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

doi:10.19401/j.cnki.1007-3639.2024.02.004

中国癌症杂志 ›› 2024, Vol. 34 ›› Issue (2): 161-175.doi: 10.19401/j.cnki.1007-3639.2024.02.004

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¹(), 孙涛², 邵志敏³, 崔久嵬⁴, 潘跃银⁵, 张清媛⁶, 程颖⁷, 李惠平⁸, 杨燕⁹, 叶长生¹⁰, 于国华¹¹, 王京芬¹², 刘运江¹³, 刘新兰¹⁴, 周宇红¹⁵, 柏玉举¹⁶, 谷元廷¹⁷, 王晓稼¹⁸, 徐兵河¹(), 宋礼华¹⁹

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。

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

LUO Yang¹(), SUN Tao², SHAO Zhimin³, CUI Jiuwei⁴, PAN Yueyin⁵, ZHANG Qingyuan⁶, CHENG Ying⁷, LI huiping⁸, YANG Yan⁹, YE Changsheng¹⁰, YU Guohua¹¹, WANG Jingfen¹², LIU Yunjiang¹³, LIU Xinlan¹⁴, ZHOU Yuhong¹⁵, BAI Yuju¹⁶, GU Yuanting¹⁷, WANG Xiaojia¹⁸, XU Binghe¹(), SONG Lihua¹⁹

1. Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing 100021, China
2. Department of Breast Medicine, Liaoning Provincial Cancer Hospital, Shenyang 110042, Liaoning Province, China
3. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
4. Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
5. Department of Oncology, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
6. Department of Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
7. Department of Thoracic Medical Oncology, Jilin Provincial Cancer Hospital, Changchun 130021, Jilin Province, China
8. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
9. Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, Anhui Province, China
10. Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
11. Department of Oncology, Weifang People’s Hospital, Weifang 261041, Shandong Province, China
12. Gynecology Department of Linyi Cancer Hospital, Linyi 276001, Shandong Province, China
13. Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang 050010, Hebei Province, China
14. Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750003, Ningxia Hui Autonomous Region, China
15. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
16. Department of Oncology, the Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
17. Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
18. Department of Breast Medical Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, Zhejiang Province, China
19. Anhui Province Key Laboratory of Gene Engineering Pharmaceutical, National and Local Joint Engineering Research Center for Precision Tumor Treatment Technology and Products, Hefei 230088, Anhui Province, China

Received:2024-01-05 Revised:2024-02-18 Published:2024-02-29 Online:2024-03-14
Contact: XU Binghe

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

中图分类号:

R737.9

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. 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[J]. 中国癌症杂志, 2024, 34(2): 161-175.

