Prof Nadia Harbeck – University of Munich, Munich, Germany
Dr Mark Beresford – RUH Bath, Bath, UK
Dr Shom Goel – Dana-Farber Cancer Institute, Boston, USA
Dr Sara Hurvitz – Ronald Reagan UCLA Medical Center, Los Angeles, USA

NH: Hi, my name is Nadia Harbeck, I head the Breast Centre at the University of Munich in Germany. We are meeting here at the San Antonio Breast Cancer Conference to discuss on one of the major improvements in oncological care of breast cancer patients which is the CDK4/6 inhibitors. I’m joined here by three distinguished colleagues, one from Europe, two from the US. Why don’t you introduce yourselves?

MB: Hi, I’m Mark Beresford, I’m an oncologist from the UK, from Bath and I’m co-Chair of the UK Breast Cancer Group.

SH: Hi, I’m Sara Hurvitz and I’m from the University of California, Los Angeles. I’m a breast oncologist.

SG: I’m Shom Goel, I’m a physician scientist at the Dana-Farber Cancer Institute in Boston.

NH: So let’s start talking about what we saw in 2017 because I think we’ve seen quite a lot of data and all of us were involved in one trial or the other. Mark, why don’t you start? What were the most impressive data for you?

MB: It’s really a follow-up from some of the data that we saw the previous year, really, in terms of first line metastatic usage. So it’s looking at the use of the CDK4/6 inhibitors in patients who haven’t previously been exposed to endocrine treatment and we’re seeing some more updated analysis of those and it’s really pretty comparable between the drugs in terms of the benefits; we’re looking at 8-10 months of progression free survival benefit first line. So that has really been solidified this year and it’s impacted on what we can do in practice in terms of availability of the drugs, certainly in the UK, and it’s going to really change how we treat people in the first line setting.

NH: Are there any trial data you particularly enjoyed seeing or do you think they all showed a similar picture?

MB: For me, between the drugs there’s nothing to choose at the moment which is kind of reassuring. I think that has been reflected on the decisions that have been made in terms of commissioning of the drugs so far.

NH: Sara, you’ve been involved not just in the metastatic breast cancer trials but also using some of these drugs earlier in the setting, what’s your take away?

SH: Yes, so I was involved in the neoMONARCH study which looked at neoadjuvant use of abemaciclib. In this study we had three arms: the first two weeks patients received either abemaciclib or anastrozole or the combination and then after two weeks, after having a second biopsy, received both drugs until the time of surgery. The final data being presented, the final clinical data, we are showing that the Ki-67 reduction is substantial in over 90% of patients who receive abemaciclib-based therapy in the first two weeks compared to anastrozole where it’s just significantly lower. The complete cell cycle arrest is also quite low and now we’re seeing data emerge from prospectively run studies like POETIC that show a Ki-67 change from baseline to two weeks does appear to be predictive of long-term event free survival or disease free survival. So we might see now more of these exciting agents be evaluated in the neoadjuvant setting which allows us to run smaller clinical trials, test hypotheses, get signal finding studies done with fewer patients in a shorter period of time. So that’s an exciting thing, not just for CDK4/6 inhibitors but for new therapies that are in development. Then there was the pre-menopausal data that we need to discuss because this is a big splash. Nadia, you were a part of that study.

NH: Yes, it was a great pleasure to be part of the steering committee and also actively recruit patients. The MONALEESA-7 study is still so far the largest study in pre-menopausal patients. We’ve seen some data from the PALOMA-3 study which had about 20% pre-menopausal and MONALEESA-7 now in the early phase, the first line setting, also recruited these pre-menopausal patients. Quite a substantial number were actually younger than 40 and even younger than 35 so there will be a lot of science. We can still dig in with regard to tolerability and also aggressiveness of the cancers but the major findings were that there was a substantial prolongation in progression free survival with a hazard ratio similar, if not even a little bit lower, than we saw in the post-menopausal women. So I don’t know what you think of the data but I thought it was great data. If I recall my own patients, they did so extremely well and a lot of physicians have the feeling that in younger patients you need to resort to chemotherapy earlier; I cannot confirm this from this trial.

SH: I agree, I thought it was phenomenal data. We haven’t seen such a large study in over 15 years that has just focussed on pre-menopausal, younger women. What I also thought was interesting is that they used both tamoxifen or an aromatase inhibitor so they didn’t require that patients receive AI and the outcomes look very similar for the two groups. All patients, of course, got the LHRH analogue.

