当前位置:肿瘤瞭望>资讯>快讯>正文

ABC7丨胡夕春&Hope S. Rugo教授:从ADC药物治疗进展看晚期三阴性乳腺癌与HR+/HER2-乳腺癌未来的治疗策略

作者:肿瘤瞭望   日期:2023/11/23 11:05:38  浏览量:1291

肿瘤瞭望版权所有,谢绝任何形式转载,侵犯版权者必予法律追究。

晚期乳腺癌国际共识会议(ABC)是晚期乳腺癌学术领域首屈一指的国际性会议,其主要目标是为晚期乳腺癌患者的管理制定国际共识指南。这些指南基于最新的证据,可用于指导全球许多不同医疗机构的治疗决策。ABC还旨在根据未满足需求的最重要领域确定研究重点,分析和讨论现有数据,以提供最准确的管理建议,影响决策者和资助机构,并最终提高护理、生存和生活质量的标准。在本届ABC7上,肿瘤瞭望特邀复旦大学附属肿瘤医院胡夕春教授和美国加利福尼亚大学旧金山分校海伦·迪勒家庭综合癌症中心Hope S.Rugo教授对于晚期三阴性乳腺癌与HR+/HER2-乳腺癌的诊疗理念发表各自观点。

编者按:晚期乳腺癌国际共识会议(ABC)是晚期乳腺癌学术领域首屈一指的国际性会议,其主要目标是为晚期乳腺癌患者的管理制定国际共识指南。这些指南基于最新的证据,可用于指导全球许多不同医疗机构的治疗决策。ABC还旨在根据未满足需求的最重要领域确定研究重点,分析和讨论现有数据,以提供最准确的管理建议,影响决策者和资助机构,并最终提高护理、生存和生活质量的标准。在本届ABC7上,肿瘤瞭望特邀复旦大学附属肿瘤医院胡夕春教授和美国加利福尼亚大学旧金山分校海伦·迪勒家庭综合癌症中心Hope S.Rugo教授对于晚期三阴性乳腺癌与HR+/HER2-乳腺癌的诊疗理念发表各自观点。
 
#1
晚期三阴性乳腺癌
Advanced Triple Negative Breast Cancer
 
肿瘤瞭望:SG和T-DXd均已获批用于mTNBC的二线治疗,尽管无头对头证据的比较,但基于既往注册研究数据和临床实践经验,您如何优化这两种ADC在mTNBC中的治疗顺序?
 
Both SG and T-DXd have been approved for second-line treatment of mTNBC.Despite the lack of head-to-head comparative evidence,based on previous registration study data and clinical practice experience,how would you optimize the treatment sequence of these two ADCs in mTNBC?
 
Hope S.Rugo教授:Sacituzumab Govitecan(Sacituzumab;SG)在大量既往接受过治疗的晚期三阴性患者中进行了临床研究。这些患者通常在晚期阶段接受了多线治疗,后续治疗选择十分有限,在Ⅲ期注册临床试验(ASCENT研究)中,SG显著改善了患者的无进展生存期(PFS)和总生存期(OS)。
 
在DESTINY-Breast04研究(DB-04研究)中,TNBC亚组作为观察终点之一,试图探索T-DXd在TNBC患者中的有效性和安全性。该探索性亚组共包括58名患者,其中对照组患者18名。DB-04研究患者在T-DXd治疗开始前接受过1~2线化疗,且经由中心实验室确认为HER2低表达,但此研究中的TNBC亚组只代表了一个相对较小的患者群体。
 
所以对于TNBC患者,基于既往数据,我会倾向于选择SG作为初始ADC治疗T-DXd作为后续治疗,这样也符合循证医学的理念。但对于HR+患者,其HER2出现转阴或阳性极弱、或者HER2低表达的情况下,我可能更倾向于选择T-DXd作为首选治疗方案。当然,我们必须考虑患者个人因素,如既往治疗史或者其他风险因素,这都会极大程度地影响治疗决策。例如,对于曾经在放疗后因紫杉醇治疗而出现肺炎并需要接受长达一年类固醇治疗的患者,T-DXd则不太适合作为首选治疗。总体而言,治疗方式的选择需要全面考虑患者的疾病特征、当前的有效循证医学证据以及患者的治疗经历等。
 
Sacituzumab Govitecan(Sacituzumab;SG)was tested in patients who had heavily pre-treated disease.So,you know,sort of three to four lines and even more of chemotherapy for metastatic disease where patients with TNBC have such limited options.I mean,really poor options.And it improved progression-free and overall survival in a phase three registration style setting.
 