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

图/表 9

图1

表1

表2

图2

表3

图3

表4

表5

表6

参考文献 31

[1]	LEI S Y, ZHENG R S, ZHANG S W, et al. Global patterns of breast cancer incidence and mortality: a population-based cancer registry data analysis from 2000 to 2020[J]. Cancer Commun, 2021, 41(11): 1183-1194. doi: 10.1002/cac2.v41.11
[2]	刘宗超, 李哲轩, 张阳, 等. 2020全球癌症统计报告解读[J]. 肿瘤综合治疗电子杂志, 2021, 7(2): 1-14.
	LIU Z C, LI Z X, ZHANG Y, et al. Interpretation on the report of Global Cancer Statistics 2020[J]. J Multidiscip Cancer Manag Electron Version, 2021, 7(2): 1-14.
[3]	FAN L, STRASSER-WEIPPL K, LI J J, et al. Breast cancer in China[J]. Lancet Oncol, 2014, 15(7): e279-e289. doi: 10.1016/S1470-2045(13)70567-9
[4]	GONDOS A, ARNDT V, HOLLECZEK B, et al. Cancer survival in Germany and the United States at the beginning of the 21st century: an up-to-date comparison by period analysis[J]. Int J Cancer, 2007, 121(2): 395-400. pmid: 17372898
[5]	LEONG S P, SHEN Z Z, LIU T J, et al. Is breast cancer the same disease in Asian and Western countries?[J]. World J Surg, 2010, 34(10): 2308-2324. doi: 10.1007/s00268-010-0683-1 pmid: 20607258
[6]	LI J, ZHANG B N, FAN J H, et al. A nation-wide multicenter 10-year (1999-2008) retrospective clinical epidemiological study of female breast cancer in China[J]. BMC Cancer, 2011, 11: 364. doi: 10.1186/1471-2407-11-364 pmid: 21859480
[7]	CHEN W Q, ZHENG R S, BAADE P D, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132. doi: 10.3322/caac.v66.2
[8]	XUAN Q J, GAO K, SONG Y, et al. Adherence to needed adjuvant therapy could decrease recurrence rates for rural patients with early breast cancer[J]. Clin Breast Cancer, 2016, 16(6): e165-e173. doi: 10.1016/j.clbc.2016.07.006 pmid: 27544692
[9]	ANDERSON B O, YIP C H, SMITH R A, et al. Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007[J]. Cancer, 2008, 113(8 Suppl): 2221-2243. doi: 10.1002/cncr.23844 pmid: 18816619
[10]	CHIA K S, REILLY M, TAN C S, et al. Profound changes in breast cancer incidence may reflect changes into a Westernized lifestyle: a comparative population-based study in Singapore and Sweden[J]. Int J Cancer, 2005, 113(2): 302-306. doi: 10.1002/ijc.v113:2
[11]	LI J J, SHAO Z M, XU B H, et al. Use of trastuzumab as an adjuvant/neoadjuvant therapy in patients with HER2-positive breast cancer in China: the Nvwa study[J]. Medicine, 2018, 97(21): e10350. doi: 10.1097/MD.0000000000010350
[12]	SAN MIGUEL Y, GOMEZ S L, MURPHY J D, et al. Age-related differences in breast cancer mortality according to race/ethnicity, insurance, and socioeconomic status[J]. BMC Cancer, 2020, 20(1): 228. doi: 10.1186/s12885-020-6696-8 pmid: 32178638
[13]	DREYER M S, NATTINGER A B, MCGINLEY E L, et al. Socioeconomic status and breast cancer treatment[J]. Breast Cancer Res Treat, 2018, 167(1): 1-8. doi: 10.1007/s10549-017-4490-3
[14]	CARRERA P M, KANTARJIAN H M, BLINDER V S. The financial burden and distress of patients with cancer: understanding and stepping-up action on the financial toxicity of cancer treatment[J]. CA Cancer J Clin, 2018, 68(2): 153-165. doi: 10.3322/caac.v68.2
[15]	KIM H, ALTEN R, AVEDANO L, et al. Correction to: the future of biosimilars: maximizing benefits across immune-mediated inflammatory diseases[J]. Drugs, 2020, 80(10): 1039-1040. doi: 10.1007/s40265-020-01333-9 pmid: 32488813
[16]	WANG J X, NIU S P, DONG W L, et al. A randomized phase I clinical trial comparing the pharmacokinetic, safety, and immunogenicity of potential biosimilar recombinant human HER2 monoclonal antibody for injection and trastuzumab in healthy Chinese adults[J]. Expert Opin Investig Drugs, 2020, 29(7): 755-762. doi: 10.1080/13543784.2020.1770226
[17]	EISENHAUER E A, THERASSE P, BOGAERTS J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[J]. Eur J Cancer, 2009, 45(2): 228-247. doi: 10.1016/j.ejca.2008.10.026 pmid: 19097774
[18]	BASELGA J, CORT&#XE; S J, KIM S B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer[J]. N Engl J Med, 2012, 366(2): 109-119. doi: 10.1056/NEJMoa1113216
[19]	Trial validates biosimilar for trastuzumab[J]. Cancer Discov, 2016, 6(7): 686-687. doi: 10.1158/2159-8290.CD-NB2016-068 pmid: 27277256
[20]	RUGO H S, BARVE A, WALLER C F, et al. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial[J]. JAMA, 2017, 317(1): 37-47. doi: 10.1001/jama.2016.18305 pmid: 27918780
[21]	MARTY M, COGNETTI F, MARANINCHI D, et al. Randomized phase Ⅱ trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group[J]. J Clin Oncol, 2005, 23(19): 4265-4274. doi: 10.1200/JCO.2005.04.173
[22]	ZHU X, DING Y, YU Y, et al. A Phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX02 to reference CN- and EU-sourced trastuzumab in healthy subjects[J]. Cancer Chemother Pharmacol, 2021, 87(3): 349-359. doi: 10.1007/s00280-020-04196-9
[23]	WISMAN L A, DE COCK E P, REIJERS J A, et al. A phase I dose-escalation and bioequivalence study of a trastuzumab biosimilar in healthy male volunteers[J]. Clin Drug Investig, 2014, 34(12): 887-894. doi: 10.1007/s40261-014-0247-5
[24]	WYNNE C, HARVEY V, SCHWABE C, et al. Comparison of subcutaneous and intravenous administration of trastuzumab: a phase Ⅰ/Ⅰb trial in healthy male volunteers and patients with HER2-positive breast cancer[J]. J Clin Pharmacol, 2013. Epub ahead of print.
[25]	BASELGA J. Phase Ⅰ and Ⅱ clinical trials of trastuzumab[J]. Ann Oncol, 2001, 12(Suppl 1): S49-S55.
[26]	VAISMAN-MENTESH A, GUTIERREZ-GONZALEZ M, DEKOSKY B J, et al. The molecular mechanisms that underlie the immune biology of anti-drug antibody formation following treatment with monoclonal antibodies[J]. Front Immunol, 2020, 11: 1951. doi: 10.3389/fimmu.2020.01951
[27]	HANSEL T T, KROPSHOFER H, SINGER T, et al. The safety and side effects of monoclonal antibodies[J]. Nat Rev Drug Discov, 2010, 9(4): 325-338. doi: 10.1038/nrd3003 pmid: 20305665
[28]	GINSBURG O, BRAY F, COLEMAN M P, et al. The global burden of women’s cancers: a grand challenge in global health[J]. Lancet, 2017, 389(10071): 847-860. doi: 10.1016/S0140-6736(16)31392-7
[29]	刘威, 王黎君, 齐金蕾, 等. 1990-2017年中国女性乳腺癌疾病负担分析[J]. 中华流行病学杂志, 2021, 42(7): 1225-1230.
	LIU W, WANG L, QI J, et al. Disease burden of breast cancer in women in China, 1990-2017[J]. Chin J Epidemiol, 2021, 42(7): 1225-1230.
[30]	HUO Q, CAI C, YANG Q F. Rural-urban disparities contributed to distinct outcomes of early stage breast cancer[J]. Oncol Res Treat, 2014, 37(10): 596-597. doi: 10.1159/000368054 pmid: 25342511
[31]	XU B H, ZHANG Q Y, SUN T, et al. Efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with recurrent or metastatic HER2-positive breast cancer: a randomized phase Ⅲ equivalence trial[J]. BioDrugs, 2021, 35(3): 337-350. doi: 10.1007/s40259-021-00475-w

