylactic effectiveness evaluation included patients who received at least one dose of mecapegfilgrastim. For subsequent cycles with records, mecapegfilgrastim administration was required for each cycle. The safety set (SS) for safety analysis comprised patients who had received at least one dose of mecapegfilgrastim and had available safety data.

Most of the data in this study were descriptive. For continuous variables, data were presented as mean and standard deviations, while categorical variables were expressed as frequencies and percentage. The mean, standard deviation, median, minimum, and maximum values of vital signs and laboratory indicators were calculated both before and after the administration of mecapegfilgrastim. Adverse events, adverse reactions, and abnormal laboratory test results occurring during the trial period were recorded, and their correlation with mecapegfilgrastim was assessed.

Subgroup analyses were focused on chemotherapy in head and neck cancer, with particular attention given to patients who received concurrent radiotherapy or combined immunotherapy. The radiotherapy group consisted of individuals with a history of radiotherapy, those who had not received radiotherapy, or those who underwent sequential radiotherapy and chemotherapy (radiotherapy administered within 3 months prior to chemotherapy initiation). The combined immunotherapy group included individuals who underwent combined immunotherapy in any cycles; received immunotherapy in the first, second, third, or fourth cycle; or those who did not receive immunotherapy.

The statistical analysis of the data was conducted using SAS 9.4 statistical analysis software (SAS Institute, Cary, NC, USA).

Results

Patient characteristics

Between May 2019 and November 2021, a total of 197 patients were identified and enrolled in the analysis, all of whom received a 6-mg dose of mecapegfilgrastim. At baseline, the majority of the patients were male (76.6%). The median age of the participants was 53 years, with 18.8% over 65. In addition to chemotherapy, 25.9% of patients also received radiotherapy, and 38.6% underwent combined immunotherapy. Further details regarding participant characteristics are provided in Table 1.

Efficacy

Among the 197 patients with head and neck cancer, 445 chemotherapy cycles with prophylactic administration of mecapegfilgrastim were analyzed (Table 2). Grade ≥3 neutropenia (ANC <1.0×10⁹/L) occurred in 26 cycles (5.8%), while grade 4 neutropenia (ANC <0.5×10⁹/L) occurred in 16 cycles (3.6%). The occurrence of grade 4 neutropenia in the first, second, third, and fourth cycles was 5.6%, 2.4%, 2.0%, and 0, respectively. In addition, 1 cycle (0.2%) resulted in FN, and infections occurred in 7 cycles (1.6%). Antibiotics were used in 22 cycles (4.9%).

Regarding the prophylactic administration of mecapegfilgrastim in the first chemotherapy cycle (Table 3), the incidence of grade ≥3 neutropenia was 5.1% in the 178 cycles that included combined immunotherapy and was 6.4% in the 267 cycles without immunotherapy. No FN was observed in patients receiving immunotherapy, while one patient not receiving immunotherapy experienced FN. Additionally, among the 119 cycles that included radiotherapy, the incidence of grade ≥3 neutropenia was 5.0% and was 6.1% in the 326 cycles without radiotherapy, with one patient experiencing FN. However, among the patients who received radiotherapy within 3 months prior to chemotherapy, the incidence of grade 4 neutropenia was 9.5%, and the incidence of FN was 2.4%.

Safety

Among the 197 patients with head and neck cancer, treatment-related adverse events (TRAEs) of any grade occurred in 18 (9.1%) patients. Of these TRAEs, grade ≥3 events occurred in one (0.5%) patient (Table 4). The most frequently observed TRAEs of any grade were increased white blood cell count (n=10, 5.1%) and decreased white blood cell count (n=5, 2.5%). The most common grade ≥3 TRAEs were decreased white blood cell count (n=1, 0.5%) and decreased lymphocyte count (n=1, 0.5%).

Furthermore, among the 51 patients who underwent chemotherapy and radiotherapy, TRAEs of any grade occurred in 6 (11.8%) patients. The most common TRAEs were increased white blood cell count (n=5, 9.8%) and decreased white blood cell count (n=2, 3.9%). Among the 76 patients who received chemotherapy and immunotherapy, TRAEs of any grade occurred in 4 (5.3%) patients. Two patients who underwent combination radiotherapy or immunotherapy experienced grade ≥3 TRAEs: one had a decreased white blood cell count and the other a decreased lymphocyte count.

Discussion

For patients with recurrent, unresectable, or metastatic head and neck cancer, the standard treatment involves a combination of chemotherapy and radiotherapy. In cases where surgery or radiotherapy is not an option, the recommended first-line standard of care is chemotherapy combined with immunotherapy (pembrolizumab) (3). However, myelosuppression is a common occurrence in patients undergoing chemotherapy and often leads to neutropenia, including FN, which is associated with increased morbidity and mortality (10). To our knowledge, the study presented here represents the first multicenter, prospective, observational investigation of the safety and efficacy of mecapegfilgrastim in preventing neutropenia in patients with head and neck cancer.

Chemotherapy serves as an effective combination partner with immune checkpoint inhibitors in head and neck cancer due to its ability to disrupt tumor architecture, prompt antigen shedding, and facilitate rapid disease management (21). In the KEYNOTE-048 trial, patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC) who received pembrolizumab with chemotherapy exhibited higher overall survival (OS) compared to patients treated with pembrolizumab alone (median 13.0 vs. 11.6 months); however, the incidence of neutropenia was higher in the combination group, with the incidence of any-grade neutropenia and grade 3–5 neutropenia being 34% and 18%, respectively; meanwhile, it was 2% and <1% in the pembrolizumab-alone group (22). In our real-world study, the use of mecapegfilgrastim for prevention resulted in a lower occurrence of grade ≥3 neutropenia (5.1%) in patients receiving both chemotherapy and immunotherapy. For patients who received chemotherapy alone, the incidence of grade ≥3 neutropenia was 6.4%. In addition, with the prophylactic administration of mecapegfilgrastim in the first chemotherapy cycle (Table 3), as the number of immunotherapy cycles increases, the incidence of grade ≥3 neutropenia gradually decreased. These findings suggest that long-term use of mecapegfilgrastim can reduce the risk of patients developing ANC.