T-DXd had a pilot,you know,really an experimental observation,you know,to try and see would the drug work in patients who had triple negative breast cancer.So it was an exploratory subset.It included 58 patients,only 18 patients in the control arm,and patients had received just a median of one line of prior chemotherapy and had to also have HER2 low centrally confirmed.So it represents a relatively small subset of patients.
 
So my approach has been in general for a true triple negative tumor in a breast cancer patient,I use Sacituzumab first,and T-DXd more as a later line therapy simply because there’s more data.I think it’s more evidence-based.But if I have a patient who had hormone receptor positive disease that becomes negative or really low,and they have very,you know,HER2-low disease,in that situation,I might choose T-DXd first.And then of course,you have to take into account the patient’s risk factors.You know,did the patient have prior pneumonitis?I just was asked about a patient who had pneumonitis to paclitaxel post-radiation and required a year of steroids.That would not be a patient where I would jump to give T-DXd first,for example.So I think that really you have to take the disease,the disease biology,and also the patient and their experiences into account.
 
胡夕春教授:我认为SG的Ⅲ期试验数据更有说服力,更有利于TNBC患者治疗决策。所以对于TNBC患者,在我的临床实践中,即使该患者首次检测为Luminal亚型,之后复发转移时做活检发现该患者为TNBC亚型,我仍然考虑首先选择SG进行治疗。
 
For the T-DXd,I think it’s like a phase two study.But for SG,and you talk to anything,I think it’s a phase three trial.So they have more,you know,more strong evidence.So I think for triple-negative breast cancer patients,even in my clinical practice,even if the first report is luminal subtype,then the disease recurred,we do a re-biopsy,found that it’s a triple-negative,I still consider the SG first.
 
肿瘤瞭望:基于既往临床研究数据和当前注册研究布局,您是如何看待ADC药物对TNBC治疗带来的影响和价值?
 
Based on past clinical research data and the current layout of registered studies,how do you perceive the impact and value of ADCs on the treatment of TNBC?
 
Hope S.Rugo教授:抗体药物偶联物(ADC)是TNBC治疗领域的巨大进展。当标准治疗方案效果不佳时,我们的治疗选择就会非常有限。特别是对于更具侵袭性的晚期TNBC,患者的中位生存期通常不到两年。因此,找到既能够改善治疗效果、延长PFS和OS的药物,对我们医生和患者来说意义重大。
 
此外,除了有效治疗晚期患者之外,我认为最重要的是患者能更早地使用这些药物。如首个获批的Trop-2 ADC SG之外,Dato-DXd也是一种靶向Trop-2的ADC,目前尚未获批。另外还有来自中国的另一种Trop-2 ADC SKB264(MK-2870)。这些药物开展的临床研究包括SG联合帕博利珠单抗的ASCENT-05研究,以及评估Dato-DXd疗效的TROPION-Breast03研究都将评估ADC在新辅助治疗后未能达到病理完全缓解患者的治疗疗效。所以我认为对于乳腺癌患者来说,这是一个相当令人激动的消息,而对于已经出现转移性疾病的患者来说拥有了更多的治疗选择。
 
I think that having antibody drug conjugates has been an enormous advance in our treatment armamentarium for triple negative breast cancer.We are so limited in our treatment options once the standard therapies don’t work.Really,you know,for most of the aggressive,not the funny,slow-growing subtypes,but most aggressive triple negative breast cancer,the median survival in metastatic disease is less than two years.Having drugs that improve both response,progression-free survival,and overall survival is a huge impact for us and for our patients.
 
And I think that,you know,besides metastatic disease,one of the most important advances is moving these drugs earlier.And there are trials going on with Sacituzumab and then an early antibody drug conjugate against Trop-2 that’s not yet approved,Datopotamab(Datopotamab Deruxtecan,Dato-DXd),and a planned additional post-neoadjuvant trial with yet another Trop-2 ADC from China,actually,where they’re collaborating with Merck.And all of those trials will look at giving the ADC in patients who didn’t get a pathologic complete response from neoadjuvant therapy.
 
