A Multicenter, Randomized, Open-Label, Phase 3 Trial of Trastuzumab Deruxtecan (Enhertu®) Plus Chemotherapy Plus or Minus Pembrolizumab Versus Chemotherapy Plus Trastuzumab Plus or Minus Pembrolizumab as First-Line Treatment in Participants With Unresectable, Locally Advanced or Metastatic HER2-Positive Gastric Or Gastroesophageal Junction (GEJ) Cancer (Destiny-Gastric05)

This clinical trial is designed to assess the efficacy and safety of the triplet combination of trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201a) plus a fluoropyrimidine plus pembrolizumab versus standard of care (SoC) chemotherapy plus trastuzumab plus pembrolizumab as first-line therapy in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS ≥1 gastric or GEJ cancer in the Main Cohort. An Exploratory Cohort will also be evaluated to assess the efficacy and safety of T-DXd plus a fluoropyrimidine versus SoC chemotherapy plus trastuzumab in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS <1 gastric or GEJ cancer.

开始日期2025-03-01

申办/合作机构

Daiichi Sankyo Co., Ltd.

NCT06686394

/ Not yet recruiting临床1/2期

HERTHENA-Breast-01: A Phase 1b/2, Multicenter, Open-label, Dose-Finding Study to Evaluate the Safety and Antitumor Activity of Patritumab Deruxtecan in Participants With HER2 Positive Unresectable Locally Advanced Breast Cancer or Metastatic Breast Cancer

Researchers want to learn if patritumab deruxtecan (MK-1022) can treat certain breast cancers. The breast cancers being studied are HER2 positive unresectable locally advanced or metastatic (the cancer has spread to other parts of the body). The goals of this study are to learn:
* About the safety and how well people tolerate of patritumab deruxtecan
* How many people have the cancer respond (get smaller or go away) to treatment

开始日期2025-02-26

申办/合作机构

Merck Sharp & Dohme Corp.

[+1]

CTR20220458

/ Active, not recruiting临床3期

Trastuzumab Deruxtecan（T-DXd）单药或T-DXd序贯THP对比ddAC-THP用于高危HER2阳性早期乳腺癌受试者新辅助治疗的III期开放性试验（DESTINY-Breast11）

pCR（ypT0/Tis ypN0）：在HER2阳性EBC受试者中通过使用中心评估结果评价pCR（ypT0/Tis ypN0），证明新辅助T-DXd单药或序贯THP相比于ddAC-THP的优效性。

开始日期2022-06-21

申办/合作机构

阿斯利康投资（中国）有限公司

[+2]

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项与曲妥珠单抗生物类似药(Synthon BV) 相关的文献（医药）

2024-01-23·Cureus

Biosimilar in Breast Cancer: A Narrative Review

Review

作者: Bandyopadhyay, Tibar ; Talukdar, Rounik ; Barman, Diplina

Breast cancer (BC) has been identified as a major public health cancer as it topped the list of most prevalent cancers among women in the last three years. Rigorous research has been conducted to improve the prognosis of cancer therapies since the time of inception. Recent advancements in cancer therapy have introduced monoclonal biosimilars as a promising treatment alternative. Monoclonal antibodies (mAbs), produced through cloning, have demonstrated effectiveness in targeting diverse antigens. Biosimilar, considered complex entities compared to small-molecule drugs, pose challenges in replication due to their biological nature. The manufacturing process involves rigorous comparability testing to ensure similarity in quality, safety, and efficacy with the reference product. Trastuzumab biosimilars, such as CT-P6, Ontruzant®, ABP 980, and PF-05280014, have shown efficacy in treating HER2-positive metastatic BCs, presenting a viable alternative to the reference product. The implications of monoclonal biosimilars extend beyond trastuzumab, with bevacizumab emerging as another significant biosimilar for BC treatment. The shift toward biosimilar aims to enhance accessibility to biologics by reducing costs. Health economic analyses indicate potential cost savings, contributing to the overall cost-effectiveness of biosimilar adoption. While concerns about switching between reference products and biosimilars exist, evidence suggests a lower risk of immunogenicity-related side effects with mAbs like trastuzumab. Monoclonal biosimilars present a promising avenue in BC therapy, demonstrating efficacy, safety, and potential cost savings. The integration of biosimilars into cancer treatment strategies offers a means to improve accessibility to effective care while addressing economic considerations in healthcare.

2023-06-01·Geburtshilfe und Frauenheilkunde

Comparison of Biosimilar Trastuzumab ABP 980 with Reference Trastuzumab in Neoadjuvant Therapy for HER2-positive Breast Cancer – an Analysis of a Large University Breast Cancer Centre

Article

作者: Hahn, Markus ; Volmer, Lea-Louise ; Engler, Tobias ; Matovina, Sabine ; Müller, Heike ; Hartkopf, Andreas Daniel ; Brucker, Sara Yvonne ; Grischke, Eva-Maria ; Staebler, Annette

Abstract:

Background ABP 980 is a biosimilar antibody to reference trastuzumab (RTZ). Aim of the following study is to confirm the similarity of ABP 980 and RTZ in terms of clinical efficacy and safety in patients with HER2-positive early breast cancer (EBC) undergoing neoadjuvant trastuzumab-containing chemotherapy in a clinical real-world situation that also includes patients receiving pertuzumab. Methods Patients with HER2-positive EBC, who were treated from 12/2010 to 03/2020 at the Department of Women’s Health at Tuebingen University Hospital, Germany, with at least four cycles of neoadjuvant chemotherapy (+/− pertuzumab) in combination with ABP 980 or RTZ were included in a retrospective analysis. For efficacy analysis patients achieving a pathologic complete remission (pCR = no invasive tumor in breast and lymph nodes) were compared. Safety was evaluated by comparing the number of patients with a decrease in left ventricular function (LVEF) of > 10%. Results 124 patients were included of whom 46 (37.1%) have received ABP 980 and 77 (62.9%) were treated with RTZ. A pCR was found in 77 patients (62.1%). For patients treated with ABP 980 as compared to RTZ, there was no significant difference regarding efficacy (pCR-rates of 60.9% versus 62.8%, p = 0.829) or cardiac safety (LVEF decline in 6.5% versus 2.6%, p = 0.274). Conclusion Similarity of ABP 980 as compared to RTZ was confirmed in a real-world situation, including a large proportion of patients that have also received pertuzumab treatment.

