AbstractThis single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS).

摘要这项单臂II期非随机试验（ACTRN12619001265167）评估了曲妥珠单抗emtansine在实体癌中的作用，通过全面的基因组分析检测到HER2扩增或突变。主要目标是客观反应（OR），而次要目标包括研究进展时间（TTP）到TTP之前的治疗比例，无进展生存期（PFS）和总生存期（OS）。

The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR.

该队列包括16个具有HER2突变的肿瘤（第1组）和16个具有HER2扩增的肿瘤（第2组）。中位随访17个月后，第1组（1例唾液腺癌（SGC），2例肺癌）和第2组（3例SGC，1例子宫癌）的ORs发生率分别为19%和25%。29名可评估TTP的患者中有14名达到TTP比率≥1.3，其中10名没有OR。

Median PFS and OS were 4.5 (95% CI 2.1–7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers..

中位PFS和OS分别为4.5（95%CI 2.1-7.0）和18.2个月（95%CI 8.1-未达到）。。。

IntroductionTrastuzumab emtansine (T-DM1) is an antibody drug conjugate that links a cytotoxic microtubule-inhibitory agent emtansine, to trastuzumab1. The antibody binds to cells expressing HER2, permitting targeted, potent, intratumoural release of emtansine2. T-DM1 has transformed the management of advanced HER2 positive breast cancer and is considered the standard of care in several related settings3.

简介曲妥珠单抗emtansine（T-DM1）是一种抗体-药物偶联物，将细胞毒性微管抑制剂emtansine与曲妥珠单抗1连接起来。该抗体与表达HER2的细胞结合，允许靶向，有效的肿瘤内释放emtansine2。T-DM1改变了晚期HER2阳性乳腺癌的管理，并被认为是几种相关环境中的护理标准3。

In the phase 3 EMILIA and TH3RESA trials, T-DM1 demonstrated an improved progression-free survival (PFS), overall survival (OS) and toxicity profile compared with lapatinib plus capecitabine and physician’s choice treatment respectively1,4,5. These trials included patients previously exposed to trastuzumab and a taxane, and an even more refractory setting following both trastuzumab and lapatinib.In other advanced cancers, T-DM1 has shown mixed results.

在3期EMILIA和TH3RESA试验中，与拉帕替尼加卡培他滨和医生选择的治疗相比，T-DM1分别显示出改善的无进展生存期（PFS），总生存期（OS）和毒性特征1,4,5。这些试验包括先前接触曲妥珠单抗和紫杉烷的患者，以及曲妥珠单抗和拉帕替尼后更难治的患者。在其他晚期癌症中，T-DM1显示出不同的结果。

In the phase 2/3 GATSBY trial, T-DM1 did not improve outcomes compared with a taxane in the second-line advanced gastric cancer setting with HER2 overexpression6. Within the NCI-MATCH precision medicine study, T-DM1 was evaluated as subprotocol EAY131-Q, comprised of HER2 amplified (copy number >7 on NGS) advanced cancers.

在2/3期GATSBY试验中，与HER2过表达的二线晚期胃癌患者中的紫杉烷相比，T-DM1并没有改善预后6。在NCI-MATCH精准医学研究中，T-DM1被评估为亚组EAY131-Q，由HER2扩增（NGS上的拷贝数>7）晚期癌症组成。

This study yielded an overall objective response rate (ORR) of 6% (2 patients with parotid gland cancers). None of the remaining 33 patients (11 colorectal, 14 gynaecological, 4 lung, 3 biliary tract cancers and a case of extramammary Paget’s of the scrotum) achieved an objective response7. Within another multi-histology basket trial of T-DM1 (NCT02675829) the salivary gland cohort (n = 10) with HER2 amplified tumours demonstrated an ORR of 90%, including five complete responses following prior HER-2 directed therapy8.