The ASCENT-05 trial,which is looking at Sacituzumab with pembrolizumab,is already enrolling patients.And then the Datopotamab Deruxtecan trial is also open and enrolling patients called TROPION-Breast03.The other one should open in the next few months or so.So I think that,you know,that’s the most exciting thing for our patients is to be able to prevent metastatic disease.But if you have metastatic disease,it’s great to have additional treatment options.
 
胡夕春教授:如何看待SG联合pembrolizumab(帕博利珠单抗)或抗VEGF药物Bevacizumab(贝伐珠单抗)的疗法呢?
 
How about the combination,the combination combining the SG with pembrolizumab or the anti-VEGF agent,Bevacizumab?
 
Hope S.Rugo教授:我们还没对此进行研究。在ESMO会议上有针对另一种癌症的三联疗法的展示,但没有使用Bevacizumab,疗效看起来不错,但毒副作用也不小。我觉得Bevacizumab是一种有效的药物,但Bevacizumab联合紫杉醇作为转移性乳腺癌的一线治疗获批适应证还是被美国FDA撤销了,令人惋惜。因此,在后续研究中Bevacizumab这一药物值得关注。目前我们还没有任何ADC结合PD-1抑制剂治疗的Ⅲ期试验数据,因此,我们还有很长的路需要走。
 
You know,we haven’t studied that.There was a triplet presentation,but not with Bevacizumab,that was presented at ESMO in another cancer type that looked encouraging,but a lot of toxicity.With Bevacizumab,I think it’s a fascinating concept.We just don’t have any data on it yet.I was very sorry that Bevacizumab approval was withdrawn in the US,because I think it’s an effective drug.And so looking at that as we move forward is important.We don’t have phase three data with any ADC plus checkpoint inhibitor yet,so we have a little ways to go.
 
#2
HR+/HER2-晚期乳腺癌
HR+/HER2-Advanced Breast Cancer
 
肿瘤瞭望:晚期一线内分泌联合CDK4/6抑制剂治疗进展后的治疗策略及化疗的应用时机?
 
What are the treatment strategies and the timing of chemotherapy application after the progression of advanced first-line endocrine therapy combined with CDK4/6 inhibitors in metastatic breast cancer?
 
Hope S.Rugo教授:这是一个非常重要的问题,因为这是我们几乎每天都能在临床上都能碰到的情况。对于一线接受内分泌治疗和CDK4/6抑制剂治疗后出现进展的HR+/HER2-晚期乳腺癌患者,有多方面因素需要考量。
 
首先,要评估他们接受内分泌治疗和CDK4/6抑制剂的时长,两年、五年、十年还是只有六个月?因为他们的治疗时间会极大程度地影响疾病对内分泌治疗的敏感度,从而影响进一步的治疗决策。其次要关注治疗开始时患者的ER表达情况。例如在治疗开始时患者的ER水平为10%或8%,那么她就不太可能从内分泌治疗中得到显著获益。第三是要了解患者的疾病进展情况。肝脏等其他器官都出现病灶的患者和出现轻微骨转移患者的治疗决策是不同的。
 
例如,我最近有一位患者在首次怀孕期间不幸确诊为新发的HR+/HER2-转移癌,肝脏出现转移灶,大量癌细胞扩散至骨头,以至于她因疼痛而无法在床上翻身。在这种情况下,一线给予卵巢功能抑制剂、芳香酶抑制剂和瑞波西利治疗,患者效果较好。肝脏病灶迅速消退,骨转移病灶消失,肿瘤标志物水平也恢复正常,她能够站起来四处走动和做她想做的事情。然而,六个月后她的肝脏出现了多处新发病变,提示内分泌疗法效果有限。通常情况下,除非对治疗没有反应,否则我会采用二线内分泌治疗方法。鉴于有诸多临床试验结果可供参考,我会选择一项与患者二代测序结果相匹配的临床试验。这些测序通常通过血液检查进行以获取患者肿瘤基因组相关的信息。
 
同时我们还对这位患者进行了肝脏活检。然而,由于活检部位不同,肿瘤有时会出现雌激素受体不表达。有时可能会观察到ESR1突变,这种情况下我们会进行下一步的内分泌治疗,如应用Elacestrant。此外,有些患者可能携带PIK3CA突变,这种突变也有助于患者的治疗决策。我治疗的这位患者携带PIK3CA突变,因此她参与了一项涉及口服SERD和新型PI3K抑制剂的临床试验。我们将密切关注该试验的结果。值得注意的是,使用正确的靶向药物,可能可以延长第二次治疗的反应持续时间。在此阶段治疗之后,患者可能需要接受化疗。我希望有ADC药物治疗的第一手数据,否则我可能会首先选择卡培他滨治疗,然后将ADC作为二线治疗。
 
It’s such an important question,because this is patients that we see every single day in clinic.Patients who’ve had treatment in the first line metastatic setting with HR positive HER2 negative disease with endocrine therapy and a CDK4/6 inhibitor.And there are many things to take into account.
 
