AK-HER2与参照药治疗HER2阳性转移性乳腺癌患者的疗效、体内代谢特征、安全性和免疫原性比较：一项多中心、随机、双盲Ⅲ期等效性临床试验

罗扬, 孙涛, 邵志敏, 崔久嵬, 潘跃银, 张清媛, 程颖, 李惠平, 杨燕, 叶长生, 于国华, 王京芬, 刘运江, 刘新兰, 周宇红, 柏玉举, 谷元廷, 王晓稼, 徐兵河, 宋礼华

  1. 1.国家癌症中心/国家肿瘤临床医学中心/中国医学科学院北京协和医学院肿瘤医院内科，北京 100021
    2.辽宁省肿瘤医院乳腺内科，辽宁 沈阳 110042
    3.复旦大学附属肿瘤医院乳腺外科，上海 200032
    4.吉林大学第一医院肿瘤科，吉林 长春 130021
    5.中国科学技术大学附属第一医院肿瘤内科，安徽 合肥 230001
    6.哈尔滨医科大学附属肿瘤医院乳腺内科，黑龙江 哈尔滨 150081
    7.吉林省肿瘤医院胸部肿瘤内科，吉林 长春 130021
    8.北京大学肿瘤医院乳腺肿瘤内科，肿瘤发生及转化研究教育部重点实验室，北京 100142
    9.蚌埠医科大学第一附属医院肿瘤内科，安徽 蚌埠 233004
    10.南方医科大学南方医院乳腺科，广东 广州 510515
    11.潍坊市人民医院肿瘤内科，山东 潍坊 261041
    12.临沂市肿瘤医院乳腺科，山东 临沂 276001
    13.河北医科大学第四医院乳腺外科，河北 石家庄 050010
    14.宁夏医科大学总医院肿瘤医院肿瘤内科，宁夏 银川 750003
    15.复旦大学附属中山医院肿瘤内科，上海 200032
    16.遵义医科大学第二附属医院肿瘤科，贵州 遵义 563006
    17.郑州大学第一附属医院乳腺外科，河南 郑州 450003
    18.中国科学院大学附属肿瘤医院（浙江省肿瘤医院）乳腺肿瘤内科，浙江 杭州 310022
    19.基因工程制药安徽省重点实验室，肿瘤精准治疗技术及产品国家地方联合工程研究中心，安徽 合肥 230088
  • 收稿日期:2024-01-05 修回日期:2024-02-18 出版日期:2024-02-29 发布日期:2024-03-14
  • 通信作者: 徐兵河
  • 作者简介:罗 扬（ORCID: 0000-0002-5501-9935），博士，硕士研究生导师。

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摘要/Abstract

摘要：

背景与目的：针对人表皮生长因子受体（human epidermal growth factor receptor 2，HER2）阳性转移性乳腺癌患者，曲妥珠单抗治疗能够延长患者总生存期，显著改善患者预后，但是原研曲妥珠单抗价格较高。生物类似药理论上具有相当的疗效和安全性。本临床试验旨在评估曲妥珠单抗生物类似药AK-HER2与原研曲妥珠单抗在HER2阳性转移性乳腺癌患者中的疗效、药代动力学、安全性和免疫原性。方法：这项多中心、随机、双盲Ⅲ期临床试验在中国43个分中心开展。本研究遵从研究方案、赫尔辛基宣言阐明的伦理学原则和药物临床试验质量管理规范，获得医院医学伦理委员会批准，临床试验注册机构为国家药品监督管理局（临床试验批件号为2015L04224，临床试验登记号为CTR20170516）。在入组前获得了受试者的书面知情同意书。入组患者随机分配至AK-HER2组与对照组，分别接受AK-HER2或原研曲妥珠单抗（赫赛汀®，初始负荷剂量8 mg/kg，维持剂量6 mg/kg，每3周为1个治疗周期，总治疗时间为16个周期）与多西他赛（剂量75 mg/m2，治疗持续至少9个周期）联合治疗。本临床试验主要研究终点是第9个周期AK-HER2组与对照组的客观缓解率（objective response rate，ORR）。次要疗效终点包括ORR16、疾病控制率（disease control rate，DCR）、临床获益率（clinical benefit rate，CBR）、无进展生存期（progression-free survival，PFS）和1年生存率。本研究在第6个周期用药后，随机选择100例受试者（AK-HER2组∶对照组 = 1∶1）进行血样采集，采集时间点分别为输注45 min时（即给药结束）、给药结束后第4、8、24、72、120、168、336、504 h。采集后血样进行PK参数（PK parameter set，PKPS）分析。其他评估指标包括安全性和免疫原性评估。结果：2017年9月—2021年3月期间共有550例HER2阳性转移性乳腺癌患者入组该临床试验。AK-HER2组（n = 275）和对照组（n = 272）的ORR9分别为试验组受试者（n = 237）达CR或PR的有129例，ORR9为54.4%，对照组受试者（n = 241）达CR或PR的有134例，ORR9为55.6%。AK-HER2组与对照组的ORR9比率为97.9%[90%置信区间（confidence interval，CI）：85.4% ~ 112.2%，P = 0.784]差异无统计学意义。在所有次要疗效终点中，两组均未观察到差异有统计学意义。本研究进行了AK-HER2组和对照组药代动力学（pharmacokinetics，PK）参数的均值比值分析，结果显示，两种药物的药代动力学特征相似。原研曲妥珠单抗治疗导致药物减量或暂停的治疗期间出现的不良事件（treatment emergent adverse event，TEAE）发生率，AK-HER2组为3.6%（10例），对照组为8.1%（22例），两组差异有统计学意义（P = 0.027）。AK-HER2组发生率较对照组明显减少，其余组间差异均无统计学意义。抗药抗体（anti-drug antibody，ADA）与中和抗体（neutralizing antibody，NAB）阳性率组间差异均无统计学意义（P = 0.385和P = 0.752）。结论：在HER2阳性转移性乳腺癌患者中，AK-HER2与参照药原研曲妥珠单抗的疗效、药代动力学、安全性和免疫原性相当。

