Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial

Yang LUO; Tao SUN; Zhimin SHAO; Jiuwei CUI; Yueyin PAN; Qingyuan ZHANG; Ying CHENG; huiping LI; Yan YANG; Changsheng YE; Guohua YU; Jingfen WANG; Yunjiang LIU; Xinlan LIU; Yuhong ZHOU; Yuju BAI; Yuanting GU; Xiaojia WANG; Binghe XU; Lihua SONG

doi:10.19401/j.cnki.1007-3639.2024.02.004

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Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial

Article | 更新时间：2025-12-31

- Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial
- China Oncology Vol. 34, Issue 2, Pages: 161-175(2024)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2024.02.004
  CLC： R737.9
- Received：05 January 2024，
  
  Revised：2024-02-18，
  
  Published：29 February 2024
- 稿件说明：
移动端阅览
Yang LUO, Tao SUN, Zhimin SHAO, et al. Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial[J]. China Oncology, 2024, 34(2): 161-175.
DOI：

Yang LUO, Tao SUN, Zhimin SHAO, et al. Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial[J]. China Oncology, 2024, 34(2): 161-175. DOI： 10.19401/j.cnki.1007-3639.2024.02.004.

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/m

，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-H

ER2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（

= 275）和对照组（

= 272）的ORR9分别为试验组受试者（

= 237）达CR或PR的有129例，ORR9为54.4%，对照组受试者（

= 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%，

= 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（

= 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（

= 0.385和

= 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。

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/m

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)

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 (

=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 (

=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%

=0.784

]

which was not statisticall

y 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 (

=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 (

=0.385 and

=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.

关键词

Keywords

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