So first is,how long did they have treatment with the endocrine therapy and CDK4/6 inhibitor?Was it two,five,10 years,or six months?Because the duration of time that a patient was on that treatment is going to have a big impact on the endocrine sensitivity of their disease and what decisions you make about treatment.The second thing I think that’s important is how ER positive their disease was when you started treatment.So if the disease was ER 10%or 8%when you started treatment,the chances that you’re gonna get more endocrine response are low.And then the third aspect is really understanding the disease progression.So if you have a liver full of tumor,you’re gonna make a different decision than somebody who has slight progression in bone.
 
For example.I have a recent patient who unfortunately during her first pregnancy was diagnosed with de novo metastatic HR positive HER2 negative disease with a lesion in the liver and then extensive bone disease,so much so that she couldn’t turn over in bed because of pain.She had a great response to first line ovarian function suppression,aromatase inhibitor and ribociclib in that setting.And the liver lesion was gone right away,her bones calmed down,her tumor markers normalized and she was able to get up,walk around and do all the things she wanted to do.And then she ended up at six months,just six months with multiple new liver lesions.So that’s one situation where you know that endocrine therapy isn’t gonna last long.But generally,unless somebody has no response to the treatment,I’ll use a second line endocrine therapy approach.We have a lot of clinical trials.So I would choose a clinical trial that matches whatever I learned from their next generation sequencing,usually in blood.
 
In this case,we also got a liver biopsy,but sometimes the tumors lose ER.Sometimes you’ll see an ESR1 mutation that might help you choose the next endocrine therapy for a patient like elacestrant.And sometimes patients have a PIK3CA mutation that might help you make decisions as well.In this case,the patient’s tumor has a PIK3CA mutation,two of them actually.And so she’s going on a clinical trial with an oral SERD and a novel PI3 kinase inhibitor.And we’ll see how that goes.I mean,sometimes when you give the right targeted agent,the response is longer to the second treatment.But then after this,she’s gonna end up going on chemo.And I hope that there’s data from the first line setting about antibody drug conjugates.If not,likely she’ll get capecitabine first and an ADC second.
 
胡夕春教授:我很好奇您对那位在瑞波西利治疗仅六个月后出现复发的患者的治疗方案。对这位患者的下一轮治疗有何建议?
 
I’m very interested about your case,one patient.How about the next treatment for patients who had recurred 6 months after initiation of ribociclib?What’s your recommendation for this patient?
 
Hope S.Rugo教授:很早复发的那位患者吗?
 
The one who relapsed very early.
 
胡夕春教授:只用了六个月的瑞波西利治疗,患者就出现疾病进展了吗?
 
Just six months with ribociclib,and they have a progressive disease?
 
Hope S.Rugo教授:这位患者的肝功能正常,骨痛也得到缓解,这是她参与内分泌疗临床试验的最好时机。鉴于她肿瘤中有PIK3CA突变,她参与了一项涉及口服SERD和新型PI3K抑制剂的临床试验。整个过程中患者采用了全口服的治疗方式,这种组合的有效性尚待验证,因为她的疾病对内分泌的敏感程度仍然不确定。患者的治疗情况有些复杂,在8月进行检查时患者的结果较好,但一个月后乳腺MRI显示肝脏有新病变。于是我们在一个月后又进行了影像学检查,发现了新发的肝脏病变。
 
Her liver function is normal,and her bone pain is well controlled.So it’s the only time that she can go on an endocrine therapy clinical trial.She has a PIK3CA mutation in her tumor.So she will go on a clinical trial with an oral SERD,and a novel PI3 kinase inhibitor.So that combination,all oral regimen.So we’ll see how that works.I mean,I don’t know how endocrine sensitive her disease is.It’s very bizarre to me.We had a scan in August,looked great.Scan and then she got an MRI of the breast,because she’s thinking,do I want surgery or not?The MRI of the breast a month later showed a new lesion in the liver.And so we imaged her and there’s new lesions in the liver a month later.
 