Item	AK-HER2 (n = 275)	Trastuzumab (n = 272)	Item	AK-HER2 (n = 275)	Trastuzumab (n = 272)
Age/year			ECOG status
Median	53.0	52.0	0	130 (47.3)	117 (43.2)
18-65	246 (89.5)	251 (92.3)	1	145 (52.7)	154 (56.8)
>65	29 (10.5)	21 (7.7)	Target lesions
Height/cm			Yes	267 (97.1)	265 (97.4)
Median	158.00	158.00	No	8 (2.9)	7 (2.6)
Weight/kg			Target lesion diameter/mm
Median	60.00	60.00	Median	57.90	61.00
Nation			History of systemic chemotherapy/targeted drug treatment for tumors
Han	257 (93.5)	257 (94.5)	Yes	185 (67.3)	172 (63.2)
Others	18 (6.5)	15 (5.5)	No	90 (32.7)	100 (36.8)
Osseous metastasis			History of endocrine therapy for tumors
Yes	123 (45.1)	118 (43.4)	No	179 (65.1)	189 (69.5)
No	150 (54.9)	154 (56.6)	Yes	96 (34.9)	83 (30.5)
ER/PgR			History of other malignant tumors
ER⁺/PgR⁺	94 (35.7)	80 (29.9)	No	273 (99.3)	271 (99.6)
ER^-/PgR^-	108 (41.1)	126 (47.0)	Yes	2 (0.7)	1 (0.4)
ER^-/PgR⁺	11 (4.2)	14 (5.2)	History of tumor radiotherapy
ER⁺/PgR^-	49 (18.6)	47 (17.5)	Yes	79 (28.8)	79 (29.0)
Unknown^*	1 (0.4)	1 (0.4)	No	195 (71.2)	193 (71.0)
HER2 positive
Yes	255 (97.0)	257 (97.7)
No	8 (3.0)	6 (2.3)

