Professor Chris Twelves – Leeds University, Leeds, UK
Dr Giampaolo Bianchini – San Raffaele Hospital, Milan, Italy
CT: Hello, I’m Chris Twelves, I’m Professor of Clinical Cancer Pharmacology and Oncology in Leeds in the UK and I’m here at the San Antonio Breast Cancer Symposium in 2018.
GB: Hi, I’m Giampaolo Bianchini, I work in the San Raffaele Hospital, I work in the breast cancer unit and I’m head of the clinical and translational immunotherapy research.
CT: As ever, there’s lots of interesting research being reported in San Antonio but what I’d like to focus on in the next few minutes is work around eribulin which is a compound that I’ve been particularly closely involved with. One of the areas that we’ve been interested in with eribulin is that in addition to its anti-proliferative cytotoxic activity we’ve seen indications over recent years that it has other effects affecting the remodelling of the tumour vasculature, also affecting EMT, epithelial mesenchymal transition, and finally effects on migration and metastasis. There’s some work here that we’ve seen at San Antonio that is interesting and will enlighten us in these areas.
GB: Yes, one of the presentations described some potential explanation of how eribulin is able to modulate within the tumour this mesenchymal pheontype to revert to the epithelial. I would interpret the data on a single experiment provocative but very highly recapitulating what happened in the heterogeneous phenotype of the patient. But I found this very interesting because it supports all the data that we have that are very strong and robust about not only the activity and the consequence of this potential reversion and making chemo work better after eribulin. What do you think about this?
CT: If we step back, the original interest here was when we saw that there was greater impact on overall survival than on progression free survival with eribulin in breast cancer and in sarcoma. So we’ve been trying to understand that a little better. As you say, we have reported here a single cell line, a triple negative cell line, exposed to eribulin and showing increased epithelial markers which may indicate, indeed, that there is an effect on EMT. What was interesting is that the same effect wasn’t seen with other microtubule inhibitors so this isn’t a class effect. It appears to be specific to a greater or lesser extent to eribulin. As you say, it’s a single observation but it does map on quite nicely to work that was published earlier this year looking in vivo in a similar way in animals exposed to microtubule inhibitors and looking at the changes in the epithelial and the mesenchymal markers. So in that in vivo study there was an increase in e cadherin, the epithelial marker, and a decrease in ZEB-3, I think it was, one of the mesenchymal markers in the animals treated with eribulin and the reverse was seen with paclitaxel. So they’re individual pieces of the jigsaw but I agree that it’s interesting and I find it quite heartening that after treating chemotherapy as being rather a blunt instrument for many years we see people now trying to understand how chemotherapy really works and look into this in a more sophisticated way.
GB: I completely agree with you. I think that the overall picture about the understanding, about the peculiar mechanism of action of eribulin adds on every year and this is another piece of information about the specific mechanism of action. It is very likely that this could be different cell by cell but the overall mechanism has been very well described. On this topic I would like you to comment with me another presentation here of the combination of eribulin with trastuzumab that is not actually the classical indication of the drug but the data are really provocative for strong activity. The real world data that was presented here, we have more than 60% response rate, extremely high, that are very similar to the data that was presented in the phase II trial. So what do you think about the use of eribulin outside the standard context, specifically in combination with a HER2 targeted agent in HER2 positive disease?
CT: It’s not an option for me in the UK because of the NHS reimbursement, we don’t have that option.
GB: In Italy we also have this problem.
CT: But there was no good reason why eribulin shouldn’t be combined with trastuzumab. As you say, there was an original phase II study headed by Linda Vahdat some years ago which showed a response rate, I think first line, of around 70%. More recently there was a Japanese small phase II study, again, which showed activity. What we haven’t seen is a large phase III trial and I suppose this real world population, although it’s not a clinical trial population, gives us a better indication as to whether those benefits in the earlier clinical trials can reasonably be expected in a wider population if you have access to that combination. Certainly, as you say, there is really quite striking concordance with response rates of 55-70% in each of these clinical trial and real world settings. So for individuals who have got access to trastuzumab in combination with eribulin, those are very reassuring data.
GB: Yes, of course we have to state to what is approved country by country and in some countries there are less restrictions in what kind of chemotherapy agent can be combined with trastuzumab, the HER2 targeting agent. But I consider this combination, as you mentioned, very, very promising because, again, we know that this is a peculiar drug and some of the activity that reverses the immune suppression can be significant also in the context of HER2. To come off this point, the third presentation that I would like to comment with you is a presentation that described a combination of eribulin with a new agent but in general I would like to make a comment on the work that is now in place to describe the combination of eribulin with other agents. For instance the combination with immune checkpoint, epithelial to mesenchymal transition is described to be a mechanism of immune escape and it is linked to many factors. TGF-β, that is another important component that eribulin has been described to decrease, is related to immune escape. So, for instance, this is very likely why the combination with pembrolizumab in the phase II trial presented last year in San Antonio in an updated follow-up showed very interesting results. What do you think about the data that also has been presented here in San Antonio about the combination of eribulin after the trials also combined paclitaxel with a new agent that specifically targets the ability of the cell to circulate across the endothelial targeting Tie2 and the vessels that regulate the dissemination? But on the general aspect, to come back to what we were discussing before, also I would like you to comment on the potential use of the specific biological effect of eribulin that reducing the epithelial to mesenchymal phenotype and TGF-β reduces the immune escape and general mechanism and the good data on the combination of pembrolizumab that has been presented last year in San Antonio with an adaptive follow-up and that looks very promising. So can you just comment about the possibility to use this particular drug in several combinations, really taking the best advantage for the unique mechanism of action?
CT: As you’ll be familiar, most of us use sequential monotherapies these days in the treatment of metastatic breast cancer but eribulin may be a particularly interesting combination partner because of these additional biological modes of action. We’ve discussed already the combination with trastuzumab, we did a study combining with capecitabine some years ago, it was only a phase II study but it showed response rates, progression free survival that were equivalent to the combination of docetaxel with capecitabine. So that is potentially an interesting combination. With such a focus on immuno-oncology at the moment the preliminary data, as you say, with eribulin with pembrolizumab really do look very encouraging. There is a rationale for combining eribulin with pembrolizumab because of its effect on the tumour microenvironment. The other study that you mentioned combining chemotherapy with this agent, rebastinib I think it is, which interacts with the Tie2 kinase and is intended to reduce intravasation of tumour cells, reduce metastasis and invasion, is again an interesting prospect, not least because eribulin does have this effect itself in addition to the anti-proliferative effect and anti-metastatic effect in preclinical models. So the clinical trial which is a phase I trial is still at a very preliminary stage, this is a very early report, but the drug rebastinib can be combined with either paclitaxel or with eribulin. There’s evidence of activity, so there’s tumour shrinkage seen and also there has been a reduction in circulating tumour cells and an increase in agiopoietin1 or 2, which suggests that this is a PD marker to suggest that there is a biological effect in addition to the anti-proliferative effect. So there are a number of interesting areas to explore for the future. I think we can be more flexible in how we look at chemotherapy and come up with more smart ways of using what are good drugs. Thank you. I hope you’ve found some of these discussions interesting, they’re only a part of what is a very big meeting full of lots of interesting information across the whole range of treatments of breast cancer and thank you again for your attention.
GB: Thank you very much.