2022-11-02·Immunopharmacology and immunotoxicology

Trastuzumab biosimilars vs trastuzumab originator in the treatment of HER2-positive breast cancer: a systematic review and network meta-analysis

Review

作者: Dong, Mei ; Liu, Tong ; Jin, Yao ; Liu, Duo

AIM:

Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer related death in women. Trastuzumab originator (Herceptin) is a monoclonal antibody used as a standard treatment for breast and metastatic gastric cancer when the cancer cells over-express human epidermal growth factor receptor type 2 (HER2). As the patent of Trastuzumab has now expired, biosimilars are moving into the market. It is still controversial to chose which trastuzumab biosimilar has the best treatment of HER2-positive breast cancer patients. We conducted this network meta-analysis to explore the best trastuzumab biosimilar in the treatment of HER2-positive breast cancer patients.

METHODS:

PubMed, Cochrane library databases, China National Knowledge infrastructure (CNKI) and WanFang database up to November 2021 were systematically searched. The following search terms were used: 'trastuzumab originator', and 'trastuzumab biosimilar'. No language restriction was imposed. The reference lists of all retrieved articles were also reviewed to identify additional articles missed by using these search terms.

RESULTS:

We got 10 studies to conduct network meta-analysis to evaluate efficacy and serious adverse reactions among various trastuzumab biosimilars and trastuzumab originator. The overall response rate (ORR) and pathological complete response (pCR) of SB3 were worse than trastuzumab originator significantly, while the ORR and pCR of other trastuzumab biosimilars had not yet reached statistical differences compared with each other. The cumulative ranking curve (SUCRA) probability indicated that the ORR from best to worst was CT-P6, Herceptin, HLX02, PF-05280014, R-TPR-016, BCD-022, MYL-1401O, SB3, and the pCR from best to worst was PF-05280014, CT-P6, Herceptin, ABP-980, SB3. The serious adverse events (SAEs) of CT-P6 were more than Herceptin and MYL-1401O significantly, while the SAEs of other trastuzumab biosimilars had not statistical differences. The SUCRA probability indicated that the SAEs from best to worst was MYL-1401O, Herceptin, PF-05280014, SB3, HLX02, BCD-22, CT-P6.

CONCLUSION:

There was no statistical difference in both ORR and pCR of various trastuzumab biosimilars and Herceptin except SB3. The ORR and pCR of SB3 were worse than Herceptin. Both CT-P6 and PF-05280014 are better in the overall curative effect, but CT-P6 had the highest serious adverse reactions when compared with others. The PF-05280014 might be a better trastuzumab biosimilar in the treatment of HER2-positive breast cancer patients.

