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胡夕春&Sandra M. Swain教授,ABC7现场对话——HER2阳性晚期乳腺癌治疗的变与不变

作者:肿瘤瞭望   日期:2023/11/22 14:35:00  浏览量:1577

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近年来,HER2阳性晚期乳腺癌的治疗取得历史性进展,新一代ADC药物德曲妥珠单抗(T-DXd,DS-8201)的出现,使抗HER2治疗进入新一轮的变革时代,对HER2阳性晚期乳腺癌的治疗预期和治疗格局产生深远影响。DESTINY-Breast03研究(DB-03研究)的突破性疗效,使T-DXd已成为HER2阳性晚期乳腺癌(mBC)的二线治疗新标准,新格局下如何相应地制订最佳的药物治疗顺序成为临床热议话题。此外,在突破性疗效之下,越来越多专家开始关注和讨论晚期能否治愈的终极话题。

编者按:近年来,HER2阳性晚期乳腺癌的治疗取得历史性进展,新一代ADC药物德曲妥珠单抗(T-DXd,DS-8201)的出现,使抗HER2治疗进入新一轮的变革时代,对HER2阳性晚期乳腺癌的治疗预期和治疗格局产生深远影响。DESTINY-Breast03研究(DB-03研究)的突破性疗效,使T-DXd已成为HER2阳性晚期乳腺癌(mBC)的二线治疗新标准,新格局下如何相应地制订最佳的药物治疗顺序成为临床热议话题。此外,在突破性疗效之下,越来越多专家开始关注和讨论晚期能否治愈的终极话题。
 
第7届晚期乳腺癌国际共识会议(ABC7)于2023年11月9~11日在葡萄牙里斯本举行,ABC7会议现场,肿瘤瞭望特邀复旦大学附属肿瘤医院胡夕春教授与CLEOPATRA研究PI——Sandra M.Swain教授对新形势下的HER2阳性晚期乳腺癌治疗进展进行对话与展望。
 
01
肿瘤瞭望:从ABC6到ABC7,在HER2阳性晚期乳腺癌的治疗中,您认为最主要的进展是什么?
 
From ABC6 to ABC7,what do you think is the most important progress in the treatment of HER2-positive advanced breast cancer?
 
Sandra M.Swain教授:我认为抗体偶联药物(ADC)是HER2阳性晚期乳腺癌治疗领域中最重要的成就,尤其是在过去两三年中研发的德曲妥珠单抗。这一重大进展从本质上改变了转移性HER2阳性乳腺癌治疗的发展方向。此外还有两种酪氨酸激酶抑制剂(TKI)显示出令人瞩目的疗效。一种是中国的吡咯替尼,其在PHOEBE研究和其他中枢神经系统疾病研究中疗效显著,但目前在美国尚未获批。另一种是图卡替尼,与卡培他滨和曲妥珠单抗联合使用,在活动性脑转移中疗效突出。这两种TKI均具有重要意义,其中图卡替尼对HER2的选择性更高,而吡咯替尼能更好地作用于所有HER家族受体。
 
I think the most important advances for HER2-positive advanced breast cancer have really been the antibody drug conjugates,including trastuzumab-deruxtecan,which has come out in the last two or three years.And it really has changed the trajectory of metastatic HER2-positive breast cancer.And also,there are two tyrosine kinase inhibitors that have shown incredible activity,one in China,Pyrotinib,which we don’t have in the U.S.,but it’s very active in the PHOEBE trial and other trials that have been presented in CNS disease.And also,the same in Tucatinib,using Tucatinib with capecitabine and trastuzumab,showing activity in active brain metastases.So both of these tyrosine kinase inhibitors,I think,are important.The Tucatinib is more specific to HER2,whereas the Pyrotinib more affects all the HER receptors.
 
胡夕春教授:据我所知,目前还有另外一种名为SYD-985的ADC,虽然还未获批。不过研究者在圣安东尼奥乳腺癌研讨会(SABCS)上公布了其III期试验数据。您对此有什么看法。
 
And as I know,also,another ADC drug is called SYD-985,but has not been approved,but then they present the data,phase III data,in San Antonio Breast Cancer Symposium.So what’s your comments about that ADC?
 
Sandra M.Swain教授:我认为SYD-985也是一种有效的ADC药物,但由于具有眼部毒性,因此似乎更适用于后线治疗。这是该药物的不足之处,我认为开发者已将其定位为后线治疗药物。
 
I think it’s also a very active drug.I think it’s going to be later-line,because it does have some toxicities,if I remember,with the eye toxicity.So I think that’s kind of a problem for that drug,and I thought they had now decided to develop it in later-line treatment.
 