NH: I think we will still need some time to digest that data and wait for the full publication. Then I think this will definitely change the landscape on how we treat these young women with metastatic hormone receptor positive, HER2 negative breast cancer. But we have one colleague here who not just treats patients clinically but also knows a lot about the translational aspects because you do a lot of translational work. Do you have an idea, are these three CDK4/6 inhibitors actually different from each other? What does the preclinical data show us?

SG: Thank you, Nadia. That’s a fascinating question. Firstly, I’d just agree with everything that Mark and Sara have said, this is a very exciting time to be working in this field. For those of us who are involved with this class of agents it’s impressive how rapidly new data and positive data just keeps coming at us. I agree, now that we have the drugs available, at least in the US, all three CDK4/6 inhibitors are approved, the next question that we start to ask ourselves is how can we best use these drugs. One question that comes to mind is are they the same?  I would agree with Mark’s point that, at present, based on the data that we have from the first line randomised studies the drugs seem to be equally effective, at least in the setting of ER positive breast cancer when given in conjunction with hormonal therapy. There are some important differences, however. It’s notable that abemaciclib has a different chemical structure to that of palbociclib and ribociclib, those two are actually quite similar. That seems to be accompanied by some unique properties that we see with abemaciclib: it has a somewhat different toxicity profile, we tend to see less neutropenia with that drug but more diarrhoea. Interestingly, and I think at the moment something that still remains unexplained, it does have a higher response rate when used as a monotherapy. In fact, last year we heard the results of the so-called MONARCH-1 study which in the US had actually led to the approval of abemaciclib being used as a single agent as well. Now, at a preclinical level, you might ask why is that, what is it about abemaciclib that’s different? Does it inhibit other things than CDK4 and CDK6? There’s a lot of debate in the field right now on that question. At present I don’t think we know the answer, especially when it comes to the effects of these drugs in patients.

NH: So you say there may be some clinical differences in the long-run but so far the side effects differ a little but you couldn’t say that there is one drug that’s more effective than the other?

SG: That’s right. At this meeting we learned some very interesting information. There was a very nice study which took my interest presented by some scientists at the Harvard Medical School who really did a very comprehensive study comparing the three different CDK4/6 inhibitors in the lab. This is not in patients, this is in the lab. They did find some specific qualities about abemaciclib, that at times it was actually able to kill breast cancer cells in a dish, which the other two drugs were not. How that manifests itself in our patients, I’d agree with you, maybe we’ll work that out with a lot more time and study.

NH: We all need more experience. When I look at the situation in Germany we have abemaciclib not approved, we have ribociclib and palbociclib approved, palbociclib obviously we have longer experience, it has quite a broad European approval, also with regard to the combination partner. The questions my colleagues always ask – when to use it. Do we use these substances first line because we do the best things first, or do we use them second line because we want to see how endocrine monotherapy works? So that’s a big debate. Mark, how is it in the UK?

MB: Yes, that’s the important question there. We’ve very just recently in the UK had approved ribociclib and palbociclib first line, which is great; we’ve got the option for both. The real question now is is there anybody who doesn’t get these drugs? Rather than looking at who should, it’s who shouldn’t. It’s hard to find from the trials a group that doesn’t benefit. We’ve said that the pre-menopausal benefit, post-menopausal, elderly, node positive, all different grades of disease and all kinds of things and not really dependent on the site of metastases, whether it’s bone or visceral. So it’s hard to find a group that don’t but it does feel a little bit like overtreatment in a certain section of the population – some elderly women who may do very well just on hormone treatment alone and then we’re confining them to the hospital every month with lots of blood tests and follow-up appointments, potential toxicities. So there is probably still a group who wouldn’t need to start with these drugs. We do know they work well in the second line setting and we have data there to show that with fulvestrant it doubles the progression free survival at that point. So you could argue that you’re getting your benefit later on, whether the two things are quite similar is difficult to know. But we don’t yet have approval in the second line so, certainly in the UK, we’re in the position where if we don’t use it first line we can’t use it which is a shame because there may be a group of patients who we could treat with hormone therapy first and then add in later on.