胡夕春教授:很难为这位患者的治疗敏感性进行定义。原发性耐药的定义主要依据接受内分泌治疗单药或内分泌治疗联合CDK4/6抑制剂或PI3K抑制剂联合治疗。尤其是目前这个时期,新药层出不穷,可能下个月内分泌治疗领域又会有新的治疗药物出现。
 
So it’s very difficult to do some exact definition.Primary resistance is defined in the context of endocrine therapy alone or endocrine plus(plus CDK4/6 inhibitor or plus the PI3K inhibitor).Especially now we have,maybe next month,the Capivasertib for AKT inhibitor.
 
Hope S.Rugo教授:也许Capivasertib这个月就能获批。11月底FDA应该会反馈给我们一些关于Capivasertib的消息。Capivasertib是一种很有效的治疗药物,当该药被批准时,这位患者可以选择Fulvestrant和Capivasertib作为下一步的治疗方案。不过,在这种情况下,有Capivasertib临床试验可参与的话最好还是参与临床试验,因为这位患者目前的状况明显比预期的更糟糕。
 
It’s supposed to be this month,Capivasertib.So by the end of November,the FDA is supposed to give some opinion on that.And we’ll find out.Capivasertib is a really good drug to bring up because when that’s approved,she could get Fulvestrant and capivasertib as her next step if she wasn’t going on a clinical trial.But of course,if there are clinical trials,that’s always preferred in that setting if we can find something,because she clearly already has a worse outcome than one would like to see.
 
肿瘤瞭望:今年的国际大会(ASCO,ESMO)上,更新了ADC重要研究TROPiCS-02的延长随访OS结果及前序化疗线数与疗效关系的回顾性分析。基于这些更新、请您谈谈SG在晚期HR+/HER2-乳腺癌诊疗中的定位及临床价值?
 
At this year’s international conferences(ASCO,ESMO),there were updates on the important ADC study TROPiCS-02,including the extended follow-up overall survival(OS)results and a retrospective analysis of the relationship between prior lines of chemotherapy and efficacy.Based on these updates,could you please discuss the positioning and clinical value of SG in the diagnosis and treatment of advanced HR+/HER2-breast cancer?
 
Hope S.Rugo教授:TROPiCS-02研究作为SG在HR+/HER2-晚期乳腺癌的注册研究,是在ADC被广泛进行探索之前就已经开展的。当时Trastuzumab-deruxtecan(T-DXd)仍处于试验早期阶段。TROPiCS-02旨在评估HR+/HER2-的乳腺癌患者,该研究中的这些患者与其他ADC的研究相比接受了更多线的治疗。这些患者既往中位治疗线数为3(2~4)线,所有患者均接受了CDK4/6抑制剂,95%的患者出现内脏转移,而从确诊转移性乳腺癌到开始临床试验治疗的平均时间为4年。结果表明,与医生选择的化疗相比,SG为患者带来了PFS和OS获益。另外,这种获益不会受到Trop-2抗体染色强度以及HER2状态(低表达或无表达)的影响。
 
SG是每3周的第一天和第八天给药,所以我们需要考虑输液频率。与许多ADC一样,SG也会导致脱发,T-DXd在这方面的副作用相对较轻。中性粒细胞减少是其主要的副作用,其次是腹泻,腹泻的发生可能也与个体情况有关。通过对这些副作用进行积极管理,我认为SG对于内分泌耐药和其他内分泌治疗选择有限的患者来说,是一种不错的治疗选择。若患者已经开始化疗,我们可以将SG作为二线治疗。
 
ASCENT-07研究正在探索SG在晚期一线患者中的疗效。ASCENT-07研究是一项开放性的研究,目前正在招募患者,旨在比较晚期未接受化疗的HR+/HER2-乳腺癌患者SG与医生选择治疗的疗效。这项研究的结果有可能改变我们的治疗策略。既往研究中我们观察到了SG在患者治疗中的显著疗效,于是我们继续探索SG的前线治疗策略。我记得曾经有一例患者在应用T-DXd治疗10天内出现了肺炎,由于她之前应用依维莫司治疗时出现了相关的肺炎,因此,对于这位患者我们换用了SG进行治疗。她在接受了大约8个月的SG治疗时,取得了不错的治疗效果。我认为越早使用这些ADC,他们的疗效似乎更好且毒副作用也更少。
 
