相遇密歇根湖畔,胡夕春教授和Giuseppe Curigliano教授分享乳腺癌新型ADC研究进展丨ASCO中外对话

作者:肿瘤瞭望   日期:2024/6/14 15:17:26  浏览量:1374

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2024年美国临床肿瘤学会年会(ASCO 2024)于当地时间5月31日至6月4日在密歇根湖滨城市芝加哥举行。本次大会上,各类新型抗体偶联药物(ADC)可谓大放异彩,尤其中国学者携多款新型ADC相关研究成果登上口头报告的学术舞台。在大会期间,《肿瘤瞭望》采访了DESTINY-Breast06研究的全球PI之一、意大利米兰大学医学院/欧洲癌症研究所Giuseppe Curigliano教授和复旦大学附属肿瘤医院胡夕春教授。两位教授各自分享了国内外的新型ADC最新研究进展,并展望中国原创药物如何进一步走向国际、影响世界。

编者按:2024年美国临床肿瘤学会年会(ASCO 2024)于当地时间5月31日至6月4日在密歇根湖滨城市芝加哥举行。本次大会上,各类新型抗体偶联药物(ADC)可谓大放异彩,尤其中国学者携多款新型ADC相关研究成果登上口头报告的学术舞台。在大会期间,《肿瘤瞭望》采访了DESTINY-Breast06研究的全球PI之一、意大利米兰大学医学院/欧洲癌症研究所Giuseppe Curigliano教授和复旦大学附属肿瘤医院胡夕春教授。两位教授各自分享了国内外的新型ADC最新研究进展,并展望中国原创药物如何进一步走向国际、影响世界。
 
01
《肿瘤瞭望》:Curigliano教授,祝贺您在本次大会上汇报了大家期待已久的DB-06研究。该研究和既往的DB-04在设计上有何差别?DB-06研究取得了怎样的结果?
 
Oncology Frontier:Professor Curigliano,congratulations on presenting the long-awaited DB-06 study at this conference.What are the design differences between this study and the previous DB-04?What results has the DB-06 study achieved?
 
Giuseppe Curigliano教授:DB-06研究的入组人群与DB-04研究有所不同,所有患者均为HR阳性,且所有患者均接受了CDK 4/6抑制剂和第二线内分泌治疗,但没有接受过化疗。我们还纳入了一组HER2超低表达的患者。研究共招募了855例患者,比较了T-DXd与研究者选择的化疗方案(TPC),主要终点是意向治疗人群的无进展生存期(PFS),关键次要终点是HER2超低表达人群的总缓解率(ORR)、生活质量和患者报告结局等。在这种患者群体中使用T-DXd可将中位PFS从TPC组的8.1个月延长到13.2个月,将ORR从HER2低表达人群的31.2%提高到57.3%,在HER2超低表达人群中提高到61.8%,且总生存期也有改善的趋势。因此,该试验具有改变实践的意义,因为我们预期与DB-04相比,可以更早地使用T-DXd治疗,并且将T-DXd的使用范围扩展到HER2超低表达人群。
 
 
Prof.Giuseppe Curigliano:The DB-06 population is a little bit different respect to the DB-06.All patients were HR positive.All of them received previous CDK 4/6 inhibitors and the second line endocrine therapy and no one received the previous chemotherapy.We included also a cohort of patients that were HER2 ultra low.We enrolled 855 patients.We compared trastuzumab deruxtecan to investigator of choice chemotherapy and the primary end point was median progression free survival in intent to treat population and key secondary end point in HER2 ultra low population overall response rate,quality of life,patient reported outcomes.The use of trastuzumab deruxtecan in this patient population improved the median PFS from 8.1 months to 13.2 months,improved overall response rate from 31.2%to 57.3%in HER2 low and 61.8%in HER2 ultra low and there is a trend also for overall survival benefit.So the trial is practice changing because we anticipate trastuzumab deruxtecan in early line of treatment compared to Destiny 04 and we expanded the use of TDXD in the HER2 ultra low population.
 
02
《肿瘤瞭望》:胡夕春教授,您如何评价DB-04和DB-06研究在HER2低表达乳腺癌取得的突破?
 
Oncology Frontier:Professor Hu,how do you evaluate the breakthroughs made by the DB-04 and DB-06 trials in HER2 low-expressing breast cancer?
 