SH: I think there’s an important point to be made as well. I agree that there are some patients, bone only metastases, very long relapse free interval, who may not benefit. But looking on the other hand I see a lot of patients who come to me from the community because their physicians have recommended first line chemotherapy with a taxane because they have liver metastases or lung metastases and are mildly symptomatic. I would argue we don’t have time to relapse data yet from these studies but you see very early responses with the use of CDK4/6 inhibitor therapy. We’re looking at response rates in excess of 40%, 50%, even 60% in patients with visceral metastases. So my argument would be we should not be knee-jerking to chemotherapy, which I know we have guidelines telling us to treat with hormonally directed therapy, but a lot of oncologists over-diagnose visceral crisis and run to chemotherapy first. I really think we should be using this doublet type of therapy in those patients.

SG: I would tend to agree and we saw data earlier this year from the PALOMA-1 study, which was a randomised phase II study using palbociclib, that in fact the use of a CDK4/6 inhibitor can delay the time until patients need to begin chemotherapy. We should not underestimate how important that is to our patients. If I could, just for a moment, go into Mark’s point about do all patients need these drugs. At the moment there’s still a big question mark there, as Mark said. But it’s worth noting that there are a lot of efforts going on at the moment to try and answer this question. So here at this meeting we saw a combined analysis of two of the abemaciclib studies, the MONARCH-2 study, which was the second line study, and the MONARCH-3, study which was the first line study, trying to address the question are there specific clinical subgroups of patients that derive particular benefit from the use of a CDK4/6 inhibitor. There was a suggestion, and it’s only a suggestion, that certain clinical subgroups may derive more or less benefit from abemaciclib. In addition, some of the more translational studies being presented at this meeting are starting to look at whether changes in the tumour tissue itself, whether it’s the activity of different genes or the presence of different mutations, may predict who does and who doesn’t need these drugs. We don’t have anything definitive there yet but in the next one or two years we may learn a lot more.

NH: So if I pick your translational brain for one more time, are there any biomarkers right now?

SG: You know, it’s very interesting. If you want an honest answer I don’t think we really have a good biomarker right now. Of course, the drugs are used at present to treat patients with oestrogen receptor positive, HER2 negative breast cancer so that is, in a sense, a biomarker. But beyond that I don’t think there are any molecular markers that you could use to pick who does or doesn’t need a CDK4/6 inhibitor.

NH: I want to be a bit provocative – you mentioned the pooled analysis of the MONARCH studies, I think we should be very careful with the subgroups there because they have the shortest follow-up time of all the studies. If you look at the PALOMA data, at also the MONALEESA data, some things don’t pan out the same way. In particular, the subgroups where you say, well, with a short disease free interval they may benefit more but those with a longer disease free interval may not benefit. I think this is a bit biased by the fact that the follow-up is short and the aggressive tumours have more relapses at the time. So I personally would be very careful with giving clinical subgroups and I would more agree with Mark that actually you could think of clinical subgroups but they’re not substantiated by the data at the moment. So in a country where I have the choice, unlike the UK, I would always go for the best therapy first unless I have a woman who says that they do not want to come in, which is very rare. If you explain to the patients the benefits of having this prolongation, which is substantial, in progression free survival I have yet to see the patient that says, ‘I don’t want to come in for the blood counts.’ Also we lose patients. There is very good data that with every line in the metastatic setting you lose about 10-20% of your patients because they just can’t go on, don’t want to or the disease is progressing so fast. So I’m a big believer in the first line use. I don’t know, Sara, you also have the choice in the US.

SH: Yes, I agree. The progression free survival benefits we are seeing have not been reported with endocrine therapy or chemotherapy in the front line setting. We’re at two years now and that’s historical. We don’t have survival data so that’s the other side of the coin but I would be shocked if, in the long run, we don’t see survival data. The fact that we have a little bit of competition between the agents is going to serve our patients well because there are efforts, at least in the US, to have blood draws done at home, EKGs to be done at home, so there are resources that are being allocated to our patients to make it easier for them to be on these therapies.

NH: In Germany a big decision when we went to the HDA assessment was that progression free survival may not be such a meaningful endpoint from a patient point of view. There is no improvement in quality of life, at least in the first line setting. They also thought that the side effects were quite substantial with the neutropenias. So you do a lot of management, I understand, in the first line setting, do you have any issues with the side effect management or the screening procedures recommended for these drugs?