Currently, concurrent chemoradiotherapy with cisplatin stands as the preferred approach for treating locally advanced head and neck cancer (3,23). However, there are concerns regarding the toxicity associated with cisplatin-based induction chemotherapy followed by high-dose cisplatin chemoradiotherapy administered every three weeks. In the Southwest Oncology Group phase II trial (S0216) trial, a regimen combining three-drug taxane-based induction chemotherapy with accelerated fractionation or concomitant boost radiation, alongside single-agent cisplatin therapy was employed for treating patients with locoregionally advanced HNSCC (24). Among the 74 patients who underwent induction chemotherapy, 59% experienced grade ≥3 neutropenia, with 18% requiring hospitalization due to FN and 1 patient experiencing toxic death as a result of FN. Subsequently, among the 58 patients who completed concurrent chemoradiotherapy, 31% experienced grade ≥3 neutropenia. Hospitalization for FN was necessary in 5% of patients, with one patient experiencing toxic death during concurrent chemoradiotherapy due to FN. Both chemotherapy and radiotherapy can lead to extended periods of malnutrition, myelosuppression, and damage to the mucosal barrier (13,25). In this real-world study, prophylactic use of mecapegfilgrastim resulted in incidences of grade ≥3 neutropenia of 5.0% in patients receiving both chemotherapy and radiotherapy and of 6.1% in those receiving chemotherapy alone. One patient undergoing chemoradiotherapy experienced FN. Therefore, the use of mecapegfilgrastim as a prophylactic measure could be an effective choice for patients with head and neck cancer. In this real-world study, it was observed that patients who had received radiotherapy within 3 months prior to chemotherapy experienced higher incidences of severe neutropenia and FN, even with the prophylactic use of mecapegfilgrastim, compared to those without a history of radiotherapy within 3 months prior to chemotherapy. This suggests that special attention should be paid to preventing myelosuppression in patients with a history of radiotherapy within 3 months prior to chemotherapy or those undergoing concurrent chemoradiotherapy.

The safety profile of prophylactic use of mecapegfilgrastim in chemotherapy combined with radiotherapy and that of chemotherapy combined with immunotherapy was generally consistent with the toxicity spectrum reported for each treatment regimen, as was the underlying head and neck disease. No new safety signals were encountered (22,24). The common grade ≥3 TRAEs that occurred in these combination regimens were the same (decreased white blood cell count and decreased lymphocyte count) and manageable.

There were several limitations in this study. Firstly, the sample size for analysis was relatively small. Secondly, the ANC data were collected as part of routine medical diagnosis and treatment, rather than through the frequent blood collection typically required in randomized controlled trials. Further studies are needed to validate our results.

Conclusions

In this study, mecapegfilgrastim exhibited promising efficacy and safety in patients with head and neck cancer, particularly in those who received chemoradiotherapy or chemotherapy in combination with immunotherapy. No new safety concerns were observed. Findings in this real-world setting provide support for the continued use of mecapegfilgrastim for the prevention of neutropenia in patients with head and neck cancer and offer insights into clinical practice.

Acknowledgments

We would like to thank all the patients who participated in this study and their families. We also thank the following employees from Jiangsu Hengrui Pharmaceuticals Co., Ltd.: Jianan Zhang and Liu Yang for data interpretation, Yuting Chen for statistical analysis, Yu Tian (former employee) and Ting He for medial writing assistance. Additionally, we sincerely thank the following hospitals/institutions for their invaluable contributions to the study (listed alphabetically by affiliation): Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China; Affiliated Hospital of North Sichuan Medical College, Nanchong, China; Anhui No. 2 Provincial People’s Hospital, Hefei, China; The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China; Changshu No. 2 People’s Hospital, Changshu, China; Linzi District People’s Hospital, Zibo, China; Nan Chong Central Hospital, Nanchong, China; Peking University People’s Hospital, Beijing, China; Ruian People’s Hospital, Ruian, China; Shandong Cancer Institute, Shandong Cancer Hospital, Jinan, China; Shandong Provincial Hospital, Jinan, China; Shanghai Jia Ding District Central Hospital, Shanghai, China; Shanghai Pudong New Area People’s Hospital, Shanghai, China; Sun Yat-Sen University Cancer Center, Guangzhou, China; The First Affiliated Hospital to Zhejiang University School of Medicine, Hangzhou, China; The First Affiliated Hospital Sun Yat-sen University, Guangzhou, China; The First Hospital of Qiqihar, Qiqihar, China; The First People’s Hospital of Changzhou, Changzhou, China; The First People’s Hospital of Kunshan, Kunshan, China; The People’s Hospital of Danyang, Danyang, China; The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China; The Second People’s Hospital of Changzhou, Changzhou, China; Tianjin Medical University General Hospital, Tianjin, China; Xinxiang Central Hospital, Xinxiang, China.

Funding: This work was supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd. While the funders were engaged in statistical analysis and data interpretation, they were not involved in shaping the study’s design, gathering data, making decisions concerning publication, or preparing the manuscript.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2035/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2035/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2035/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2035/coif). All authors report that this work was supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of the Harbin Institute of Hematology and Oncology (No. 2019-006). All participating hospitals/institutions were informed and agreed with this study, and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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