SECTION 1: ADCs : DESTINY-Breast 03 & TULIP

Matteo Lambertini:
Dear colleagues. Welcome to ESMO 2021. My name is Matteo Lambertini. I’m a medical oncologist from the University of Genova San Martino Hosptial in Genova, Italy. And today we have the pleasure to have Evandro de Azambuja from the Institut Jules Bordet in Brussels, to discuss with VJOncology the most important news presented at ESMO 2021 in the breast cancer field. So thanks Evandro for being here and discussing.

Evandro de Azambuja:

Thanks Matteo.

Matteo Lambertini:

So I will start Evandro, with the most important news in the breast field, the Presidential session, the first presentation by Javier Cortés, the DESTINY-Breast03 data. So just a brief overview. This is a Phase III randomized trial in patients with HER2-positive breast cancer that received at least one prior treatment. So it’s a kind of second line treatment trial and a head-to-head comparison between T-DM1 and trastuzumab deruxtecan. We have the PFS data, incredible data, large advantage favoring trastuzumab deruxtecan over T-DM1. Even not reached the progression free survival with this agent. So what are your take home messages from this study? So should we, like, completely change the second line treatment?

Evandro de Azambuja:

Yeah. This trial is really clinical practice changing for our HER2-positive metastatic breast cancer patients. Improvements that you have seen with trastuzumab deruxtecan over T-DM1 are impressive. The hazard ratio is 0.28. We do not reach the median progression-free survival, for deruxtecan, but if you look in investigators, you have 25 months versus 7 months. So it’s really a huge improvement in progression-free survival. Overall survival, the data is too immature, but you see a separation of the curves. The separation in the median progression-free survival starts very early. So after the first scans, about three months, you see really a separation of the curves. I think there is no way you can deny that this is going to be the standard second line. So for the moment, we still have pertuzumab, trastuzumab and taxane as first line, but the second line, as available, we should use trastuzumab deruxtecan.

Matteo Lambertini:

Yeah, this is actually something that’s really surprised me, is to see this PFS, the medium PFS of 25 months, which is actually longer than what we have seen in the first-line treatment with taxane, pertuzumab, trastuzumab. So my next question will be, we should move this drug earlier on?

Evandro de Azambuja:

Yeah, that’s a very interesting question. There are clinical trials looking for that, comparing to the first line, duplicated pertuzumab versus trastuzumab deruxtecan because maybe you can have improvements in first line as well. And they are also looking to comparing, I guess the T-DM1, in the post- neo-adjuvant setting for those patients receiving neoadjuvant chemotherapy and HER2 drugs. They are operated, they still have residual disease. Those patients, they are today randomized to trastuzumab deruxtecan or T-DM1. So this drug is really moving and trying to move into the earlier settings, first line and post-neoadjuvant, but okay, this is still at clinical trial, you have to have the results. This trial is still ongoing. They are recruiting patients.

Matteo Lambertini:

Yeah, but this is of course, very promising. Also looking at the response rate, like 80% response rate in the advanced setting, something that we are not so used to seeing.

Evandro de Azambuja:

Yeah, we see that we see that with the chemotherapy, pertuzumab, trastuzumab, we see also 80%, but important, we see 16% of the complete response in second line with trastuzumab deruxtecan. So there is a chance you can really cure some patients in the metastatic setting with this drug.

Matteo Lambertini:

And this probably could also potentially change in the future the way we approach advanced disease, also in terms of local control and local treatment, maybe to add on so active systemic treatments, so I think it’s…

Evandro de Azambuja:

Yeah. In my current practice, I still, I look for that, if you have a primary tumor in place in metastatic disease, I treat with systemic treatment like pertuzumab, trastuzumab, and taxane as first line, and then you see the response. If they have a very good response, I’m in favor of operating on those patients because they have such prolonged survival, if you can control also local treatment. Okay, some trials in the past didn’t show improvement in survival, but I think they did not take into account the subtypes, they didn’t take into account the most active treatments that you have today. I think this should be explored further.