	AK-HER2 (n = 275)	Trastuzumab (n= 272)	Ratio (%)	P value
Primary endpoint (PPS)
CR	10 (4.2)	7 (2.9)
PR	119 (50.2)	127 (52.7)
SD	95 (40.1)	90 (37.3)
PD	11 (4.6)	14 (5.8)
NE	2 (0.8)	3 (1.2)
ORR9 ^*	129 (54.4)	134 (55.6)	97.9	0.784
90%CI/%	48.9-59.9	50.1-61.0	85.4-112.2
Secondary endpoint (FAS)
ORR16	142 (51.6)	142 (52.2)		0.894
DCR	248 (90.2)	241 (88.6)		0.549
CBR	159 (57.8)	164 (60.3)		0.556
PFS
Censored	161 (58.5)	175 (64.3)
Number of events	114 (41.5)	97 (35.7)
Kaplan-Meier t/months
25% (95% CI)	6.1 (4.2-6.3)	6.2 (5.4-7.7)
50% (95% CI)	10.3 (8.6-11.2)	11.7 (10.3-NE)
75% (95% CI)	NE (NE-NE)	NE (NE-NE)
PFS stratified analysis^α
Statistics	1.980			0.159
HR (95% CI)	1.21 (0.92-1.59)
PFS stratified analysis^β
Statistics	1.405			0.236
HR (95% CI)	1.18 (0.90-1.54)
OS
Censored/%	273 (99.3)	269 (98.9)
Number of events/%	2 (0.7)	3 (1.1)
Kaplan-Meier (months)
25% (95% CI)	NE (NE-NE)	NE (NE-NE)
50% (95% CI)	NE (NE-NE)	NE (NE-NE)
75% (95% CI)	NE (NE-NE)	NE (NE-NE)
OS stratified analysis^α
Statistics	0.208			0.648
HR (95% CI)	0.66 (0.11-3.98)
OS stratified analysis^β
Statistics	0.214			0.643
HR (95% CI)	0.66 (0.11-3.93)
Month 12	99.3 (97.1-99.8)	98.9 (96.6-99.6)

Parameter	Group	N	GMLS mean	95% CI	AK-HER2/trastuzumab
Parameter	Group	N	GMLS mean	95% CI	Ratio/%	90% CI
C_max,ss (μg/mL)	AK-HER2	54	141.43	134.59-148.61	95.76	90.25-101.59
	Trastuzumab	52	147.70	140.43-155.34
AUC_0-τ(h*μg/mL)	AK-HER2	49	20 911.74	19 699.20-221 98.91	97.87	91.13-105.12
	Trastuzumab	47	21 366.27	20 102.08-22 709.96
T_1/2z (h)	AK-HER2	49	164.58	153.78-176.15	98.75	91.05-107.11
	Trastuzumab	47	166.66	155.50-178.63
CLss (mL/h)	AK-HER2	49	17.20	16.15-18.32	102.21	94.80-110.20
	Trastuzumab	47	16.83	15.78-17.95
V_z (L)	AK-HER2	49	4.08	3.82-4.36	100.94	93.27-109.23
	Trastuzumab	47	4.05	3.78-4.33

Item	AK-HER2 (n=267)	Trastuzumab (n=256)	Statistics	Pvalue	Method
ADA
N (N Miss)	267 (8)	256 (16)
Pre-existing ADA)	17 (6.4)	13 (5.1)	0.402	0.526	Chi-square test
Post-baseline ADA^*	20 (7.5)	10 (3.9)	3.105	0.078	Chi-square test
Negative	239 (89.5)	236 (92.2)	1.121	0.290	Chi-square test
Treatment-induced ADA^**	11 (4.1)	7 (2.7)	0.755	0.385	Chi-square test
NAB
N (NMiss)	267 (8)	256 (16)
Post-baseline NAB^*	14 (5.2)	6 (2.3)	2.988	0.084	Chi-square test
Treatment-induced NAB^**	6 (2.2)	4 (1.6)	NA	0.752	Fisher