120

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2024-12-28

·ioncology

抽丝剥茧洞幽烛微——傅芳萌教授分享乳腺癌脑转移的临床思考丨SABCS 2024

编者按：脑转移（BM）治疗是乳腺癌医生时常面临的一大难题，标准的局部治疗可存在副损伤风险，而传统系统治疗的颅内控制效果较差。近年来，小分子酪氨酸激酶抑制剂（TKI）和新一代抗体偶联药物（ADC）在乳腺癌脑转移治疗领域取得较多突破，这些“新入局者”是否能够与局部治疗产生新的碰撞，带来新的治疗策略？近年来，小分子酪氨酸激酶抑制剂（TKI）联合放疗治疗HER2+乳腺癌脑转移患者的研究显示具有积极的疗效和安全性，那么ADC联合放疗是否也能够安全地提升疗效？在近日举行的ESMO Asia和SABCS大会上，报道了T-DXd联合放疗的个案和回顾性研究，显示了积极疗效和安全性[1-2]。系统治疗联合局部治疗乳腺癌脑转移仍是充满争议的话题，国内外指南共识并未明确推荐联合方案。《肿瘤瞭望》特邀福建医科大学附属协和医院傅芳萌教授回答读者所关心的问题。 01 《肿瘤瞭望》：新型ADC和小分子TKI在HER2+（或HER2表达）乳腺癌脑转移的治疗中已取得不少突破性进展，取得较为满意的全身和颅内疾病控制，能否介绍一下这方面的最新进展？傅芳萌教授：近年来，小分子TKI和新型ADC在乳腺癌脑转移治疗中取得不少突破性进展。小分子TKI由于有较好的血脑屏障穿透性，经常被用于HER2+脑转移治疗，HER2CLIMB、TBCRC-022、PERMEATE等研究已证实图卡替尼、奈拉替尼、吡咯替尼等小分子TKI有良好的中枢神经系统（CNS）客观缓解率（ORR）。这些研究纳入患者差异较大，包括活动性或稳定性脑转移，经治或未经治患者，CNS ORR大约在30%~60%，无进展生存期（PFS）在3~12个月不等[3]。在ADC方面，T-DXd可治疗HER2+和HER2低表达的乳腺癌脑转移患者，3期DB-03、DB-04研究中纳入了基线脑转移的患者，以及1/2/期TUXEDO-1、DASIY研究，均显示T-DXd有非常不错的的颅外和颅内控制效果。而2024年ESMO大会报道的3/4期DESTINYBreast-12研究[4]是今年最受关注的研究，在包括263例脑转移（包括稳定性157例、活动性106例）患者中，T-DXd治疗的中位PFS达17.3个月，CNS-ORR达71.7%，1年CNS-PFS也达到了58.9%，意味着有将近60%的患者可保持1年颅内疾病无进展，T-DXd展现了强大的全身和颅内疾病控制效果。 △DB-12研究不同人群的ORR和PFS结果 02 《肿瘤瞭望》：临床实践中，活动性脑转移患者特别受关注，这部分患者往往优先进行手术、放疗等局部治疗。DB-12研究中脑转移队列中有近一半为活动期患者，也包含了初治的患者，且单药治疗取得了不错的疗效，这些数据会影响您的临床实践吗？傅芳萌教授：目前，国内外各大指南均推荐乳腺癌脑转移治疗以手术切除、全脑放射治疗（WBRT）和立体定向放射治疗（SRS）等局部治疗法为主，尤其是活动性脑转移患者，为了快速缓解症状和控制疾病，更常以手术、放疗优先，系统治疗通常用于局部治疗之后。近年来，有越来越多的研究探讨了脑转移患者局部治疗和系统治疗的新模式，以期达到更快、更好的颅内和颅外疾病控制。例如，JAMA Oncology发表一项我国的单中心单臂2期研究显示，放疗联合小分子TKI吡咯替尼和化疗治疗HER2+脑转移患者，1年CNS PFS率达74.9%，中位CNS-PFS达18.0个月，且安全性良好[5]。 DB-12研究则是使用T-DXd单药治疗，而且包含了稳定性和活动性脑转移患者、初治和经治患者，也就是说部分患者是先于局部治疗使用T-DXd。研究结果显示T-DXd具有和TKI联合局部治疗相似的颅内控制效果，CNS ORR为62.3%，其中初治的活动性脑转移患者CNS ORR高达82.6%[4]。从DB-12研究的疗效结果来看，T-DXd取代局部治疗似乎是可行的。当然，该研究入组的活动性脑转移患者为不需要立即接受局部治疗的患者，也就是说没有存在剧烈的CNS症状、脑出血或脑占位症状。对于这类“相对稳定”的活动性脑转移，临床上先使用T-DXd这类高效的新型药物是可行的。 03 《肿瘤瞭望》：您刚才提到了放疗联合小分子TKI的研究，我们看到近期ESMO Asia、SABCS大会报道了T-DXd联合放疗治疗HER2+脑转移患者的病例和研究。您认为T-DXd联合放疗是否具有可行性吗？傅芳萌教授：回答这个问题时，首先我们要考虑的是联合治疗可以增效吗？ADC联合放疗具有一定理论基础的，例如电离辐射引起的组织形态和功能改变，可诱导癌细胞表面新抗原的表达，从而增加ADC对肿瘤的免疫原性和识别能力；此外，ADC的载药毒素使肿瘤细胞周期停滞（尤其是G2/M期对放疗最敏感），从而发挥放疗增敏的效果[6]。目前，仍缺乏ADC联合放疗的前瞻性临床试验。既往Khatri VM等人报道的一项多中心回顾性研究，分析了34例接受T-DXd和SRS治疗的HR+/HER2-L脑转移患者，显示了积极的疾病控制效果，1年颅内控制率达97%[7]。这次ESMO Asia报道的个案，也采用了T-DXd联合SRS使患者取得了长达25个月的PFS[1]。然而，脑转移患者的治疗需要有“全局观”，即如何达到“两全其美”的全身和局部控制效果。对于稳定性脑转移或活动性脑转移无需立即局部治疗的患者，当前研究显示T-DXd等药物全身治疗能够达到不错的全身控制效果，在联合治疗缺乏明确的循证医学证据之前，单独使用药物治疗是可行的。对于活动性、症状性脑转移患者，在局部治疗基础上联合ADC系统治疗，可能有助于提高疗效，但需考虑联合放疗是否会增加放射性脑坏死（SRN）的风险。那么，T-DXd联合治疗安全吗？既往研究显示T-DM1联合放疗可增加放射性脑坏死的风险，例如荟萃分析中，T-DM1联合放疗的≥3级放射性坏死发生率高达17%[8]。因此，欧洲癌症研究和治疗组织（EORTC）对全脑放疗或脑立体定向放疗的患者不建议同步联合T-DM1治疗[9]。但新型ADC的表现有所差异。2023年Lebow ES等人报道一项使用ADC联合SRT治疗脑转移患者当时最大规模的回顾性研究，包含了T-DXd和SG等新型ADC的研究，结果显示该队列的2年SRN累积发生率为8.5%，多因素分析显示联合ADC是SRN的独立危险因素（HR4.31，P < 0.001）；但总体上接受放疗疗程少的患者SRN风险是适度的，而较大病变、既往有过放疗脑坏死病史的患者风险更高[10]。实际上，SRN受到的影响很多，包括放疗剂量（包括分割大小）、疗程、肿瘤部位等，而不同ADC药物也存在较大差异，例如T-DM1的半衰期大约为4天，而T-DXd的半衰期为6天，戈沙妥珠单抗（SG）仅为16小时，这些药代动力学特征的差异可能导致的SRN风险并不相同，因此不能由一个或一类药物外推至另一个药物。例如在Khatri VM等人报道的35例患者中，T-DXd联合SRS患者每个病灶的2年SRN累积发生率仅为2.1%，表现出可以接受的SRN风险[7]。在近日举行的SABCS大会上，还报道了一项欧洲的多中心回顾性研究，分析了33例T-DXd联合放疗（包括姑息放疗和立体定向消融放疗），结果显示中位随访18个月，与非放疗患者相比，＞2级不良事件发生率无显著差异（P=0.79），联合组仅观察到1例3级疲劳和4例2级ILD，没有报告放射性脑坏死事件[2]。这些回顾性数据表明T-DXd联合放疗具有较好的疗效和安全性，未来值得进行扩大样本的前瞻性研究加以验证。 04 《肿瘤瞭望》：从既往研究（HER2CLIMB2研究、吡咯替尼相关研究、DB12研究等）来看，对于稳定性或者症状尚可接受的活动性脑转移患者，先接受系统治疗是可以接受的。那么，局部治疗的介入时期是什么时候？而系统治疗时又应该如何考虑TKI和ADC的使用顺序？傅芳萌教授：回答这个问题要考虑局部联合系统治疗的患者最佳的联合治疗模式，如应该采用序贯治疗还是同步治疗？序贯治疗时系统治疗和局部治疗的间隔时间应该是多长？临床实践和研究中，放疗的洗脱期通常在1个月甚至更久，相较于ADC或TKI的半衰期更长。上述JAMA Oncology发表的我国研究，采用的是放疗同步药物治疗，从放疗的第1天到放疗结束后的第7天开始使用吡咯替尼+卡培他滨；HER2CLIMB研究则允许患者暂停放疗6周以内，而且可以在SRS术后至少7天或全脑放射治疗后21天重新接受药物治疗[11]；Lebow ES等人报道的ADC同步SRS，定义为≤7天内或≤21天（大约3个半衰期）进行SRS[10]。在DB-12研究中，也有60%患者先前用过放疗，总体人群是在经过中位164天后使用T-DXd全身治疗的。尽管当前临床研究的方案和基线情况存在较大差异，但说明了系统治疗与局部治疗序贯和联合都是可行的，也给未来临床研究设计提供了宝贵的经验。