Matteo Lambertini:

Yeah, I fully agree with that. Also in my practice with all these active treatment, I think the local control is, is more important that won’t show with all these trials in the past, when we didn’t have these treatment. So now Evandro, we will move to another ADC in the HER2-positive field, the TULIP trial, with trastuzumab duocarmazine, which is another ADC that was assessed in a Phase III trial, but in a more advanced patient population. So patients that were heavily pre-treated for five prior lines of treatment, most of them pertuzumab or T-DM1. So this study was also positive, met its primary endpoint in terms of improvement in progression-free survival around two months, improvement in median PFS, with a trend but was not significant in overall survival, objective response rate, very similar around 30% in the two arms. This was a head-to-head comparison, these new ADC versus physician choice treatment. So how do you interpret these data? When we, we have trastuzumab deruxtecan in earlier line and with the data we have also in terms of objective response rate with trastuzumab deruxtecan.

Evandro de Azambuja:

Yeah, with these new treatments that we have seen, the new clinical trials, it’s very difficult to put everything in the context because we have the activity of pertuzumab, trastuzumab, and now we have the activity of trastuzumab deruxtecan. We don’t know what is going to happen if you use T-DM1 after trastuzumab deruxtecan. So we don’t know the activity. And also for the trastuzumab duocarmazine, we see improvement in progression-free survival, we see some ocular toxicity which is some concern, but again, I don’t know the activity of ADC after not an ADC that’s very active, like trastuzumab deruxtecan. So it might well be that you remain a possibility or treatment for our patients, but it’s difficult to put in a context of how I’m going to look. Another thing to take into account, is also brain metastasis, because we have active treatments with tucatinib, trastuzumab and capecitabine, particularly for those patients with brain metastasis. I think you really need to put the metastatic setting into context and try to individualize, personalize the treatment for a patient. But for me again, first-line pertuzumab, trastuzumab, second line, trastuzumab deruxtecan.

Matteo Lambertini:

Yeah, I completely agree. I think the good news is that we have several active anti-HER2 agents that are coming to the clinic, which is of course something good, but something challenging is how, actually to sequence all this treatment and how to do the best sequencing for our patients.

Evandro de Azambuja:

We have other options like neratinib as well, and that they have been demonstrating neratinib with capecitabine which remains option, trastuzumab with other component of chemotherapy remain an option. Some patients, trastuzumab with endocrine therapy, but really it needs to be, the sequence is going to be very difficult, but at least these drugs are moving very fast to the early setting.

Matteo Lambertini:

I agree. I agree.

SECTION 2: MONALEESA2 & GIM4

Matteo Lambertini:

So now let’s move to, uh, another disease subtype, the hormone receptor positive, HER2-negative, still remaining in the advanced setting. We have seen the overall survival data from the MONALEESA-2 trial, which were highly awaited because in the endocrine sensitive population, we are still missing strong overall survival data from the CDK4/6 inhibitor trials. And here this study, which is a fully endocrine sensitive population, postmenopausal women, first-line, letrozole with or without ribociclib, clearly shows a significant improvement in overall survival, more than one year absolute improvement in median overall survival, more than one year delay in chemotherapy initiation. And I think the other very nice news from the study is to see that the median overall survival in the experimental arm, so in the ribociclib arm, was exceeding five years. First time that we have seen in the advanced setting, such a long median overall survival.