Safety data	AK-HER2 (n = 275)	Trastuzumab (n = 272)	Safety data	AK-HER2 (n = 275)	Trastuzumab (n = 272)
Number of TEAE	4 738	5 049	AESI related to study drug	79 (28.7)	78 (28.7)
Any TEAE	265 (96.4)	270 (99.3)	Grade 1	58 (21.1)	58 (21.3)
Grade 1	259 (94.2)	259 (95.2)	Grade 2	32 (11.6)	32 (11.8)
Grade 2	232 (84.4)	233 (85.7)	Grade 3	6 (2.2)	3 (1.1)
Grade 3	164 (59.6)	173 (63.6)	Grade 4	3 (1.1)	0 (0.0)
Grade 4	100 (36.4)	90 (33.1)	Grade 5	0 (0.0)	0 (0.0)
Grade 5	3 (1.1)	5 (1.8)	Treatment-related AEs occurring in≥10% of patients
TEAE related to study drug	173 (62.9)	176 (64.7)	Decreased white blood cell count	200 (72.7)	200 (73.5)
TEAE leading to drug withdrawal	6 (2.2)	3 (1.1)	Decreased neutrophil count	198 (72.0)	199 (73.2)
SAE	43 (15.6)	37 (13.6)	Increased alanine aminotransferase	69 (25.1)	70 (25.7)
Grade 1	5 (1.8)	7 (2.6)	Increased aspartate aminotransferase	66 (24.0)	72 (26.5)
Grade 2	17 (6.2)	18 (6.6)	Weight gain	56 (20.4)	49 (18.0)
Grade 3	12 (4.4)	15 (5.5)	Decreased platelet count	26 (9.5)	36 (13.2)
Grade 4	15 (5.5)	13 (4.8)	Anemia	114 (41.5)	125 (46.0)
Grade 5	2 (0.7)	4 (1.5)	Alopecia	66 (24.0)	62 (22.8)
SAE related to study drug	16 (5.8)	12 (4.4)	Pyrexia	32 (11.6)	45 (16.5)
Deaths	1 (0.4)	3 (1.1)	Asthenia	25 (9.1)	33 (12.1)
Deaths related to study drug	0 (0.0)	1 (0.4)	Hyperglycemia	43 (15.6)	42 (15.4)
AESI	160 (58.2)	161 (59.2)	Diarrhea	30 (10.9)	39 (14.3)
			Upper respiratory infection	36 (13.1)	22 (8.1)