胡夕春教授:对于DB-04和DB-06,我认为可以总结为DB-04主要是将T-DXd作为化疗后的二线治疗,而DB-06研究则比较了(内分泌治疗失败后)一线化疗和一线T-DXd治疗,而且这两个试验都取得阳性结果。在DB-04研究中,我们可以看到PFS和OS的双重获益,但对于DB-06研究,我们还需要等待OS结果。
 
Prof.Xichun Hu:For DB-04 and DB-06,I think it can be summarized as follows:DB-04 mainly focuses on T-DXd as a second-line treatment with chemotherapy,while DB-06 compares first-line chemotherapy with first-line T-DXd treatment(after endocrine therapy failure).Both trials have achieved positive results.In the DB-04 study,we can see double benefits in PFS and OS,but for the DB-06 study,we need to wait for the OS results.
 
03
《肿瘤瞭望》:胡夕春教授,您在本次大会的快速口头报告中汇报了ACE-Breast-02研究。能否介绍一下这是一种什么样的ADC?在这项II/III期研究中取得了怎样的结果?
 
Oncology Frontier:Professor Hu,you presented the ACE-Breast-02 study in a rapid oral prsentation at this ASCO.Could you introduce what kind of ADC it is?What results were achieved in this phase II/III study?
 
胡夕春教授:ARX788是一种新型的ADC药物,其新颖之处在于使用了细胞特异性偶联技术,使抗体和药物载体能够细胞特异性地偶联。第二点也是非常重要的一点,但因为我明天要做演讲,所以现在还不能透露具体结果(编者注:采访时ACE-Breast-02研究尚未公布,主要数据结果见下图)。简而言之,这是一个阳性试验。其毒性与目前已批准用于转移性乳腺癌的药物完全不同,与Trastuzumab deruxtecan(德曲妥珠单抗,T-DXd)和Sacituzumab govitecan(戈沙妥珠单抗,SG)也不同。因此,我认为对于ARX788这种新型ADC,特别是在T-DXd治疗后的背景下,有很大的应用潜力。此外,在美国也有一些研究正在进行这种ADC在新辅助治疗中的应用。
 
 
Prof.Xichun Hu:ARX788 is a novel ADC drug whose novelty lies in the utilization of site-specific conjugation technology,enabling the specific conjugation of antibodies and drug carriers to cells.The second point is also crucial,but I cannot reveal the specific results yet as I will have a presentation tomorrow.In brief,this is a positive trial.Its toxicity is entirely different from that of currently approved drugs for metastatic breast cancer,as well as Trastuzumab deruxtecan(T-DXd)and Sacituzumab govitecan(SG).Therefore,I believe that ARX788,as a novel ADC,has great potential for application,especially in the context of post-T-DXd treatment.Additionally,there are some ongoing studies in the United States exploring the application of this novel ADC in neoadjuvant therapy.
 
04
《肿瘤瞭望》:Curigliano教授,您如何评价ACE-Breast-02研究结果以及中国原研的HER2 ADC(ARX788)?
 
Oncology Frontier:Professor Curigliano,how do you comment the results of the ACE-Breast-02 trial and the Chinese originally developed HER2 ADC(ARX788)?

Giuseppe Curigliano教授:现在如果算上正在研发的ADC,已有近346种ADC已经或正在研发中,其中许多都是在中国生产的。该研究的具体数据明天才会公布。我会非常想了解其作用机制和安全性。可以确定的是,几乎所有的ADC都通过可裂解连接子来增加载药的治疗指数。它们能够诱导更多的细胞死亡,具有旁观者效应,并延长载药的半衰期。所以我很期待明天看到这些数据。
 
Prof.Giuseppe Curigliano:You know,in China,actually,if you consider the number of ADCs under development,we have almost 346 ADCs under development and many of them are produced in China,specifically.I didn’t see this data because they are going to be disclosed tomorrow.I will be very interested to understand which is the mechanism of action and the safety profile.What I can tell you is that almost all ADCs increase their therapeutic index of the payload because they have a cleavable linker.They can induce much more cell death.They have a bystander effect and they prolong the half-life of the payload.So I will be interested to see this data tomorrow because I don’t know this data still.
 
05
《肿瘤瞭望》:胡夕春教授,中国原研药物在本次大会上表现非常亮眼,比如您汇报的新型HER2 ADC(ARX788)和新型CDK4/6i(Lerociclib)等。您如何看待抗肿瘤新药的研发?
 
Oncology Frontier:Professor Hu,Chinese original drugs have performed remarkably well at this conference,such as the new HER2 ADC(ARX788)and the new CDK4/6i(Lerociclib)that you presented.What are your thoughts on the development of new anti-tumor drugs?
 
