Background: Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim.
Materials and methods: Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double-blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single-arm, open-label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 109/L after the expected nadir. Results were combined for cycles 1-4.
Results: A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim-related. The most frequently reported filgrastim-related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim-related). No patient developed antidrug antibodies during the study.
Conclusion: Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer.
Implications for practice: The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.
摘要
背景.对关键注册试验和正在进行的上市后监测中的不良事件（AE）进行评估对所有生物制剂（包括生物仿制药）而言都很重要。对两项关键注册研究进行了综合分析, 以加强接受骨髓抑制化疗的乳腺癌患者使用生物仿制药非格司亭EP2006（这是一个敏感的临床情况, 目的是确定非格司亭的生物相似性）的安全性证据。
材料与方法.数据来自生物仿制药非格司亭EP2006的两个III期研究。美国注册研究在接受TAC（多西他赛+多柔比星+环磷酰胺）（新）辅助治疗的年满18岁女性乳腺癌患者中进行了生物仿制药非格司亭和参比非格司亭的随机双盲比较。欧盟注册研究是在接受多柔比星+多西他赛治疗的年满18岁女性乳腺癌患者中进行生物仿制药非格司亭的单组、开放标签研究。患者在每个周期的第2天接受非格司亭皮下注射<14天或者直到绝对中性粒细胞计数达到预期最低点后的10 x 109/L。将1‐4周期的结果合并。
结果.共有277名患者接受了生物仿制药非格司亭EP2006给药。患者平均（±标准差）年龄为51.1（±10.8）岁, 78.7%的患者患有II期或III期乳腺癌。共46例（20.6%）接受生物仿制药非格司亭治疗的患者发生了与非格司亭相关的AE。最常报告的与非格司亭相关的AE是肌肉骨骼或结缔组织疾病（15.2%）, 包括骨痛（7.2%）。有一例接受生物仿制药非格司亭治疗的患者死亡（死亡原因为肺栓塞, 认为与非格司亭无关）。在研究期间没有患者产生抗药物抗体。
结论.生物仿制药非格司亭的安全性特征与以前的非格司亭研究一致, 可有效预防乳腺癌患者的发热性中性粒细胞减少症。
对临床实践的提示： 生物仿制药非格司亭EP2006（Zarzio, Zarxio, 生物仿制药非格司亭‐sndz）已于2009年在欧洲获得批准, 于2015年在美国获得批准。两项III期研究的综合分析提供了额外的临床证据, 证明生物仿制药非格司亭EP2006的安全性特征与以前的参比非格司亭研究一致, 并且支持欧洲EP2006的大型上市后研究。加强生物仿制药非格司亭的安全性证据可帮助提高生物仿制药的接受程度, 增加患者获得生物制剂的机会
Keywords: Biosimilar; EP2006; Filgrastim; Granulocyte colony‐stimulating factor.
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