Evandro de Azambuja:

Yep. This is very interesting. It’s a very good news for our patients because patients with luminal disease, hormone receptor positive, HER2-negative, we don’t see much improvement in overall survival. But now with the CDK4/6 inhibitors, they use it in first or second line. You see particularly in the first line therapy. So now we have MONALEESA-2. It shows that we have three trials with ribociclib, first or second line, and all of them, they prolonged overall survival. This one prolonged 12.5 months, the others about 12 as well. So it’s very interesting. This drug really changes it. And another important thing is you delay chemotherapy to all patients, you have to take into account it is not because you have metastatic disease, you have visceral disease, those patients require chemotherapy. That’s not true. CDK4/6 inhibitors, they come as a very important treatment for our patients. So you give an effective treatment that prolongs overall survival over five years, like you mentioned, but also delay chemotherapy. And the ribociclib, the MONALEESA-2, we were waiting for the results. We have also, the MONALEESA-7, with only premenopausal patients, also prolonged overall survival. So today we have three possibilities of CDK4/6 inhibitors: palbociclib, ribociclib, abemaciclib, and they showed different overall survival benefit. But I think the ribociclib, it for the moment, is the one showing the most advantage in overall survival. So we really need to think when you are prescribing, which type of CDK4/6 you want to use for your patients. Of course, everything will depend, patients characteristics, co-morbidities, disease, co-medications. So we have to take everything to account. But today with this overall survival benefit, I think we have an answer of what we have to do.

Matteo Lambertini:

Yeah. Especially in the endocrine sensitive population where the other, the other drugs have not really, like shown overall survival benefits so far. So we are still waiting for some updated, or longer follow-up data from the other, from the other trials. I think something that the MONALEESA-2 trial has told us is that, also the concept of advanced disease in the luminal-like population is changing, as for the HER2-positive population. Like in the past, also back in 2018, the NCI has drafted some guidelines on the most important end points that should be used. And for the luminal-like population, it was still PFS in the first line because the OS is too long, so it’s difficult to see a potential benefit, but here, actually, with such effective treatment, also this concept has changed. So if you have active treatment, you can see an overall survival benefit.

Evandro de Azambuja:

Yeah. The trials, they should be powered to demonstrate overall survival benefits. That’s the most important. It can be a secondary endpoint, it doesn’t need to be the primary, but needs to be powered to demonstrate survival, overall survival.

Matteo Lambertini:

And I think another implication for the future trials is to have a long follow-up because to see a potential OS benefit with such effective treatment, you need to follow the patient for many years, more than five years median overall survival. So this is something else to consider. And we’ll be staying in the luminal-like population, some consideration in the early setting with the GIM4 trial results. So what are the clinical implications of these findings? Just a brief overview. GIM4 was a study that addressed the best extended adjuvant endocrine treatment option. In this study, patients received two, three years of tamoxifen and then were randomized to complete five years of treatment with AI or to prolong the AI for an additional five years, meaning a total duration of seven, eight years. So we have had a lot of controversy in the past on how to extend the adjuvant endocrine treatment, especially in postmenopausal women. I think that these data, together with the recent New England publication from the Austrians’ trial, are telling us that the optimal duration is seven, eight years, probably not more than that. And in these seven, eight years, is probably five years of AI is probably enough. What’s your take on these data?

Evandro de Azambuja:

Yeah. This is the recommendation that we have in some guidelines, to use at least seven to eight years for luminal breast cancer patients in the adjuvant setting. And we need to have at least five years of aromatase inhibitors. I think the Austrian data and the GIM4 data, they consolidate that not all patients need to go to 10 years because you should give endocrine therapy, seven, eight years of aromatase inhibitors will increase the risk of fractures, osteoporosis, so an impact to quality of life, cardiovascular events as well. So I think it really showed that in the majority of patients, that we can stop treatment at seven, eight years, maybe some, those patients that are at a very high risk of disease, you may continue to 10, but I think that this consolidates seven, eight years as a good duration of endocrine therapy. And this is also going to play a role because now you’re going to have some CDK4/6 inhibitors in the adjuvant setting. So we have one trial that’s positive, it’s too short follow-up, but it might be that this drug got registered. So you don’t need to extend it for 10 years, the endocrine therapy.