未来需要更多研究确定系统治疗和局部治疗的治疗模式和最佳介入时机。对于TKI和ADC的使用顺序应该如何考虑？目前尚缺乏二者头对头比较的前瞻性研究证据。我们可以从以下几方面来考虑。首先，从现有研究报道的PFS获益来看，整体上T-DXd治疗脑转移的PFS在数值上更长，可以达到1年半左右；而TKI类药物的PFS大多在1年以内。 △已报道HER2+或HER2表达乳腺癌脑转移治疗的TKI和ADC研究（非头对头比较，请谨慎解读）再者，从药物机制来看，TKI的主要优势在于由于分子量小、BBB穿透性好，但需注意肿瘤异质性问题，一旦肿瘤发生分子改变，可能导致靶向药物的作用降低。与TKI或化疗有所不同毒素，T-DXd治疗脑转移的机制是多方面的。新型ADC的药物改进，使得BBB对其影响似乎很小，尤其是双靶点的新型ADC大大提高了BBB穿透性，已有研究将新型ADC作为阿尔茨海默病、帕金森病这类神经系统疾病的候选药物[12]。对于HER2+乳腺癌脑转移，T-DXd通过识别HER2靶点，内吞进入肿瘤细胞，不会增加脑部转移灶的负担[13]。本次SABCS公布的DB-12研究PRO数据显示，T-DXd对脑部神经功能有稳定作用[14]。这可能由于高药物抗体比（DAR）、抗肿瘤“旁观者效应”等作用下，即使少量T-DXd进入颅内也可发挥强大的疗效。此外，BBB具有开合功能，ADC可以别内皮细胞的受体，在血脑屏障闭合的情况下也能进入，用微量的载荷发挥杀伤作用。因此，基于当前的循证医学证据和治疗机制，T-DXd这类新型ADC具有出色的颅内和全身疾病控制效果，且安全性良好，可作为脑转移系统治疗的优选方案，用于无需立即接受局部治疗的稳定性或活动性脑转移患者。此外，在T-DXd基础上联合或序贯使用局部治疗，以及局部治疗的最佳介入时机，仍有待更多的研究探讨，期待为了能够从大样本的真实世界研究或前瞻性研究中找到答案。傅芳萌教授福建医科大学附属协和医院乳腺外科，副主任主任医师，副教授，医学博士，硕士生导师中国临床肿瘤学会（CSCO）青委会（常委）中华医学会肿瘤学分会乳腺学组青年委员福建省医学会外科学分会乳腺外科学组秘书福建省医学会外科学分会转化医学组副组长主持国自然、福建省重点项目自然科学基金等多个项目研究成果发表在”JAMA NETW OPEN ””AJSP”“NPJ breast cancer”“breast”“INT NURS STUD”等参考文献上下滑动查看更多内容 [1]Meng Teng, et al.Trastuzumab deruxtecan and Stereotactic radiosurgery (SRS) in HER2-positive (HER2+) breast cancer with brain metastases (BM).ESMO Asia 2024.YO1 [2]Luca Visani,et al.Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in patients with metastatic breast cancer: a multicentre international retrospective cohort study.SABCS 2024;P2-10-06 [3]HER2阳性乳腺癌脑转移诊疗新进展.闫敏.2021年COMB大会 [4]Lin N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINYBreast-12 primary results. 2024 ESMO LBA18 [5]Yang Z, Meng J, Mei X, et al. Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases: A Nonrandomized Phase 2 Trial. JAMA Oncol. Published online January 04, 2024. doi:10.1001/jamaoncol.2023.5791 [6]J Hematol Oncol. 2024 Jan 4;17(1):1. doi: 10.1186/s13045-023-01509-2.The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors [7]Khatri VM, Mestres-Villanueva MA, Yarlagadda S, et al. Multi-institutional report of trastuzumab deruxtecan and stereotactic radiosurgery for HER2 positive and HER2-low breast cancer brain metastases. NPJ Breast Cancer. 2024;10(1):100. Published 2024 Nov 21. doi:10.1038/s41523-024-00711-w [8]Salvestrini V, Kim K, Caini S, et al. Safety profile of trastuzumab-emtansine (T-DM1) with concurrent radiation therapy: A systematic review and meta-analysis. Radiother Oncol. 2023;186:109805. doi:10.1016/j.radonc.2023.109805 [9]Meattini I, Becherini C, Caini S,et al.Consensus Panellist Group. International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. Lancet Oncol. 2024 Feb;25(2):e73-e83. doi: 10.1016/S1470-2045(23)00534-X. PMID: 38301705.23, 41: 1830-1840. [10]Lebow ES, Pike LRG, Seidman AD, Moss N, Beal K, Yu Y. Symptomatic Necrosis With Antibody-Drug Conjugates and Concurrent Stereotactic Radiotherapy for Brain Metastases. JAMA Oncol. 2023;9(12):1729-1733. doi:10.1001/jamaoncol.2023.4492 [11]Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer [published correction appears in N Engl J Med. 2020 Feb 6;382(6):586. doi: 10.1056/NEJMx190039]. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609 [12]https://www.acimmune.com/our-science/technology-platforms/ [13]Dharmini Manogna, et al.Genomic and tumor microenvironment dynamics of brain metastases in breast cancer.ASCO 2024,abstract 1018 [14]Nadia Harbeck,et al.Effects of trastuzumab deruxtecan (T-DXd) on health-related quality of life (HRQOL) & neurological function in patients (pts) w/ HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12(DB-12) results.PS14-10 会议预告 2024年，T-DXd领衔的ADC药物领域迎来了激动人心的飞跃。“凡是过往，皆为序章”，ADC领域会创新不止，逐光勇进，成为历史上最耀眼的明珠 2025年1月11日，“第二届肿瘤-抗体偶联药物2025年度论坛”将为ADC发展再启新篇，在乳腺癌，肺癌，胃癌等多癌种领域开花结果。本条媒体报道为中国医药教育协会主办，由第一三共（中国）投资有限公司提供支持。（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