So we,you know,the TROPiCS-02 trial was conducted before there were a lot of ADCs,right?So I know the trastuzumab-deruxtecan(T-DXd)was just getting going,and TROPiCS-02 was organized to evaluate hormone receptor-positive or HER2-negative disease.Patients were more heavily pretreated than the other ADC studies.So they had received a median of three lines of prior chemo.They all had CDK4/6 inhibitors.95%had visceral metastases,and they were a median of four years from diagnosis of metastatic disease to treatment on study.That study showed that Sacituzumab,compared to chemotherapy of physician choice,improved both progression-free and overall survival,that the benefit was independent of the intensity of Trop-2 staining by an antibody,and independent of HER2 low versus zero,as you would have expected.
 
We,of course,are managing the side effects of Sacituzumab.Sacituzumab is given day one and day eight every three weeks,so I think the infusion frequency needs to be taken into consideration.It causes hair loss,as do many of the ADCs,just trastuzumab-deruxtecan stands out as causing a little less.All the other ones cause hair loss also.And its primary side effect is neutropenia,and then,to a lesser degree,diarrhea,which may be related to individual metabolism.So if we’re aware of those side effects and manage them proactively,I think it’s a great treatment option for patients whose tumors have become endocrine-resistant and really don’t have options of therapy with endocrine treatment,and then you’re starting on chemotherapy,we can give this in the second-line setting.
 
We are studying Sacituzumab in the first-line setting in the ASCENT-07 trial,which is open and enrolling patients,which will look at Sacituzumab versus treatment of physician choice as first-line chemotherapy for HR-positive HER2-negative disease.So that will sort of change our positioning a little bit.It’s been a very effective treatment for my patients.They’ve been able to stay on,and I actually had one patient who went on T-DXd and developed pneumonitis in like 10 days.She had had pneumonitis to everolimus before,and we switched her to Sacituzumab,and she stayed on that for about eight months,so that was great.The earlier we’re using these ADCs,the longer we’re seeing them be effective,and there’s better toxicity as well.
 
胡夕春教授:对此我分两点说下我的看法。首先,TROPiCS-02试验是一项出色的研究。该研究表明即使在经过多线治疗的HR+/HER2-乳腺癌患者中,我们仍能看到SG单药也可以显著提高患者的总生存率。我相信如果在临床试验的早期阶段采用类似的干预措施,我们也可以期待更多积极的结果。其次,SG治疗带来的血液毒性和化疗诱发的恶心呕吐属于化疗常见的毒性范畴。作为肿瘤内科医生,我们对预防和处理这些问题应得心应手。
 
I will draw two comments.TROPiCS-02 trial is an excellent trial,and in the patients,in the heavily pre-treated patients,we can still see a drug can improve the patient’s overall survival.I think if we move to the early setting in your clinical trial,there will be more,another positive trial.And also,for the second comment,for hematological toxicity,for chemotherapy-induced nausea,vomiting,it’s a common chemotherapeutic toxicity,so as a medical oncologist,I think we are very familiar to this prevention.
 
Hope S.Rugo教授:是的,我完全同意。作为从业者,我们对处理这些问题习以为常。例如,某种ADC可能引起更强烈的恶心感,而SG则可能增加中性粒细胞减少的风险。我们需要注意到这些药物及其相应的副作用。另外,我觉得间质性肺病也可能是这样的,即在开始用药之前患者接受的治疗越少,药物的效力就越高,毒性就越小,与我们一直以来观察的药物一样。
 
Yeah,I agree with that completely.I think we’re used to it,and for example,one of the ADCs has more nausea,Sacituzumab has more neutropenia.We just have to be aware of it,but what is interesting to me,and I’m guessing it’s gonna be true of interstitial lung disease also,is that the less you’ve treated the patient before you start the drug,the better it works,and the less toxicity,just like all drugs that we give.
 
胡夕春教授:此外,一些数据表明,既往COVID-19相关肺炎患者出现与T-DXd治疗相关肺炎的风险更高。
 
And also,some data shows in the patients with prior COVID-19 related pneumonitis,the patients will have a higher chance to develop T-DXd-related pneumonitis.
 