胡夕春教授:我们有很多ADC药物和CDK4/6抑制剂正在研发中。今年,我们在乳腺癌方面有三场口头报告。第一场是由徐兵河教授主讲的,第二场是由张剑教授主讲的,第三场是我主讲的。三位主讲人讨论的都是ADC药物。我介绍ADC药物ARX788是针对HER2阳性乳腺癌的。徐教授介绍的TROP-2 ADC药物是针对三阴性乳腺癌的,张剑教授则聚焦于Nectin-4 ADC。因此,我们有很多ADC药物正在研发中。但是,所有这些数据都是基于中国乳腺癌患者的研究结果。我们希望在国际上开展多中心临床试验,以便能获得来自全球研究的确证性结论。
 
Prof.Xichun Hu:We have many ADC drugs and CDK4/6 inhibitors under development.This year,we have three oral presentations on breast cancer.The first is led by Professor Binghe Xu,the second by Professor Jian Zhang,and the third by me.All three presenters are discussing ADC drugs.I introduced ARX788,an ADC drug targeting HER2-positive breast cancer.Professor Xu’s TROP-2 ADC drug is for triple-negative breast cancer,while Professor Zhang focuses on Nectin-4 ADC.So,we have a lot of ADC drugs in the pipeline.However,all these data are based on research results from Chinese breast cancer patients.We hope to conduct multinational clinical trials internationally to obtain confirmatory conclusions from global studies.
 
06
《肿瘤瞭望》:Curigliano教授,您作为欧洲肿瘤研究所早期药物开发部的负责人,领导过不少新型药物的临床试验。您如何评价中国原研药物在欧美国家的准入?作为欧洲抗肿瘤药物试验的先锋,如果有可能成为中国药物试验的全球PI,您会给出怎样的建议?
 
Oncology Frontier:Professor Curigliano,as the head of the Early Drug Development Department at the European Institute of Oncology,you have led many clinical trials of new drugs.How do you comment the access of Chinese originally developed drugs in Europe and the United States?As a pioneer in European anti-tumor drug trials,if you had the possibility to become the global PI for Chinese drug trials,what advice would you give?
 
Giuseppe Curigliano教授:从战略上看,我觉得全球在技术和创新主导权方面正在迅速变化。中国已经成为世界第二大经济体。在过去十年中,中国在生物技术和科学方面的巨大进步。正如胡教授所说,今年就有三场口头报告是由中国专家汇报的。我个人认为中国在医药研发领域有相当不错的竞争力。我知道很多双功能抗体是由中国研发和生产的,而后被西方公司采购。我认为,中国会继续在医药领域发挥更大的作用,一方面是更充分地参加全球合作研究,另一方面是促成更多中国原研药物开展国际多中心临床试验,在患者招募方面提高全球化。
 
Prof.Giuseppe Curigliano:Well,you know,From a strategic perspective,I think the world is undergoing rapid changes in technology and innovation leadership.China has become the second largest economy in the world.In the past decade,China has made great progress in biotechnology and science.As Professor Hu said,There 3 oral presentations given by Chinese experts this year.Personally,I think China has considerable competitiveness in the field of pharmaceutical research and development.I know that many bifunctional antibodies are developed and produced in China,and then purchased by Western companies.I believe that China will continue to play a greater role in the pharmaceutical field,on the one hand,to participate more fully in global collaborative research,and on the other hand,to promote more Chinese original drugs to conduct international multi-center clinical trials and improve globalization in patient recruitment.
 
胡夕春教授
复旦大学附属肿瘤医院大内科首席博士研究生导师
复旦大学附属肿瘤医院福建医院(福建省肿瘤医院)大内科主任
ESMO乳腺癌Faculty Member
国际ABC 5-7 panelist
中华医学会肿瘤分会肿瘤内科专家委员会副主任委员
中国抗癌协会多原发和不明原发肿瘤专委会荣誉主委
中国抗癌协会临床化疗专委会副主委
中国抗癌协会分子靶向专委会副主委
中国研究型医院学会乳腺专业委员会副主委
上海市医师协会肿瘤分会副会长
上海市抗癌协会常务理事
上海抗癌协会肿瘤药物临床研究专业委员会主任委员
上海抗癌协会癌症康复和姑息治疗委员会前任主任委员
国家食品药品监督管理总局审评中心审评专家
发表论著300多篇,包括Lancet Oncol和JCO杂志等
主编《肿瘤内科方案的药物不良反应及对策》和《肿瘤科常见诊疗问题问答-胡夕春医生查房实录》等
主持十三五“重大新药创制”科技重大专项等
上海市领军人才、中国抗癌协会科技奖二等奖、全国妇幼健康科学技术奖一等奖和上海市医学科技进步奖一等奖等
 
Giuseppe Curigliano
医学博士
意大利米兰大学医学院副教授
意大利IRCCS欧洲肿瘤研究所早期药物开发部门的负责人

 

 

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