Role of chemotherapy in the treatment of metastatic breast cancer patients

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Published: 10 Dec 2018
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Professors Joseph Gligorov, Yen-Shen Lu, Chris Twelves and Dr Reshma Mahtani

Professors Joseph Gligorov, Yen-Shen Lu, Chris Twelves and Dr Reshma Mahtani meet in San Antonio at the San Antonio Breast Cancer Symposium 2018 annual meeting for an educational breast cancer panel discussion. Their talk covers the role of chemotherapy in the treatment of metastatic breast cancer patients.

Professor Gligorov chairs the discussion, opening by asking Dr Mahtani to comment on recent data surrounding novel chemotherapy combinations used to treat metastatic breast cancer patients, in particular in the triple-negative population. Here Dr Mahtani discusses the combination of eribulin with gemcitabine referencing the data seen at SABCS. Prof Twelves then comments on eribulin’s efficacy as a single agent, and the group discuss the use of eribulin as a backbone regimen in the treatment of mBC patients.

The panel then discuss the importance of individualising dosage in breast cancer patients, and the need for precision medicine and personalised chemotherapy, here referencing BRCA status, SNPs and treating patients with disease recurrence.

The discussion then moves to Prof Lu who comments on the combination of chemotherapy with anti HER2 regimens, and Prof Twelves discusses the phase II and real-world equivalent data.

Prof Gligorov then asks Prof Twelves to comment on the combination of chemotherapy with antiangiogenic agents. Here the panel discuss the use of 2nd line eribulin in combination with bevacizumab following taxane treatment, and the efficacy and toxicity profile of the drug in this setting.

The discussion is summarised by speaking through the role of chemotherapy in the treatment pathway of mBC patients, and the importance of understanding both the safety and efficacy of the chemotherapeutic agent used alongside the individual needs of the patient.

Novel chemotherapy combination regiments
Personalised treatment approaches for breast cancer patients
Chemotherapy and anti-HER2 agents
Chemotherapy and anti-angiogenic agents
Disease control with taxane and eribulin
Treatment strategies in the clinic

This programme has been supported by an unrestricted educational grant from Eisai

Professor Joseph Gligorov – Paris-Sorbonne University, Paris, France
Professor Yen-Shen Lu – National Taiwan University Hospital, Taipei, Taiwan
Professor Chris Twelves – Leeds University, Leeds, UK
Dr Reshma Mahtani – Sylvester Comprehensive Cancer Center, Miami, USA

JG: Welcome everybody, we are here with an ecancer video session. My name is Joseph Gilgorov, I’m a medical oncologist, professor at the Sorbonne University in Paris, and it’s my pleasure to chair this meeting with my colleagues devoted to the place of chemotherapy in metastatic breast cancer nowadays.

RM: I’m Reshma Mahtani, I’m a medical oncologist at the University of Miami Sylvester Cancer Center in Florida.

YSL: I’m Yen-Shen Lu, medical oncologist from The National Taiwan University Hospital from Taiwan.

CT: And I’m Christ Twelves, I’m a Professor of Clinical Cancer Pharmacology and Oncology and medical oncologist in Leeds in the north of the UK.

JG: So we’re here in San Antonio and we have seen a lot of communication devoted to biology, devoted to new targeted treatments but at the end of the day when we will be back to the clinics next week we’ll still use a lot of chemotherapy because a huge part of our patients are treated in the metastatic situation with chemotherapy. So, Reshma, I would like to ask you, have you seen some interesting information regarding new combinations of chemotherapy or ways to treat the patient in the metastatic situation? Particularly for the triple negative, even we know that we have some advances with immunotherapy and novel targeted treatment but we still use a lot of chemotherapy.

RM: Sure. At this year’s San Antonio meeting we also were fortunate enough to see some abstracts surrounding chemotherapy and specifically in the use of chemotherapy combination regimens for metastatic triple negative breast cancer. Specifically there was an abstract presented regarding the use of eribulin in combination with gemcitabine in these patients, a small study but showed a pretty impressive response rate and good tolerability. I think it’s important to recognise that in the treatment of metastatic breast cancer in general we tend to reserve combination chemotherapy regimens for patients that are in visceral crisis or really in need of a response but these data were reassuring in identifying this as a tolerable and efficacious regimen.

