Dr.Hu Xichun &Hope S. Rugo: Future treatment strategies for advanced triple-negative breast cancer and HR+/ HER2-breast cancer from the perspective of ADC drug treatment progress

The International Consensus Conference on Advanced Breast Cancer (ABC) is the premier international conference in the academic field of advanced breast cancer, whose primary goal is to develop international consensus guidelines for the management of patients with advanced breast cancer. These guidelines are based on the latest evidence and can be used to guide treatment decisions in many different healthcare Settings around the world. The ABC also aims to identify research priorities based on the most important areas of unmet need, analyze and discuss existing data to provide the most accurate management recommendations, influence policymakers and funding agencies, and ultimately improve standards of care, survival, and quality of life. On the ABC7,Oncology Frontier invited Professor Hu Xichun, Affiliated Cancer Hospital of Fudan University, and Professor Hope S.Rugo, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, to present their views on the diagnosis and treatment concept of advanced triple-negative breast cancer and HR+/ HER2-breast cancer.

Oncology Frontier：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?

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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.

Oncology Frontier：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?

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：How about the combination, the combination combining the SG with pembrolizumab or the anti-VEGF agent, Bevacizumab?

Dr. Hope S. Rugo：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.

HR+/HER2-Advanced Breast Cancer

Oncology Frontier：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?

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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?

Dr. Hope S. Rugo：The one who relapsed very early.

Dr. Hu Xichun：Just six months with ribociclib,and they have a progressive disease？

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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.

Dr. Hope S. Rugo：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.

Oncology Frontier：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?

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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.

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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.

Dr. Hope S. Rugo：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.

Oncology Frontier：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 view points.

Dr. Hope S. Rugo：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.

Dr. Hu Xichun：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.

Dr. Hope S. Rugo：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.