Hope S.Rugo教授:我观察到感染COVID-19的患者出现了严重的肺毒性。那些接受T-DXd治疗的患者和一段时间前接受过其他ADC治疗的患者在这方面都需要警惕。对于那些曾经感染过COVID-19并出现肺部并发症的患者,他们出现肺毒性的风险似乎更高。
 
I’ve seen some bad pulmonary toxicity in patients who got COVID-19,and we need to watch out for it all the time,even patients who didn’t get T-DXd,but had another ADC a while beforehand.They just seem to be more susceptible if they get the pulmonary involvement from COVID-19.
 
肿瘤瞭望:晚期乳腺癌随着临床管理的完善和新型治疗手段的不断涌现,近年来患者的生存和生活质量得到不断提高,但临床上仍存在未满足治疗需求。Trop-2 ADC作为新靶点、新一代ADC,在乳腺癌治疗的前景如何?基于现有高级别循证证据,是否会改写晚期乳腺癌诊疗现状、未来的方向又在哪里?请专家发表观点。
 
With the improvement of clinical management and the continuous emergence of new treatment methods,the survival and quality of life of patients with advanced breast cancer have been steadily improving in recent years.However,there are still unmet treatment needs in clinical practice.As a new target and a new generation of ADC,how promising is Trop-2 ADC in the treatment of breast cancer?Based on existing high-level evidence,will it potentially reshape the current landscape of diagnosis and treatment for advanced breast cancer,and what lies ahead in terms of future directions?Could you please share your viewpoints.
 
Hope S.Rugo教授:我们目前拥有为几乎所有乳腺癌亚型患者提供无进展生存期和总生存期获益的ADCs,包括HER2阳性、三阴性、激素受体阳性和HER2低表达的乳腺癌。我觉得令人兴奋的是可以将这些治疗方案提前到一线治疗、新辅助治疗结束后甚至更早的应用到新辅助治疗方案当中。
 
例如,现在有几种Trop-2 ADC正在进行临床研究,其中一个提交Ⅲ期数据的Trop-2 ADC是来自TROPION-Breast 01的datopotamab-deruxtecan(Dato-DXd),该药物在ESMO 2023上报告的数据显示PFS得到了改善,但总生存终点尚未达到。值得注意的是,与T-DXd相比,这一ADC导致口腔炎、恶心和脱发的风险更高。口腔炎可通过类固醇漱口液进行治疗,目前的研究正在评估其治疗效果。有趣的是,TROPICS-02研究与TROPION-Breast 01研究中位PFS的风险比(HR)非常相似(0.60 vs 0.63),尽管与TROPICS-02相比,TROPION-Breast 01的患者既往只接受了一次化疗,而TROPICS-02的患者既往中位治疗线数为3(2~4)线,TB-01入组患者既往接受CDK4/6抑制剂治疗的比例较少,出现的内脏疾病的比例也较少,但改善PFS的风险比几乎相同。因此,我们认为,Trop-2 ADCs,特别是这两种药物(SG和Dato-DXd)在HR+/HER2-中的疗效应该是相似的。HER2 ADC在HER2低表达患者中疗效似乎更强。但总体而言,这些药物的效果显著,为乳腺癌生物学提供了全面的治疗范围,这对于乳腺癌治疗来说是一个重要的里程碑。
 
You know,we have ADCs that have improved PFS and OS for HER2 positive disease,for triple negative disease,for hormone receptor positive disease,for hormone receptor positive and triple negative HER2 low disease,basically covering all of the subtypes.So I think what’s exciting to me is really moving them earlier in the whole treatment landscape to the first line setting where these are all being studied,and then to even earlier post neoadjuvant,neoadjuvant.
 
For example.There are numerous Trop-2 ADCs that are out on the landscape now.The only other Trop-2 ADC that has presented phase three data is datopotamab-deruxtecan(DATO-DXd)from TROPION-Breast 01,where there was data presented at ESMO 2023 showing that progression-free survival was improved.The overall survival endpoint hasn’t been met yet.There aren’t enough events.Interestingly,this ADC causes more stomatitis.It also causes the same nausea that we see and more hair loss than with T-DXd.The stomatitis we might be able to largely control with the steroid mouthwash.Those studies are going on.But the interesting thing to me was that hazard ratios were very similar,even though the patients only had received a median of one line of prior chemo compared to TROPICS,where it was three lines,less had CDK4/6 inhibitors,less visceral disease,but the hazard ratio for improved PFS was almost the same.So it makes us think,unless there’s some surprises,that Trop-2 ADCs,those two are relatively similar.The HER2 ADC seems to be more potent in HER2 low disease.But I think that overall,all of these agents are effective and now we have effectiveness across the entire spectrum of breast cancer biology.So that’s really,I think,important.
 