02
肿瘤瞭望:本次ABC7共识在HER2阳性晚期乳腺癌治疗领域主要关注的话题是什么?
 
What are the main topics that the ABC7 Consensus focuses on in the field of HER2-positive advanced breast cancer treatment?
 
Sandra M.Swain教授:本次ABC7共识会议关于HER2阳性晚期乳腺癌讨论的要点之一是炎性乳腺癌,炎性乳腺癌通常表现为HER2阳性。多年来,我们逐渐认识到炎性乳腺癌并非一种孤立的疾病;它可以表现为三阴性(比例比较高)、HER2阳性或激素受体阳性。因此,治疗决策必须根据每种疾病的生物标志物进行治疗。另一个有趣的特征是那些伴有脑膜转移的HER2阳性患者,图卡替尼和T-DXd疗效显著。虽然这是一类很小的患者人群,但这些药物的治疗效果极好,对患者而言非常鼓舞人心。
 
One of the topics that was discussed for HER2-positive advanced breast cancer included inflammatory breast cancer,which we talked about,and a large percentage of inflammatory breast cancer does have HER2 positivity.So that was something that has changed over the years,maybe not since ABC 6,but we now know that inflammatory breast cancer is not just one specific disease.It can be triple negative,which is a high percent,and also HER2 positive,and also ER positive.So you really have to treat it according to the biomarker.The other interesting feature is that with leptomeningeal disease,those patients who have HER2-positive disease,there’s activity with Tucatinib,a tyrosine kinase inhibitor,and also trastuzumab-deruxtecan.So these are very small,small,small series of patients,but they’ve done exceptionally well with these new drugs,which is really encouraging for patients.
 
胡夕春教授:另外,今年的ABC7共识中我们也会讨论不同的乳腺癌临床场景,包括老年患者、体弱患者和HIV患者,战争和冲突期间的乳腺癌患者治疗情况,以及如何管理晚期乳腺癌患者。
 
Also,in this year’s ABC7 consensus,we will discuss different clinical scenarios,including older patients,frail patients,and patients with HIV disease,treatment situations during war and conflict,and how to manage patients with advanced breast cancer.
 
03
肿瘤瞭望:您如何看待当前HER2阳性晚期乳腺癌的治疗顺序选择?
 
How do you think about the treatment sequence selection of HER2-positive advanced breast cancer?
 
Sandra M.Swain教授:如果是转移性HER2阳性乳腺癌,特别是当患者为新诊断转移性疾病时(在HER2阳性乳腺癌中现在较以前更为常见,约有一半的HER2阳性晚期乳腺癌患者为新诊断转移),我会以CLEOPATRA研究中的方案为首选:曲妥珠单抗+帕妥珠单抗+紫杉醇作为一线治疗。在二线治疗中,我会考虑使用T-DXd。三线治疗在美国考虑使用图卡替尼,在中国则可以考虑吡咯替尼。对于接受新辅助治疗的HER2阳性乳腺癌患者,在完成治疗的一年或两年后出现复发,我也会采取类似的策略。一线参照CLEOPATRA研究方案,二线选择T-DXd,三线选择TKI。
 
如果患者在新辅助治疗后很早期就出现复发,我可能会考虑将T-DXd作为一线治疗选择。唯一不同的是对于存在活动性脑转移的患者,尽管有新数据显示T-DXd在活动性脑转移患者中也有效,但也可以考虑图卡替尼或吡咯替尼的方案。
 
If we’re talking about metastatic HER2-positive disease,if a patient presents with de novo metastatic disease,which is much more common than it used to be,at least in HER2-positive,probably half the cases present de novo,then I would treat them with a CLEOPATRA regimen,the Trastuzumab,Pertuzumab,and a taxane first.And second line would be trastuzumab deruxtecan.And then third line would be Tucatinib in the U.S.and probably Pyrotinib in China.
 
If a patient already has been treated in the neoadjuvant setting for HER2-positive disease and has a recurrence a year or two later after treatment is finished,I would do the same thing.I would do first line would be the CLEOPATRA regimen,then second line T-DXd,then the tyrosine kinase inhibitor.Now,if they presented very early with a recurrence after their neoadjuvant treatment was finished,then I might go straight to trastuzumab deruxtecan.The only change could be in a patient who had active brain metastases.You might want to consider the Tucatinib or the Pyrotinib regimen at that point,though the data now is showing,even though it’s in limited numbers of patients,that trastuzumab deruxtecan does work in patients with active brain metastases.
 