关键词: 乳腺癌, 曲妥珠单抗, AK-HER2, 疗效, 药代动力学, 安全性

Abstract:

Background and purpose: For patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients. However, the reference original research trastuzumab (Herceptin®) is more expensive. Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment. This clinical trial aimed to evaluate the efficacy, pharmacokinetics, safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer. Methods: This multi-center, randomised, double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China. This study complied with the research protocol, the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials. It was approved by the hospital's medical ethics committee. The clinical trial registration agency is the State Food and Drug Administration (clinical trial approval number: 2015L04224; clinical trial registration number: CTR20170516). Written informed consent was obtained from subjects before enrollment. Enrolled patients were randomly assigned to the AK-HER2 group and the control group, respectively receiving AK-HER2 or trastuzumab (initial loading dose 8 mg/kg, maintenance dose 6 mg/kg, every 3 weeks as a treatment cycle, total treatment time is 16 cycles) in combination with docetaxel (75 mg/m2, treatment duration is at least 9 cycles). The primary endpoint of this clinical trial was the objective response rate (ORR9) between the AK-HER2 group and the control group in the 9th cycle. Secondary efficacy endpoints included ORR16, disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS) and 1-year survival rate. In this study, 100 subjects (AK-HER2 group to control group=1:1) were randomly selected for blood sample collection after the 6th cycle of medication, The collection time points were 45 minutes after infusion (the end of administration), 4, 8, 24, 72, 120, 168, 336, and 504 hours after the end of administration. After collection, blood samples were analyzed by PK parameter set (PKPS). Other evaluation parameters included safety and immunogenicity assessment. Results: A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep. 2017 and Mar. 2021. In the AK-HER2 group (n=237), 129 subjects in the experimental group achieved complete response (CR) or partial response (PR), and the ORR9 was 54.4%. There were 134 subjects in the control group (n=241) who achieved CR or PR, and the ORR9 was 55.6%. The ORR9 ratio between the AK-HER2 group and the control group was 97.9% [90% confidence interval (CI): 85.4%-112.2%, P=0.784], which was not statistically significant. In all secondary efficacy endpoints, no statistically significant differences were observed between the two groups. We conducted a mean ratio analysis of pharmacokinetics (PK) parameters between the AK-HER2 group and the control group, and the results suggested that the pharmacokinetic characteristics of the two drugs are similar. The incidence of treatment emergent adverse event (TEAE) leading to drug reduction or suspension during trastuzumab treatment was 3.6% (10 cases) in the AK-HER2 group and 8.1% (22 cases) in the control group. There was statistically significant difference between the two groups (P=0.027). The incidence rate was significantly lower in the AK-HER2 group than in the control group, and there was no statistically significant difference among the other groups. The differences in the positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAB) between groups were of no statistical significance (P=0.385 and P=0.752). Conclusion: In patients with HER2-positive metastatic breast cancer, AK-HER2 was comparable to the trastuzumab (Herceptin®) in terms of drug efficacy, pharmacokinetics, safety and immunogenicity.

Key words: Breast cancer, Trastuzumab, AK-HER2, Efficacy, Pharmacokinetics, Safety

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