SECTION 3: BrighTNess

Matteo Lambertini:

And in the early setting, another study that has direct clinical implication from Monday morning, I think is the survival data from the BrighTNess trial. Just to briefly remind, the study was a Phase III trial in the neoadjuvant setting. Patients with triple negative disease that were randomized to receive paclitaxel with or without carboplatin and with or without the PARP inhibitor veliparib, followed by four cycles of anthracycline, cyclophosphamide-based chemo, dose-dense or three weekly regimen in the neoadjuvant phase. So the study reported a PCR rate showing higher PCR rate with the addition of carboplatin, but no impact of anything on the top of carboplatin, also the PARP inhibitor veliparib. Here at ESMO, we had the presentation of the survival data. We had a significant improvement in event-free survival for the addition of carboplatin, no difference if to add also veliparib and a trend also in overall survival. So at least in my practice, I tend to include carboplatin in patients that are fit for this regimen, together with a taxane portion and then followed by AC or EC for actually dose-dense, in my practice, for triple-negative patients. So do you think that these data now will end the controversy around carboplatin? So we should do it in all patients or there is still controversy there?

Evandro de Azambuja:

Yeah. So before ESMO 2021, I used to do carboplatin in patients with BRCA 1 or 2 mutations, germline mutations, all those patients where you started with anthracycline and you didn’t get a very good response, tumor response. So those ones, I would give taxane-carboplatin. After ESMO 2021, I’m convinced that we should offer carboplatin to our patients. You increase pathologic complete response but most importantly, you improve survival of those patients. And it is four years now that you can see that improvement, in four years. I think it’s going to be very difficult to not offer this to our patients. And I convinced that as from next week, I’m going to offer. The question here is how we are going to give the carboplatin. You give every three weeks, you give a weekly and the dose, because if you give every three weeks, the dose is six, but you know that they have some toxicity. You cannot go, you have to go to five AUC. And if you go weekly, it’s two, the recommended dose, but normally you cannot go up to the end of the chemo and you have to reduce to 1.5. I think you just need to adapt it, which is the dose that are going to start. And three weekly or weekly, for me, doesn’t matter, but you just need to have the right dose to ensure that you can give all chemotherapy to your patients and try to reach pathologic complete response.

Matteo Lambertini:

And I think it’s also important, not only the dose but also the sequencing. Like in my practice, I start as in the BrighTNess trial with the taxane portion first, so weekly paclitaxel and carboplatin, AUC2, in this case, a weekly regimen, which appears to be better tolerated than the other way around, so starting with anthracycline and then taxane carboplatin. There, I’ve seen also in my practice, more dose reduction, more cycles without carboplatin. So I will use the approach of BrighTNess: paclitaxel, carboplatin and then dose-dense EC or AC after this combination.

Evandro de Azambuja:

We are used to, you are used to using the anthracycline then taxane, but we’ve seen the most recent trials, BrighTNess, also the trials with immune checkpoint inhibitors, they always start with the reverse sequence, taxane and then anthracycline, so maybe something that we have to consider too.

Matteo Lambertini:

Yeah, I’ve changed recently, my practice, based on all these data. And as you have mentioned, the keynote, the pembrolizumab data, also positive in terms of survival, there they’ve included carboplatin as part of the neoadjuvant chemo. So I think these are now strong data to support this type of regimen. So Evandro, thank you very much for commenting on all these studies and we are looking forward to more live and in-person conferences in the future.

—END—

Recording date: 18-Sept-2021; Webinar broadcast date: 28-Sept-2021; Feature publication date: 29-Sept-2021.

Matteo Lambertini:

Advisory role: Roche, Lilly, Novartis, Exact Sciences, AstraZeneca

Speaker honoraria: Roche, Lilly, Novartis, Pfizer, Takeda, Sandoz

Evandro de Azambuja:

Honoraria and advisory board: Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, Elli Lilly,  Pierre Fabre, MSD

Travel grants: Roche/GNE and GSK/Novartis

Research grant to my institution: Roche/GNE, Astra-Zeneca, GSK/Novartis, and Servier