胡夕春教授:在今年的ESMO大会上,DB-01、02、03三项临床试验的探索性汇总分析也显示,T-DXd在经治和未经治的脑转移患者中均表现出高效的颅内活性,患者能从T-DXd的治疗中获益。
 
Also,in this year ESMO,they combined the three clinical trials,DB-01,02,and 03,to analyze the patients with brain metastasis.For both patients with active brain metastasis or stable brain metastasis,both can derive benefit from trastuzumab deruxtecan.
 
04
肿瘤瞭望:HER2阳性晚期乳腺癌的预后已取得长足进步,随着更好的抗HER2药物的出现,HER2阳性晚期乳腺癌患者是否有可能走向治愈?
 
The prognosis of HER2 positive advanced breast cancer has made great progress.With the emergence of better anti HER2 drugs,are HER2 positive advanced breast cancer patients likely to be cured?
 
Sandra M.Swain教授:虽然很多人可能不会这么说,但我认为HER2阳性晚期乳腺癌患者确实有可能实现治愈。支持这一观点的证据来自CLEOPATRA研究,根据我们在第8年的最终分析,有16%的患者仍在接受治疗且未出现疾病进展。这表明存在长期应答患者(long-term responders)或者可以说潜在的治愈患者。值得注意的是,在分析长期应答患者的特征时,一个关键因素是无PIK3CA突变。如果肿瘤的PIK3CA基因为野生型(wild type),那么实现长期应答或者实现治愈的可能性更大。另一个方面是,有限的病灶数量,特别是实现完全缓解的患者,有更大的治愈机会。尽管我对此抱有希望,但我们还在摸索中,目前尚不能肯定的下结论。
 
I really think that most people wouldn’t want to say this,but I would like to say I think that is a possibility that patients with HER2-positive advanced breast cancer can be cured.And one of the pieces of evidence is with a CLEOPATRA study in which we found that 16%of the patients at eight years,which was our final analysis,were still on treatment and still not progressing.So I think that you have these long responders or patients,when we looked at the analysis to see which of those patients were which were long responders,number one,they didn’t have a PIK3CA mutation.That’s one example.So if they don’t have that,if it’s wild type,then they have a better chance,I think,of being a long responder or,if you want to say,a cured patient.The other piece of that is that the patients who have only small sites of disease,again,who have a complete response,those patients are more likely to potentially be cured.Now,I hope that’s true.We don’t know for sure.And it’s always hard to say that.
 
胡夕春教授:我认为在早期乳腺癌,特别是HER2阳性的早期乳腺癌患者当中讨论治愈比较有意义。对于晚期乳腺癌,即使是HER2阳性患者,我们可将其看作一种慢性病,类似于糖尿病。我们需要持续使用药物来控制疾病。转移性或复发性疾病的治愈可能性非常低。您对此有何看法?
 
For the early breast cancer patients,I think we can think of cure for early breast cancer patients,especially for HER2-positive early breast cancer patients.But for ABC,for recurrent or metastatic breast cancer,even in the HER2-positive,I think we can think it as a chronic disease,such as,like,diabetes.We have to continue to use the drug to control the disease.The cure for metastatic or recurrent disease,the chance is very,very low.What’s your comments on that?
 
Sandra M.Swain教授:是否需要对那些在较长时期内取得良好疗效的患者进行持续治疗是一个存在争议的话题。在CLEOPATRA研究中,我们曾尝试探索这一点,我们观察到非常多的患者在很长的时间内都没有复发,长达八年。我非常理解这个问题,因为这些患者一直在持续接受治疗。这些患者需要持续接受治疗,可以被认为是慢性疾病。但是不是可以停止治疗?我们不知道答案。在ABC7会议上也对这个问题进行了讨论,对于诸如HER2阳性患者获得极佳疗效的情况下,我们何时可以停止治疗?我们认为这类人群,可能可以考虑停药或暂停用药一段时间(药物假期),以观察他们的情况。在美国,我们正在进行一项名为STOP HER、STOP ATR的研究,这是一项观察患者停止治疗后的前瞻性研究,这些患者已接受了长期治疗,该研究尝试得到一些数据以评估是否存在一部分获得治愈的患者。
 
Well,I mean,that’s the controversy.And we don’t have the data.We tried to look at that in the CLEOPATRA study,because we had so many patients who did well for so long,for eight years.So I do understand your point,because those patients were all on treatment.So it would be chronic in that they needed to continue the therapy.But again,we don’t even know the answer to that.Could we stop?That was another discussion we had at ABC7.When do we stop treatment for patients like the HER2-positive patients that are doing well?And we intended that that would be one group where you could consider stopping treatment and doing a drug holiday to see how they do.And I think we,in the U.S.,we have a study called STOP HER,STOP ATR,which is just a prospective study looking at patients who do stop their treatment,who have been on for a long time,to see how they do,to try to get some data to see if there is a cured subset of patients.
 