JG: Do you think that the use of this combination based on eribulin treatment is due to the fact that this is probably one of the only chemotherapy regimens of the new generation chemotherapy regimens that have demonstrated an overall survival benefit?

RM: I think that is driving the responses that we’re seeing. It’s very difficult to identify any drug in breast cancer, in metastatic breast cancer, that has shown a survival benefit and eribulin is unique in that setting.

CT: That abstract was quite interesting because they maintained the dose of gemcitabine and actually sacrificed the dose of eribulin in the combination. I think I would probably have come at it from the other direction because we know that as a single agent eribulin has got pretty impressive activity, specifically in the triple negative population. If you look across the molecular phenotypes there was improvement in survival but that was most striking in the triple negatives. So if I was looking at the combinations I’d probably start from the position of the eribulin being the backbone and looking at what might be added on on top of that.

JG: Yes, I agree with you. There was also another poster discussing about the possibility to use what they call the metronomic approach with eribulin. But in any case it seems that the dose intensity in general of the chemotherapy in aggressive triple negative disease makes sense and using the most effective drug is probably the backbone, as you mentioned before, of a combination regimen strategy. I totally agree with you.

CT: We see this quite often with drugs where as they move into wider use that either the schedule or the dose is changed. I suppose what struck me looking at that particular poster was that this wasn’t really metronomic because it was simply going from the day one. eight and then day fifteen off, repeated every three weeks with eribulin, and going back to what was actually the original schedule of one, eight, fifteen every 29 days. They’d come down a couple of levels on the dose which meant that it was well tolerated, there was still activity there but I suppose my sense is that the risk of that approach is that we’re moving back to the one size fits all approach, trying to find the lowest dose which will be tolerated by everybody rather than starting with what we would expect to be an appropriate and active dose and then tailoring that to the individual patient. With eribulin in particular I find that if you reduce the dose as toxicities start to emerge then you can very often continue effectively indefinitely from that standard starting dose but modifying the dose down as necessary rather than across the board.

JG: Yes, you mentioned the Musolino presentation on the poster session. I was, I would say as a clinician, very interested by the approach of trying to, let’s say, be in a real world situation when you can identify the patient that might have some issue with liver toxicity. We know that triple negative disease is pretty aggressive regarding the evolution of the disease from the metastatic spread, particularly in liver, and we know that we have several data with eribulin and they’ve also, again, explored this and tried to very, very properly and well defined how to use it in patients that have potentially some liver mets and some liver issues. This was very helpful from a clinical point of view.

CT: It was interesting, they looked at the BRCA status and found that the mutated patients tended to do worse. But they also looked at some of the SNPs that were potentially related to drug metabolism and they were small numbers but there seemed to be some correlations there and potentially some correlation with overall survival. So hypothesis generating but it was a nice, compact study that generated quite a few talking points.

RM: I was really interested to see that information on SNPs because it points to the personalisation or precision medicine as we go forward. Moving away from a one size fits all but really understanding how different drugs are metabolised and how different patients may tolerate these agents.

JG: I think it’s important to have personalised chemotherapy because we all deal with what we know are the predictors of sensitivity to treatment but we usually don’t use this kind of approach with classical chemotherapy. Do you want maybe to add something?

YSL: Specifically, even though it’s only a phase II study but for triple negative disease the majority of them have received anthracycline and taxane as adjuvant treatment. Nowadays we have data from CREATE-X, so if a patient receives neoadjuvant if they are not getting pCR maybe they will receive capecitabine as extended adjuvant. Then for those patients who have disease recurrence what can we do? Especially if they have a visceral crisis now we have good data from eribulin plus gemcitabine. These two drugs are not used in the adjuvant setting so that would be very good information for us regarding the safety profile, how we can plan in a schedule, that would be very informative for us.

JG: Yes, I agree. It’s interesting, really, really important. You’ve maybe seen some interesting data also regarding the combination of chemotherapy plus anti-HER2 regimens?