抗体药物偶联物临床结果临床3期

2024-12-27

·ioncology

SABCS 2024丨要生存，也要生活——许锐教授解读T-DXd治疗乳腺癌脑转移的研究进展

编者按：乳腺癌脑转移治疗棘手，预后较差，制定治疗方案既要考虑快速控制颅内病灶、缓解中枢神经系统（CNS）症状，也要顾及全身的疾病控制。以往指南通常将手术、放疗等局部治疗作为脑转移的“头等”推荐，但近年来层出不穷的小分子酪氨酸激酶抑制剂（TKI）和新型抗体偶联药物（ADC）也显示疗效非常“上头”。本文中，《肿瘤瞭望》特邀广东省中医院许锐教授结合既往报道以及2024年SABCS大会的最新研究，介绍T-DXd在HER2表达乳腺癌脑转移治疗中的应用价值和探索方向。乳腺癌“命运交响曲”DESTINY-Breast（DB）系列研究已创造许多突破，尤其是DB-03研究奠定了T-DXd作为晚期HER2+乳腺癌二线治疗的新标准，DB-04研究则首次将抗HER2治疗药物拓展至HER2低表达（IHC 1+，IHC 2+/ISH-）人群。这两项研究均入组了基线脑转移的患者，加之既往报道的2期TUXEDO-1、DEBBRAH、DAISY研究，今年ESMO大会上非常吸睛的DB-12研究，均显示T-DXd有不俗的颅外和颅内控制疗效[1-5]。目前，国内外指南仍推荐手术、放疗等局部治疗作为乳腺癌脑转移的主要治疗手段，尤其是症状明显、需要快速控制颅内病变的患者。但局部治疗存在不同的副损伤风险，如手术感染、出血、放射性脑坏死等，可影响患者的生活质量和神经功能。那么，系统治疗对脑转移患者的生活质量和神经功能有怎样的影响？目前尚无此类研究报道，本次SABCS大会报道了DB-12研究的患者报告结局（PRO）和神经功能评估结果。脑转移治疗“集大成者” DB-12生活质量和神经功能报告 DB-12研究可谓目前乳腺癌脑转移治疗研究的“集大成者”，这项3b/4期研究样本量大（N=504），包含了基线脑转移（包括活动性、稳定性脑转移患者）和基线非脑转移，验证了T-DXd对活动性和稳定性脑转移的疗效和安全性。今年ESMO大会首次报道的研究结果显示：在包括基线脑转移（稳定性157例、活动性106例）患者中，T-DXd治疗的中位无进展生存期（PFS）达到17.3个月，中枢神经系统客观缓解率（CNS-ORR）达71.7%，而且稳定性（71.7%）、活动性（79.2%）脑转移患者均显示一致的颅内控制，尤其初治患者的CNS-ORR达到了82.6%；非基线脑转移患者的全身疗效则与既往报道一致，ORR为62.7%[6]。 2024年SABCS大会报道了T-DXd治疗对患者健康相关生活质量（HRQOL）和神经功能的影响[7]。在脑转移队列（N=263）中，根据EORTC QLQ-C30（欧洲癌症研究与治疗组织生活质量核心问卷）评估生活质量的变化，中位治疗持续时间达11.5个月，至数据截止时，仍有118例患者在继续接受T-DXd治疗。大部分脑转移患者的认知功能、情感功能、身体机能、社会功能方面在T-DXd的治疗下能够得到长期维持（预估12个月无恶化率＞50%）。 △脑转移队列的EORTC QLQ-C30评分使用NANO量表评估神经功能（见下图），共有220/254（86.6%）例患者在首次评分时神经功能状态稳定，其中140例（55.1%）患者在T-DXd治疗期间仍维持神经功能稳定。并且有相当比例（18/25，72%）的基线神经系统功能障碍的患者经T-DXd治疗神经功能可恢复稳定。此外，患者的脑肿瘤特异性MDASI症状日记（包括难以集中注意力、说话和理解、易怒、癫痫发作、视力）均未观察到具有临床意义的变化。 △脑转移队列的NANO评分在非脑转移队列（N=241）中，中位T-DXd治疗时间为12.0个月，至数据截止时，有95例患者仍在继续接受治疗。有4例患者出现新发症状性CNS转移，发病率为1.7%。通过EORTC QLQ-C30评估患者的认知、情绪、躯体功能、社会功能和疼痛等，预估12个月无恶化率＞50%。 △非脑转移队列的EORTC QLQ-C30评分 NANO评估显示，共有217/236（91.9%）例患者基线时神经功能稳定：其中，172例（72.9%）患者在T-DXd治疗期间神经功能稳定，45例（19.1%）发生神经功能恶化。有相当比例（6/16，37.5%）基线评估为神经功能障碍的患者，在T-DXd治疗期间神经功能可恢复稳定。 △非脑转移队列的NANO评分 DB-12研究结果显示，T-DXd有非常不错的颅内和颅外的疾病控制作用及生存获益，对维持或保护神经功能症状有重要意义。这在DB-12研究的PRO数据中得到证实，大多数患者的健康相关生活质量（HRQOL）和神经功能得以维持。小分子TKI也是HER2+乳腺癌脑转移患者的重要治疗选择。前已报道图卡替尼HER2CLIMB、吡咯替尼PERMEATE、奈拉替尼TBCRC022等多项研究，但这些研究入组患者差异较大，所获CNS-ORR在33%～75%之间，中位PFS则为3.1～13.6个月不等[8-12]。目前这些研究对活动性脑转移患者的入组，以及对神经功能影响的数据报道十分有限。DB-12研究以其非常全面的数据，包括入组人群之多样性、样本量之大、出色的全身和颅内疾病控制、PFS获益，以及对生活质量、神经功能的维持和改善作用，为HER2表达脑转移乳腺癌患者的T-DXd治疗提供了高质量的循证医学证据。难度系数“Buff叠满” T-DXd治疗软脑膜转移潜力巨大软脑膜转移可谓治疗难度系数“Buff叠满”的转移情况，既往被称为四大内脏危象之一，具有高度致命性，不加干预的患者中位OS仅为1～2个月，且颅高压、脑膜刺激征等症状显著，严重影响患者生活质量。2023年SABCS大会曾报道DEBBRAH研究的队列5数据，7例HER2表达（3例HER2+，4例HER2低表达）的软脑膜转移接受T-DXd治疗，中位OS为13.3个月，中位PFS为8.9个月，且7例患者均没有发生颅内进展[13]。T-DXd在治疗这类极其致命性的软脑膜转移患者中展现了令人惊艳的生存获益。 2024年SABCS大会则报道了一项更大样本的回顾性研究[14]，纳入了18例软脑膜转移的实体瘤患者，包括6例HER2+乳腺癌、8例HER2低表达或阴性乳腺癌、2例HER2+胃食管癌、2例HER2突变型非小细胞肺癌（NSCLC）。研究结果显示，分别有4/6例（67%）例HER2+乳腺癌、2/8例（25%）HER2低表达/阴性乳腺癌达到部分缓解（PR）。开始使用T-DXd后（即未计算既往治疗的OS）的中位OS为5.8个月。与HER2低表达/阴性乳腺癌和HER2变异型非乳腺癌患者相比，HER2+乳腺癌患者的OS更长（13.9 vs 5.2 vs 4.6个月）。Landmark分析显示，在2.5个月内对T-DXd治疗出现影像学软脑膜应答的患者OS更长（14.2 vs 2.6个月，HR 0.18，95%CI：0.05-0.63，P<0.05），且在开始使用T-DXd后3.5个月和4.5个月的Landmark分析中也显示出类似的趋势。 △该研究T-DXd治疗软脑膜转移患者的游泳图 △该研究T-DXd治疗软脑膜转移患者的OS 从上述研究可见，T-DXd无论是在稳定性、活动性脑转移，抑或致命性极高的软脑膜转移HER2表达乳腺癌患者中，均展现出极高的颅内疾病控制疗效。这些数据将进一步改变当前的临床实践，例如即将更新的2025版CBCS指南推荐：对于HER2+晚期乳腺癌二线治疗，无论是否有脑转移均应优选T-DXd；而在线更新的ESMO-MBC指南则推荐：对于二线治疗或新辅助/辅助治疗进展的患者，无/未知/稳定性脑转移的情况下均可优选T-DXd[16]。 △ESMO-MBC指南HER2+MBC二线治疗推荐 T-DXd脑转移治疗也带来更多可以探索的未知，例如局部治疗的介入时机，联合治疗是否可行？既往出于对放射性脑坏死的顾虑而不推荐TKI或ADC联合SRS，但已有小样本（N=34）研究提示，接受T-DXd和SRS治疗的HER2+或HER2低表达脑转移患者，显示了积极的疾病控制疗效，1年颅内控制率达97%，而且没有显著增加放射性脑坏死的发生率[15]。