这项研究产生的总体客观缓解率（ORR）为6%（2例腮腺癌患者）。其余33例患者（11例结直肠癌，14例妇科，4例肺癌，3例胆道癌和1例阴囊乳腺外佩吉特）均未达到客观反应7。在另一项T-DM1（NCT02675829）的多组织学篮试验中，具有HER2扩增肿瘤的唾液腺队列（n=10）显示ORR为90%，包括先前HER-2指导治疗后的五个完全反应8。

The advanced HER2 mutant NSCLC cohort within this trial also yielded a positive resu.

该试验中的晚期HER2突变NSCLC队列也产生了阳性结果。

Data availability

数据可用性

The molecular data on which MTB recommendations are made is available upon reasonable request. The authors declare that the data supporting the findings of this trial are available within the manuscript and its supplementary information.

可根据合理要求提供MTB建议的分子数据。作者声明，支持该试验结果的数据可在手稿及其补充信息中找到。

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Download referencesAcknowledgementsThe Molecular Screening and Therapeutics (MoST) Program is funded by the Commonwealth and the NSW governments through the Office of Health and Medical Research, NSW. The authors thank all study participants and their families. We kindly acknowledge Roche Product Pty Limited for funding support and provision of study medication for the MoST-Kadcyla pan-cancer trial.Author informationAuthors and AffiliationsNHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, AustraliaSubotheni Thavaneswaran, Frank Lin, David Espinoza, Sarah Chinchen, Lucille Sebastian, Tony Mersiades, Chee Khoon Lee & John SimesThe Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, NSW, AustraliaSubotheni Thavaneswaran, Anthony M.

下载参考文献致谢分子筛查和治疗（MoST）计划由英联邦和新南威尔士州政府通过新南威尔士州健康与医学研究办公室资助。作者感谢所有研究参与者及其家人。我们衷心感谢罗氏产品私人有限公司为MoST Kadcyla泛癌试验提供资金支持和研究药物。作者信息作者和附属机构新南威尔士州悉尼大学HMRC临床试验中心，澳大利亚新南威尔士州悉尼圣文森特医院，澳大利亚新南威尔士州悉尼圣文森特医院，澳大利亚新南威尔士州圣文森特医院，金霍恩癌症中心。

Joshua & David M. ThomasSchool of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, AustraliaSubotheni Thavaneswaran, Frank Lin, Min Li Huang & Anthony M. JoshuaGarvan Institute of Medical Research, Sydney, NSW, AustraliaSubotheni Thavaneswaran, Frank Lin, John P. Grady, Maya Kansara, Anthony M.

Joshua＆David M.ThomasSchool of Clinical Medicine，Faculty of Medicine and Health，新南威尔士大学，悉尼，新南威尔士州，Australiassubotheni Thavenewaran，Frank Lin，Min Li Huang＆Anthony M.JoshuaGarvan Institute of Medical Research，悉尼，新南威尔士州，Australiassubotheni Thavenewaran，Frank Lin，John P.Grady，Maya Kansara，Anthony M。

Joshua & David M. ThomasKinghorn Centre for Clinical Genomics, Sydney, NSW, AustraliaFrank LinSydPath Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, NSW, AustraliaMin Li HuangPeter MacCallum Cancer Centre, Melbourne, VIC, AustraliaJayesh DesaiChris O’Brien Lifehouse, Sydney, NSW, AustraliaPeter GrimisonRoyal Adelaide Hospital, Adelaide, SA, AustraliaMichael BrownLinear Clinical Research & University of Western Australia, Perth, WA, AustraliaMichael MillwardRoyal Hobart Hospital, Hobart, TAS, AustraliaRosemary HarrupPrincess Alexandra Hospital and Queensland University of Technology, Brisbane, QLD, AustraliaKen O’ByrneWestmead Hospital, Sydney, NSW, AustraliaAdnan Nagri.