胡夕春教授:您提到的研究患者纳入标准是什么?
 
What’s the inclusion criteria for that study?
 
Sandra M.Swain教授:患者必须一直处于治疗状态,持续两年或三年。我认为应该是三年,并且病情稳定没有疾病复发或疾病进展迹象。
 
They have to have been on therapy,I think it’s three years.It’s either two or three years,but I think it’s three years and have stable or no evidence of disease.
 
05
肿瘤瞭望:ADC药物在HER2治疗中取得突破,您如何看待ADC药物未来在HER2阳性晚期乳腺癌一线治疗中的潜力?
 
With the breakthrough of ADC drugs in HER2 treatment,how do you see the potential of ADC drugs in the future first-line treatment of HER2-positive advanced breast cancer?
 
Sandra M.Swain教授:一项已完成或即将完成患者招募的试验正在探索T-DXd在HER2阳性新辅助治疗中的疗效。此外,还有一项已完成招募的正在进行中的试验,在晚期一线治疗中比较T-DXd和CLEOPATRA方案(曲妥珠单抗+帕妥珠单抗;HP)的疗效,该研究旨在确定T-DXd是否优于CLEOPATRA方案。我担忧的是在这项试验中T-DXd会持续使用直至疾病进展,与CLEOPATRA研究中的方案相同。在CLEOPATRA研究中在进行最多6或8个周期的化疗后会停止化疗,考虑到T-DXd携带一种化疗药物,长时间的给药可能导致毒性增加。然而,如果疗效显著提高,就必须权衡患者的获益和风险。
 
Trastuzumab deruxtecan is in the neoadjuvant setting already in a study that’s completed accrual,or it’s close to completing accrual,and then there’s the first-line metastatic trial that’s being done,which compares Trastuzumab deruxtecan to trastuzumab+pertuzumab to the CLEOPATRA regimen.So that study is ongoing.Hopefully we’ll finish accrual and we’ll see if it beats the CLEOPATRA regimen.The concern I have for that study is they continue the trastuzumab deruxtecan like we did in CLEOPATRA.They continue until progressive disease,and trastuzumab deruxtecan is a chemotherapy,so you’re giving much more therapy than we did in CLEOPATRA where we stopped chemotherapy for the most part after six or eight cycles and then continued the HER2-targeted therapy for years.So I’m concerned that with continuing trastuzumab deruxtecan for years that you might have more toxicity.However,if efficacy is a lot greater,then we’ll just have to work that out for the benefit risk for the patient.
 
胡夕春教授:我完全同意您的观点,对于HER2阳性乳腺癌,曲妥珠单抗+帕妥珠单抗比T-DXd用药更方便,毒性更小。但我认为我们需要等待数据以进行全面评估。
 
I totally agree with you that for the HP,trastuzumab plus pertuzumab is very convenient and is less toxic than the trastuzumab deruxtecan.I think we have to await the data.
 
胡夕春教授
教授、主任医师、博士研究生导师
复旦大学附属肿瘤医院肿瘤内科主任,博士研究生导师
ESMO乳腺癌Faculty Member
ABC5 panelist
中国抗癌协会多原发和不明原发肿瘤专委会主任委员
中国抗癌协会临床化疗专委会副主任委员
中华医学会肿瘤分会肿瘤内科专家委员会副主任委员
中国研究型医院学会乳腺专委会副主任委员
中国抗癌协会乳腺癌专委会委员
国家食品药品监督管理局审评中心审评专家
发表论著200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
 
Sandra M.Swain
CLEOPATRA研究PI
医学博士,教授,乔治敦大学医学教授,F.Edward Hebert医学院医学副教授,乳腺癌科主任和癌症治疗科主任。曾任美国国立癌症研究所(NCI)、美国国立卫生研究院(NIH)癌症研究中心医学分会副主任,终身首席研究员。
Swain博士目前的研究转移性和炎性乳腺癌的临床和转化研究,是三项国际3期随机研究的主席,主要研究乳腺癌的辅助治疗;在dexrazoxane获批用于乳腺癌治疗的心脏保护和蒽环类药物方面发挥了重要作用;发表了200多篇期刊和评论文章,并在国内外数百篇关于乳腺癌和乳腺健康的演讲中担任特邀演讲人;荣获2012年克劳德·雅克莱特临床癌症研究奖。Swain博士是ASCO前任主席(2013-2014年),是MeSTAR华盛顿医院中心和MeSTAR华盛顿医院中心基金会的董事会成员。20多年来,她一直是全国外科辅助性乳肠项目的积极成员,目前在董事会任职,并担任乳腺委员会副主席。她是美国癌症研究协会的成员,也是征服癌症基金会的董事会成员。

 

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