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

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

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 9

参考文献 31

相关文章 15

编辑推荐

Metrics

本文评价

[1]	张琪, 修秉虬, 吴炅. 2023年中国乳腺癌重要临床研究成果及最新进展[J]. 中国癌症杂志, 2024, 34(2): 135-142.
[2]	张思源, 江泽飞. 2023年改变晚期乳腺癌临床实践的重要研究成果及进展[J]. 中国癌症杂志, 2024, 34(2): 143-150.
[3]	王昭卜, 黎星, 于鑫淼, 金锋. 2023年改变早期乳腺癌临床实践的重要研究成果及进展[J]. 中国癌症杂志, 2024, 34(2): 151-160.
[4]	陈远香, 余涛, 杨诗雨, 曾涛, 魏兰, 张彦. KDM4A通过下调BMP9促进乳腺癌细胞MDA-MB-231的迁移和侵袭[J]. 中国癌症杂志, 2024, 34(2): 176-184.
[5]	胡晓钰, 蔡毓文, 叶富贵, 邵志敏, 胡伟刚, 余科达. BRCA1/2胚系突变对三阴性乳腺癌患者放疗后第二原发肿瘤的影响[J]. 中国癌症杂志, 2024, 34(2): 185-190.
[6]	金奕滋, 林明曦, 张剑. 乳腺癌原发灶与肝转移灶受体表达差异研究[J]. 中国癌症杂志, 2023, 33(9): 834-843.
[7]	杨忠毅, 许晓平, 王明伟, 张勇平, 杨建伟, 陈跃, 徐文贵, 李亚明, 章英剑, 宋少莉. 乳腺癌¹⁸F-FES雌激素受体PET技术和应用标准[J]. 中国癌症杂志, 2023, 33(8): 801-808.
[8]	王若曦, 吉芃, 龚悦, 陈盛. HER2低表达乳腺癌新辅助化疗效果及其预后特征：一项单中心回顾性研究[J]. 中国癌症杂志, 2023, 33(7): 686-692.
[9]	邬思雨, 李俊杰, 邵志敏. 乳腺癌前哨淋巴结活检术的发展历史及研究进展[J]. 中国癌症杂志, 2023, 33(6): 551-559.
[10]	毕钊, 王永胜. 1~2枚前哨淋巴结阳性早期乳腺癌患者治疗策略降阶梯新理念[J]. 中国癌症杂志, 2023, 33(6): 560-565.
[11]	赵谦, 凌云霄, 柳光宇. 乳腺癌患者保乳手术后再次前哨淋巴结活检的最新研究进展及展望[J]. 中国癌症杂志, 2023, 33(6): 566-573.
[12]	丛斌斌, 曹晓珊, 王春建, 邱鹏飞, 孙晓, 陈鹏, 刘雁冰, 赵桐, 张朝蓬, 石志强, 毕钊, 王永胜. 临床查体阴性但超声检查及穿刺确诊腋窝淋巴结转移的乳腺癌前哨淋巴结活检的可行性分析[J]. 中国癌症杂志, 2023, 33(6): 574-580.
[13]	任恒宇, 郝爽, 陈嘉健, 杨犇龙, 曹阿勇, 柳光宇, 邵志敏, 吴炅. 国内外乳房重建研究的现状和重点：一项文献计量学研究[J]. 中国癌症杂志, 2023, 33(6): 581-588.
[14]	陈璐艳, 王丽雪, 傅佩芬. 新发Ⅳ期乳腺癌患者手术价值探讨[J]. 中国癌症杂志, 2023, 33(5): 431-436.
[15]	左学良, 陈志强, 董润雨, 王智雄, 蔡娟. 联合检测LDHA和PD-L1在晚期胃癌PD-1抑制剂疗效预测及预后评估中的价值[J]. 中国癌症杂志, 2023, 33(5): 460-468.

	Actual value		Change value (post-pre)
	AK-HER2	Trastuzumab	AK-HER2	Trastuzumab
Baseline
N (NMiss)^*	275 (0)	271 (1)
Mean±SD	64.738±4.872	64.140±5.035
Median	64.000	64.000
C4D1
N (NMiss)	229 (46)	222 (50)	229 (46)	222 (50)
Mean±SD	63.855±4.376	64.149±4.642	-0.578±4.974	-0.161±5.332
Median	64.000	64.000	0	0
C7D1
N (NMiss)	178 (97)	174 (98)	178 (97)	174 (98)
Mean±SD	63.718±4.085	63.856±4.564	-0.701±5.069	-0.446±5.300
Median	63.000	64.000	-1.000	-1.000
C10D1
N (NMiss)	149 (126)	147 (125)	149 (126)	147 (125)
Mean±SD	63.124±3.942	63.766±4.270	-1.294±4.989	-0.582±4.930
Median	63.000	63.000	-1.000	-0.800
C13D1
N (NMiss)	117 (158)	118 (154)	117 (158)	118 (154)
Mean±SD	63.286±4.099	63.869±4.875	-0.557±4.884	-0.415±5.985
Median	63.000	63.100	0	0
C16D1
N (NMiss)	89 (186)	93 (179)	89 (186)	93 (179)
Mean±SD	63.431±3.951	63.080±4.683	-0.159±5.276	-0.991±5.747
Median	64.000	62.000	1.000	-1.000
EOT
N (NMiss)	245 (30)	237 (35)	245 (30)	237 (35)
Mean±SD	63.503±4.560	62.876±4.564	-1.199±5.107	-1.308±5.735
Median	63.000	62.700	-1.000	-1.000