YSL: Yes. Also for HER2 disease we all know that continuing maintaining the anti-HER2 antibody plus any kind of chemotherapy would be the main treatment strategy. So for us that continues except for TDM-1, continue to use trastuzumab then if our patient has a disease progression you have to shift to another chemotherapy. So we need a safety profile and the preliminary results of this different combination. We already have taxane, vinorelbine, capecitabine data but now we have the eribulin plus trastuzumab result. Even though the result is not so outstanding but it’s showing a very good expected result. So for us, I am convinced by that small study, phase II study, that for patients who are already refractory to conventional taxane and anthracycline, okay it’s in the adjuvant, but in a stage 4 setting then we have to shift the partner, capecitabine, and now we have eribulin to be used in the clinic. Very important.

CT: No, the question often comes up because there is a conspicuous paucity of studies of eribulin with trastuzumab and people often ask you is there a reason for this, is there a problem? Historically the reason was simply that the development of eribulin went into the HER2 negative space because there were other agents being developed in HER2 positive disease. But some years ago Linda Vahdat did a 60-70 patient study looking in phase II at eribulin combined with trastuzumab. The response rate, I think, was 65% in that study. There was a Japanese study published just a year or so ago with very similar results. So we’ve got those phase II data and what we saw that we were just talking about, was the so-called real world equivalent where Dr Mougalian this time had looked at the community oncologists and pulled together 50-60 patients treated with eribulin and trastuzumab and the response rate. It’s not monitored in the same way as it would be within a trial, but the response rate was around 70% from what I remember so very similar to what had been seen in the trials. So it’s a valid point that this isn’t an area where eribulin has got approval so it’s not somewhere that is a focus of activity for the company but for individual clinicians where it’s possible for them to prescribe the combination, it is an active, well-tolerated combination.

RM: I was quite reassured by that data as well because in HER2 positive disease in the metastatic setting we have pretty clear data in the first and second line with the CLEOPATRA approach, transition to the EMILIA approach with Kadcyla, but after that things become a little bit more wide open and to see a lot of investigational drugs that are coming down the pipe but no specific agent really established in that setting, seeing data with eribulin in combination with HER2 targeted approaches was reassuring to me.

JG: Yes, it’s clear that looking to all the databases that we have access to in different countries that the population, the metastatic breast cancer population, where we have made the huge progress is HER2 positive disease. Actually the first two or three lines are pretty easy, I would say, regarding the guidelines and regarding the results and overall survival benefit but people are living, patients, longer and longer and, as you mentioned, we need more and more treatment possibilities. We know that the blockade of HER2 is the backbone but what will be the optimal partner? Having this clear data from the real world, data from different phase II trials, we probably don’t need huge trials, we need just clear signals that it works, it’s safe and we can use it in clinics.  But back to the combination of targeted treatment, we have seen also some interesting data out of the new immune approach but also all these ones with antiangiogenic drugs. Chris, have you seen some interesting data for chemotherapy combinations?

CT: Yes. You mentioned the antiangiogenics, that’s in the UK an area where we’re not accessing bevacizumab. We were using it in patients with triple negative disease but that’s no longer an option for us so it was interesting to see another abstract from Italy looking this time at second line eribulin. These were patients who had had a taxane plus bevacizumab and then have progressed and received eribulin in the second line setting and this was given alongside bevacizumab. So I was interested to see that in Italy they’re still able to use bevacizumab in the first line setting and clearly there was activity, it was tolerated in the second line. What the bevacizumab added to eribulin, in the context of what we know to be already an effective drug, wasn’t clear but clearly and encouragingly it shows that in that particular group of patients, and maybe this was of more interest to me than the bevacizumab side, was that they were identifying as the second line agent after the paclitaxel is to go to eribulin which, of course, is not the case in the US as I understand it but in Europe we do have regulatory approval for second line use. For many of us that would be our preferred setting to be using the more effective agents sooner. So it was interesting and encouraging to see eribulin used in that setting.

JG: Yes, and from a biological point of view what is always interesting with the eribulin data of patients treated just after taxane progression is that we see a clear signal of efficacy even if they are from the same family of chemotherapy drugs. It seems that the cross-resistance is not very important so you can achieve disease control with eribulin even if you have progressed after taxane which is a very, very important and informative message that we have learned from this kind of data.