除了联合放疗以外，ADC联合TKI、全身给药联合鞘内给药，以及序贯或同步治疗等问题仍需进一步探索，以期为乳腺癌脑转移患者提供更加高效、安全的个体化治疗方案，获得生存和生活质量的“双赢”。许锐教授副主任医师，医学博士硕士研究生导师广东省中医院乳腺病专科医院副院长岭南名医，第四届羊城好医生中华中医药学会乳腺病分会委员/副秘书长中国抗癌协会肿瘤微创治疗专业委员会乳腺学组常委委员中国抗癌协会肿瘤标志专委会肿瘤多学科诊断协作组委员广东省中医药学会乳腺病专业委员会副主任委员广东省医院协会乳腺科管理专业委员会副主任委员广东省医疗行业协会乳腺肿瘤内科管理分会副主任委员《中国普通外科杂志》青年编委 2017及2023 中华中医药学会科学技术二等奖 2018 CBCS乳腺肿瘤菁英赛（MDT竞赛）全国总冠军 2019 高等学校科学研究优秀成果二等奖 2023 广东省科技进步二等奖参考文献上下滑动查看更多内容 [1]A Pooled Analysis of Trastuzumab Deruxtecan (T-DXd) in Patients (pts) With HER2-Positive (HER2+) Metastatic Breast Cancer (mBC) With Brain Metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03 [2]Tsurutani J,Jacot W,Yamashita T,et al.Subgroup analysis of patients(pts）with HER2-low metastatic breast cancer(mBC）with brain metastases(BMs）at baseline from DESTINY-Breast04,a randomized phase III study of trastuzumab deruxtecan(T-DXd）vs treatment of physician's choice(TPC）.2023 ESMO 388P. [3]Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med. 2022;28(9):1840-1847. doi:10.1038/s41591-022-01935-8 [4]Pérez-García JM, Vaz Batista M, Cortez P, et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro Oncol. 2023;25(1):157-166. doi:10.1093/neuonc/noac144 [5]Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023;29(8):2110-2120. doi:10.1038/s41591-023-02478-2 [6]Nancy U Lin, et al.Trastuzumab deruxtecan in patients with HER2+ advanced/metastatic breast cancer with or without brain metastases: DESTINY-Breast12 primary results.ESMO 2024;LBA18 [7]Nadia Harbeck,et al.Effects of trastuzumab deruxtecan (T-DXd) on health-related quality of life (HRQOL) & neurological function in patients (pts) w/ HER2+ advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12(DB-12) results.PS14-10 [8]Bachelot T, Romieu G, Campone M, et al. Lapatinib plus Capecitabine in Patients with Previously Untreated Brain Metastases from HER2-Positive Metastatic Breast Cancer (LANDSCAPE): A Single-Group Phase 2 Study.[J]. Lancet Oncology, 2013, 14(1). [9].Freedman R A, Gelman R S, Anders C K, et al. TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases[J]. Journal of Clinical Oncology, 2019. [10].Saura C, Oliveira M, Feng Y H, et al. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial[J]. Journal of Clinical Oncology, 2020, 38(27): JCO.20.00147. [11].Murthy R K, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer[J]. New England Journal of Medicine, 2019, 382(7). [12]Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for pa- tients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single- arm, two-cohort, phase 2 trial. Lancet Oncol. 2022;23(3):353–361. [13]Batista MZ., et al.Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study.SABCS 2023;PS11-05 [14]Ma Q., et al.Trastuzumab deruxtecan (T-DXd) in leptomeningeal metastases from HER2-altered cancers.SABCS 2024;P5-03-25 [15]Khatri VM, Mestres-Villanueva MA, Yarlagadda S, et al. Multi-institutional report of trastuzumab deruxtecan and stereotactic radiosurgery for HER2 positive and HER2-low breast cancer brain metastases. NPJ Breast Cancer. 2024;10(1):100. Published 2024 Nov 21. doi:10.1038/s41523-024-00711-w [16]https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline 会议预告 2024年，T-DXd领衔的ADC药物领域迎来了激动人心的飞跃。“凡是过往，皆为序章”，ADC领域会创新不止，逐光勇进，成为历史上最耀眼的明珠 2025年1月11日，“第二届肿瘤-抗体偶联药物2025年度论坛”将为ADC发展再启新篇，在乳腺癌，肺癌，胃癌等多癌种领域开花结果。本条媒体报道为中国医药教育协会主办，由第一三共（中国）投资有限公司提供支持。（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床结果抗体药物偶联物临床2期临床研究