胡夕春教授:我们目前有三种针对乳腺癌治疗的、已获批的ADCs。T-DM1是第二代ADC,第三代包括T-DXd和Trop-2 ADC SG。临床试验正在研究的第四代ADCs是一种名为AX788的ADC药物,不同于SG和T-DXd,它采用了特定的偶联技术。此外,还有一些多肽偶联药物(PDC),如针对HER2的PDC,以及一些新型的ADC,可以同时靶向两个抗原——HER2和潜在的PD-1抗原。尽管ADC已经在许多临床场景中取得了显著进展,并成为标准治疗手段。但我们也认识到这些ADC药物并非全能,还需要进行改进。
 
For the breast cancer,we have three ADCs approved now.So we have T-DM1,it’s the second generation of ADC,and the third generation included T-DXd and Trop-2 ADC SG.So actually,there’s a fourth generation of ADC being explored in our clinical trials.I just mentioned that we have one ADC drug called AX788,it’s a site-specific conjugation ADC,but for other drugs,for SG and T-DXd,there’s no site-specific conjugation.But for AX788,it’s a special patent technique,I think.Also,we have some PDC(Peptide-Drug Conjugates)and also we have some new forms of ADC can target the two antigens,one for HER2 and the other for the PD-1 antibody,maybe the PD-1 antigen.So all these are in development progress.Now,ADC makes a great progress,and it’s a standard of care for a lot of situations,a lot of clinical scenarios,but it is still not perfect.We still have to improve.
 
Hope S.Rugo教授:目前有很多ADC正在研发中,包括HER2 ADC、免疫治疗的ADC。正如你所提到的,AX788也正在美国进行针对HER2阳性和HER2低表达患者的Ⅱ期试验。我知道您正在开展AX788相关的随机试验,可以在明年年初看到结果。我认为所有这些ADC都显示出了一定的疗效,探索药物组合方案以及用药顺序将是我们未来十年面临的巨大挑战。
 
There’s a lot of ADCs out there.I did mention the HER2 ADCs,the immunotherapy ADCs,and as you mentioned,AX788 is being tested in the United States also in phase two studies,both in HER2 positive and in HER2 low disease.And I think that you conducted a randomized trial with that drug.We’ll see results from sometime early next year,maybe.And I think all these other antibody drug conjugates all have shown some efficacy.So how they all fit in and how we sequence them,that’s a huge challenge for us over the next decade.
 
后记:作为第七届晚期乳腺癌国际共识会议(ABC7)投票小组的成员,两位专家在对话结束后一起参与了ABC7会议最后的投票环节。根据投票小组的意见,此次关于SG在ABC中应用的投票,恶心、呕吐和预防性治疗被取消,中性粒细胞减少被保留。投票显示,在经过多重治疗的人群中观察到的OS获益使SG成为HR+/HER2-ABC(既往至少接受1线ET、紫杉和CDK4/6抑制剂治疗,至少接受2~4线化疗)患者的治疗选择,其中HER2低表达和HER2 0表达患者的中位PFS和中位OS分别改善了1.5个月和3.2个月。根据临床研究,SG常见的不良反应包括中性粒细胞减少、腹泻、恶心、贫血、便秘、呕吐等,无神经毒性、眼毒性和ILD的发生,也没有观察到其他新的安全信号。使用药物前对患者进行教育、预防和早期处理副作用,仍然很重要。这一数据结果得到了95.3%(41/43)的支持率(LoE/GOR:I/B)。
 
 
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
 
Hope S.Rugo教授
美国加利福尼亚大学旧金山分校海伦·迪勒家庭综合癌症中心血液和肿瘤学部门医学教授乳腺肿瘤学和临床试验教育主任

 

版面编辑:张靖璇  责任编辑:无医学编辑

本内容仅供医学专业人士参考


乳腺癌

分享到: 更多