RM: How do you see the toxicity profile in that setting because in the US, as you mentioned, we’re not using it second line. It tends to be used later because of the approval but in terms of sequencing a taxane and then eribulin have you had any major issues with neuropathy?

JG: Usually not. The point is that if the patient had neuropathy at the time you discuss about initiation of eribulin you will take it into account for the global strategy. But usually the patients are treated with taxanes for several administrations, close to 4.5-6 months, then you have, again if you have access to bevacizumab, a kind of maintenance treatment with just bevacizumab, for example, and then you can reintroduce at the progression eribulin. So usually there is one proportion of patients that might have some residual neuropathy but in general…

RM: It’s not dose limiting.

JG: Yes, correct.

CT: It was one of the helpful features of the trials that patients were allowed into the trials with residual neuropathy because many of them would have been… well, all of them had received a taxane so those patients were allowed in. It was clear if you looked at the patients who got… most patients didn’t get severe neuropathy with eribulin but the minority who did get the more severe neuropathy, those weren’t exclusively the patients who had gone in with the underlying neuropathy. So the presence of neuropathy isn’t a reason not to use eribulin but you clearly need to make the appropriate dose modifications if you do that. And coming back to your point about the use of the taxane followed by eribulin, it does give legs to the fact that the interaction between eribulin and the microtubules is different compared to other agents. The so-called alternative modes of action, these non-cytotoxic, non-antiproliferative effects that eribulin appears to have, potentially affecting the vascularisation of the tumour, potentially affecting migration and invasiveness and the so-called epithelial mesenchymal transition. So it maybe that there is more to eribulin than simply the anti-proliferative effects and this may be why, as you say, perhaps a little counterintuitively, in patients who have progressed on the taxane we still see activity with eribulin.

JG: Yes, and even across the tumour types we have some data with sarcomas showing that even if sometimes you think that the clinical benefit at the beginning seems important but not enormous, you have this overall survival benefit at the end. That means that probably, I totally agree with you, the overall mechanisms of action are at least as important as just the cytotoxic effect of the chemotherapy drug. That might explain the activity in clinics and maybe, back to your question about the second or the third line strategy utilisation of this kind of drug, I will say that in my personal way of treating the patients if I’m convinced that one drug is effective, and it’s potentially more effective than the other one, I don’t want to take the risk not to use it clearly up front. Because the more you wait, the more you take the risk not to expose the patient to this kind of very active drug at one moment.

RM: We tend not to save our best therapies.

JG: That’s the problem, sometimes we have some concern about, as you mentioned, quality of life, safety. You have to remember that all the trials exploring the quality of life impact are pretty good and do not show any negative effect of eribulin compared to the overall chemotherapy regimen when this was avoided. But on the other point, at the end of the day the patient wants to have effective drugs and live longer. I think that this is probably one of the main drivers we have in general regarding the treatment strategy we will apply.

CT: Certainly whereas ten or fifteen years ago I was very much in the camp in treating patients with metastatic breast cancer with a relatively short course of more intensive chemotherapy and then a break off treatment, now I’m much happier with prolonged periods of time, treatment to progression, because with agents like eribulin, capecitabine, if you tailor the dose to that individual patient they basically can get on with their everyday life to a very large extent. So that paradigm has shifted, for me, with eribulin, capecitabine compared to anthracyclines and docetaxel ten or fifteen years ago.

JG: So, I agree, we have seen that even if we have made a lot of progress regarding the knowledge of the biology of the cancers, the possibility of using some particular targeted treatment in not only hormone receptor positive or HER2 positive disease but even in some triple negative disease in the future, we have clear data showing some very interesting results. But the chemotherapy will be still here and we have to be very clear and aware about the profile of important safety and efficacy of this treatment and how to use it in everyday practice, particularly because the patients that are enrolled in clinical trials are not usually the phenotype of the patient that we treat in everyday practice. Eribulin gives interesting results, every year with clinical practice, with real world data, showing that what we have seen in clinical trials exactly on the same level regarding the efficacy and the safety that we may observe also in our everyday practice. So I’d like to thank my colleagues for this exchange and I hope that you will have enjoyed and learned some interesting things regarding this video session. Thank you.