Joshua＆David M.ThomasKinghorn临床基因组学中心，新南威尔士州悉尼，澳大利亚新南威尔士州圣文森特医院解剖病理学系，澳大利亚新南威尔士州悉尼，澳大利亚维多利亚州墨尔本Li HuangPeter MacCallum癌症中心，澳大利亚新南威尔士州悉尼Ajayesh DesaiChris O'Brien Lifehouse，澳大利亚格里米松皇家阿德莱德医院，澳大利亚阿德莱德，澳大利亚布朗线性临床研究和西澳大利亚大学，珀斯，西澳大利亚米勒沃德皇家霍巴特医院，塔斯马尼亚州霍巴特亚历山德拉医院和昆士兰科技大学，昆士兰布里斯班，昆士兰，澳大利亚新南威尔士州悉尼O'Byrnestmead医院，澳大利亚纳格里。

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PubMed Google ScholarContributionsA.M.J., S.T., L.S., and D.M.T. contributed to the conceptualisation and development of the trial. M.K., M.L.H., S.T., F.L., and D.M.T. contributed to the tertiary correlatives within this manuscript. S.T., F.L., D.E., S.C., A.M.J., C.K.L., J.D., P.G., M.B., M.M., R.H., K.O., A.N., P.C., A.M.J., J.S., and D.M.T.

PubMed谷歌学术贡献。M、 J.，S.T.，L.S。和D.M.T.为试验的概念化和发展做出了贡献。M、 。S、 T.，F.L.，D.E.，S.C.，A.M.J.，C.K.L.，J.D.，P.G.，M.B.，M.M.，R.H.，K.O.，A.N.，P.C.，A.M.J.，J.S.，和D.M.T。

contributed to the implementation, investigation, and clinical trial analysis. J.P.G., F.L., S.T., M.L.H., M.K., A.M.J., and D.T. played a key role in the bioinformatics and genomics analysis of patients screened and enroled on the trial. All authors were involved in writing, reviewing, and editing the manuscript.Corresponding authorCorrespondence to.

为实施，调查和临床试验分析做出了贡献。J、 P.G.、F.L.、S.T.、M.L.H.、M.K.、A.M.J.和D.T.在筛选和纳入试验的患者的生物信息学和基因组学分析中发挥了关键作用。所有作者都参与了手稿的撰写，审阅和编辑。对应作者对应。

Subotheni Thavaneswaran.Ethics declarations

苏博特尼·塔瓦内瓦兰。道德宣言

Competing interests

相互竞争的利益

D.M.T. as CEO of Omico, a non-profit organisation has received grants, consultancies or research support from Roche, Astra Zeneca, Pfizer, Eisai, Illumina, Beigene, Elevation Oncology, RedX Pharmaceuticals, Sun-Pharma, Bayer, Abbvie, George Clinical, Janssen, Merck, Kinnate, Microba, BioTessellate, Australian Unity, Foundation Medicine, Guardant, Intervenn, Amgen, Seattle Genetics and Eli Lilly.

D、 作为Omico的首席执行官，这家非营利组织获得了罗氏（Roche）、阿斯特拉·捷利康（Astra Zeneca）、辉瑞（Pfizer）、卫材（Eisai）、Illumina、Beigene、Elevation Oncology、RedX Pharmaceuticals、Sun Pharma、拜耳（Bayer）、艾伯维（Abbvie）、乔治临床（George Clinical）、詹森（Janssen）、默克（Merck）、Kinnate、Microba、BioTessellate、Australian Unity、Foundation Medicine、Guardant、Intervent、Amgen。

D.M.T. also serves on the advisory boards or committees for Canteen, UNSW SPHERE and NSW government in respect to genomics and translational medicine..

D、 M.T.还在食堂、新南威尔士州和新南威尔士州政府的基因组学和转化医学咨询委员会或委员会任职。。

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Reprints and permissionsAbout this articleCite this articleThavaneswaran, S., Lin, F., Grady, J.P. et al. A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

转载和许可本文引用本文Thavenewaran，S.，Lin，F.，Grady，J.P.等人对携带HER2扩增或突变的肿瘤中曲妥珠单抗emtansine的信号寻求2期研究。

npj Precis. Onc. 8, 195 (2024). https://doi.org/10.1038/s41698-024-00698-4Download citationReceived: 18 March 2024Accepted: 29 August 2024Published: 09 September 2024DOI: https://doi.org/10.1038/s41698-024-00698-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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Cancer genomicsPredictive markers

癌症基因组预测标记