2024-12-27

·Pharmaceutical Technology

Eisbach Bio positions HRD-targeting therapy to supplant PARP inhibitors

Eisbach Bio is developing EIS-12656, which works by inhibiting ALC1 (chromodomain-helicase-DNA-binding protein 1-like), a chromatin remodeller and DNA helicase also involved in DNA repair. Image credit: Shutterstock/PeopleImages.com – Yuri A Eisbach Bio plans to use a $4.75m grant to advance EIS-12656, a small molecule ALC1 inhibitor to disrupt the genome structure in hard-to-treat cancer cells, says CEO Dr. Adrian Schomburg. Last month, the Martinsried, Germany-based biotech secured the funding from the Cancer Prevention and Research Institute of Texas (CRPIT) as part of the Texas Therapeutics Company Award. The company intends to direct the grant towards the ongoing Phase I/II MATCH trial (NCT06525298) of EIS-12656 in advanced, refractory solid tumours, as per the announcement. Schomburg said Eisbach views EIS-12656 as an alternative to poly-ADP-ribose polymerase inhibitors (PARP) inhibitors in therapy for many hard-to-treat cancers. PARP proteins are involved in DNA repair, and their targeted inhibition can hinder the proliferation of tumour cells. However, Schomburg notes, “there’s FDA scrutiny about the label of these inhibitors because of toxicity”. In September 2022, GSK voluntarily withdrew Zejula (niraparib) indication for treating advanced gynecological cancers in patients who had previously treated with three or more chemotherapy regimens and who had tumours that tested positive for homologous recombination deficiency (HRD). The withdrawal was due to updated information on the negative impact on overall survival seen in two studies with PARP inhibitors in that same setting. The mechanism of action for EIS-12656 is similar to PARP inhibitors, but it is one step further downstream, said Schomburg. The small molecule works by inhibiting ALC1 (chromodomain-helicase-DNA-binding protein 1-like), a chromatin remodeller and DNA helicase also involved in DNA repair. In what Schomburg terms a “’winner takes all’ market”, Eisbach believe their candidate can supplant PARP inhibitors as a less toxic option. Following IND approval in May 2024, EIS-12656 is currently being assessed as a monotherapy against HRD-positive tumours in the Phase I/II MATCH trial, and compared against a combination regimen of the drug with the PARP inhibitor olaparib, marketed as Lynparza by AstraZeneca, or trastuzumab deruxtecan, marketed by AstraZeneca and Daiichi Sankyo as Enhertu. Eisbach aims to initiate the Phase II portion of this study within Q2 2025. The company plans to focus on hard-to-treat indications, including ovarian, pancreatic, and prostate cancers, where long-term regimens mean high toxicity can be an especially limiting factor. Beyond these areas, Schomburg said Eisbach is interested in expanding EIS-12656 into lung cancers, colorectal cancers, and glioblastoma, utilising the drug’s blood-brain barrier penetrative qualities. These indications are also of particular interest for other helicase-targeting therapies, such as Accent Therapeutic’s DHX9 inhibitor ATX-559 , which is being studied in a Phase II trial (NCT06625515). Eisbach is developing other helicase-targeting therapies in preclinical studies, for which Schomburg stated IND-enabling trials are planned for 2025. He added that combination therapies, such as with antibody-drug conjugates where no combinatorial toxicity has been reported in preclinical models so far, are being considered.