MB: That’s a really interesting question because, as Shom said, they are subtly different in their side effects. The neutropenia is common, it’s about 60-65% of patients get neutropenia, but very rarely associated with sepsis, it’s only 1-2% of neutropenic sepsis rate so it’s not a big issue clinically. It’s something that needs watching and managing but dose adjustments and dose holidays can cope with that. With abemaciclib the concern is the diarrhoea and that may be more impactful on patients than a blood test result which they don’t see any symptoms from. Practically, of course, with ribociclib you need to do the ECG monitoring, that makes things a little bit more tricky, particularly if patients live a long way away. So there may be a little push, certainly in the UK, to use more palbociclib. It’s very dependent on what you’re used to and what you’ve been using.

NH: Sara, you’re the one among us who has the experience with women who have not had any other pre-treatment in the early stage setting with the neoMONARCH. How is the tolerability in women without any cancer pre-treatment?

SH: NeoMONARCH was designed with primary prophylaxis with Imodium. It was an overshot. We were making our patients quite constipated by using up front use of Imodium so the aggressive use of Imodium, it’s not like neratinib where we really need to be pre-treating patients. But patients do need to go home with a prescription or a bottle of Imodium with careful instructions in terms of when to call, when to take it and how to moderate. Now, the patients I had on abemaciclib in the neoMONARCH there were GI side effects – the tummy rumble, there’s a little nausea, GERD, even though the diarrhoea could be controlled. They were aware they were on this medication but it was tolerable. I didn’t have any patients come off of therapy early for this.

NH: So do you think, if you were looking at the adjuvant trials that are going on, the toxicities will be manageable?

SH: They are definitely going to be manageable. There’s a learning curve there in terms of how to best manage it.

NH: So that was already a little bit of a look into the future with the adjuvant trials because for all three CDK4/6 inhibitors there are now adjuvant trials ongoing in some parts of the world, maybe they have not started in other parts of the world. Is there any other data you would like to see in the next one or two years which you think you need in order to manage your patients better with CDK4/6 inhibitors? Why don’t we start here again?

MB: I’m keen to see how the HER2 positive patients would respond. We do have some posters at the meeting which are starting to just report on that. There’s a group with brain metastases who seemingly didn’t respond very well to the combination with abemaciclib but it’s very early data, small patient populations and we don’t know what’s happening viscerally as well. So there may be a role for these drugs in HER2 positive disease.

SH: I’m really excited to see biomarker data come out. We really need to encourage our patients who are going on these studies to sign the optional consent to have a tumour biopsy taken at the time of progression. I, like Shom, am very interested in markers of resistance, cyclin E amplification, CDK2, Phospho-Rb, loss of Rb, etc. and how that plays into the development of resistance. I’m also interested in hearing more about CDK2/4/6 inhibitors, historically they’ve been quite non-specific and toxic but there are a couple that are being developed now that might help circumvent these areas of resistance if they’re tolerable. That’s a big if.

SG: Like Mark and Sara I’m interested in seeing a lot more translational work being done over the next one or two years so we can optimise the way we use these drugs. The HER2 positive issue is important. I think it’s worth mentioning that there may actually be, we don’t know yet, even a subset of triple negative cancer patients who could derive some benefit from these drugs. Certainly laboratory studies suggest that and there are some posters at the meeting discussing ongoing trials that are designed to specifically ask that question. Then the next wave of information that I’m looking for is what else can we combine a CDK4/6 inhibitor with apart from hormonal therapy? Or are there triplets, are there additional agents we can add in addition to hormonal therapy that could improve the efficacy of these drugs. A lot of the preclinical investigators at this meeting are presenting some very encouraging preliminary data on various combinations.

NH: So there is going to be great data. Do we expect it for the next year or two? From my point of view I’m excited about the adjuvant trials. I think it’s very important that we get these drugs into the early breast cancer setting. I’m still a bit worried about that we may not define the patient population properly. We saw, like you mentioned, data from the POETIC trial seeing that the Ki-67 is actually a very good indicator of who is going to be endocrine resistant and may need an add on. We presented from our own ADAPT study data at ESMO showing that patients with a Ki-67 of 40 or more at baseline had a five year outcome despite state of the art chemotherapy that was worse than the triple negative population. So we’re underestimating the risk in the luminal B population, that’s why I’m excited about the adjuvant trials.

So I think that was a great discussion and my take-home message is that CDK4/6 inhibitors are exciting medications and we’re all glad we have them. We like to use them rather earlier than later and there was quite a good consensus about how to use them and the management across the Atlantic. If I take it, so I would like to thank you all very much for discussing this with me and thank you all for joining us and watching this podcast.