临床2期上市批准

100 项与曲妥珠单抗生物类似药(Synthon BV) 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	-	L01XC03	DB00072

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
胃食管交界处腺癌	美国	Amgen, Inc.	2019-06-13
HER2阳性乳腺癌	澳大利亚	Amgen Australia Pty Ltd.	2019-05-16
HER2阳性胃食管交界处癌	澳大利亚	Amgen Australia Pty Ltd.	2019-05-16
HER2阳性胃腺癌	澳大利亚	Amgen Australia Pty Ltd.	2019-05-16
HER2阳性胃癌	日本	Daiichi Sankyo Co., Ltd.	2018-09-21
乳腺癌	欧盟	Amgen Europe BV	2018-05-16
乳腺癌	冰岛	Amgen Europe BV	2018-05-16
乳腺癌	列支敦士登	Amgen Europe BV	2018-05-16
乳腺癌	挪威	Amgen Europe BV	2018-05-16
转移性乳腺癌	欧盟	Amgen Europe BV	2018-05-16
转移性乳腺癌	冰岛	Amgen Europe BV	2018-05-16
转移性乳腺癌	列支敦士登	Amgen Europe BV	2018-05-16
转移性乳腺癌	挪威	Amgen Europe BV	2018-05-16
胃癌	欧盟	Amgen Europe BV	2018-05-16
胃癌	冰岛	Amgen Europe BV	2018-05-16
胃癌	列支敦士登	Amgen Europe BV	2018-05-16
胃癌	挪威	Amgen Europe BV	2018-05-16

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适应症	最高研发状态	国家/地区	公司	日期
胃食管交界处癌	临床3期	-	Daiichi Sankyo Co., Ltd.	2025-03-01
转移性 HER2 阳性胃食管结合部癌	临床3期	-	Daiichi Sankyo Co., Ltd.	2025-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03329378 (CTgov)	临床2期	局部晚期乳腺癌 \| 早期乳腺癌	7	Pertuzumab+Cyclophosphamide+Trastuzumab+doxorubicin+Paclitaxel (ddACTHP)	糧齋糧築廠獵鑰艱襯夢(範繭積獵衊壓壓糧願憲) = 簾網顧襯廠顧壓艱醖觸製獵鑰選構遞鬱製鏇簾 (網願積築糧獵簾築齋餘, 壓鑰鏇築廠齋觸構積獵 ~ 醖觸鏇糧餘構遞願衊憲) 更多	-	2023-08-22
				Pertuzumab+Trastuzumab+Carboplatin+Paclitaxel+docetaxel (TCHP)	糧齋糧築廠獵鑰艱襯夢(範繭積獵衊壓壓糧願憲) = 遞醖夢廠膚鬱顧觸選獵製獵鑰選構遞鬱製鏇簾 (網願積築糧獵簾築齋餘, 網顧鑰鬱繭鑰顧淵鏇築 ~ 鏇積膚膚顧襯齋積願淵) 更多
NCT01901146 (LILAC, CTgov)	临床3期	HER2阳性乳腺癌	725	Sentinel Node or Axillary Node Dissection+ABP 980+Paclitaxel (ABP 980)	襯觸範鬱壓廠製構築網(膚繭衊製襯膚淵選鹽願) = 築構鏇餘夢艱餘鹽夢構遞窪窪壓餘鑰觸繭構網 (構網顧簾蓋顧醖餘鏇願, 衊鏇憲繭窪製窪顧衊範 ~ 築窪構鏇餘顧製範鑰顧) 更多	-	2019-08-07
				Sentinel Node or Axillary Node Dissection+Trastuzumab+Paclitaxel (Trastuzumab)	襯觸範鬱壓廠製構築網(膚繭衊製襯膚淵選鹽願) = 憲夢構窪壓窪鏇醖齋鹹遞窪窪壓餘鑰觸繭構網 (構網顧簾蓋顧醖餘鏇願, 膚構鏇願積夢鬱襯網構 ~ 鹽憲廠襯廠繭鹹顧夢築) 更多
NCT01901146 (LILAC, ASCO2019)	临床3期	HER2阳性乳腺癌新辅助 \| 辅助	725	ABP 980	顧簾鹹鏇蓋築窪襯餘壓(獵願積獵鹽鏇積觸鏇鹹) = The incidence of cardiac AEs was low and comparable in treatment groups 襯淵窪夢範夢糧艱鹽餘 (網範醖鑰壓繭憲選壓齋 ) 更多	积极	2019-05-26
				Trastuzumab reference product
NCT01901146 (LILAC, Pubmed) 人工标引	临床3期	HER2阳性乳腺癌辅助 \| 新辅助 HER2-positive	825	ABP 980	夢艱夢觸窪選蓋製範淵(網艱淵廠廠廠鏇選遞繭) = 夢膚膚獵襯簾願壓獵遞膚餘鬱積積糧願憲鑰鏇 (觸鑰築簾鑰鑰鹽餘製衊 ) 更多	非劣	2018-07-01
				trastuzumab	夢艱夢觸窪選蓋製範淵(網艱淵廠廠廠鏇選遞繭) = 簾遞夢鹹繭蓋淵齋鬱衊膚餘鬱積積糧願憲鑰鏇 (觸鑰築簾鑰鑰鹽餘製衊 ) 更多
NCT01901146 (LILAC, ASCO2018)	临床3期	HER2阳性乳腺癌	725	ABP 980	構願鏇襯廠願鑰壓製襯(壓餘膚願壓齋淵膚憲簾) = 構繭襯蓋鑰餘鏇齋選顧艱窪壓齋鏇膚繭蓋構範 (遞願遞蓋願糧鹹築壓獵 )	积极	2018-06-01
				Trastuzumab	構願鏇襯廠願鑰壓製襯(壓餘膚願壓齋淵膚憲簾) = 襯膚鏇鏇願餘廠範淵憲艱窪壓齋鏇膚繭蓋構範 (遞願遞蓋願糧鹹築壓獵 )