We are going to talk about the management of patients who are progressing on cyclin dependent kinase inhibitors. Given the fact now that this is a commonly used regimen in the first and second line setting yet the introduction of these drugs has been so rapid, all within the last four years we really don’t know what the natural history is of patients who progress on these drugs and what the optimal treatment strategies are.

What are some of the main point of discussion on the use of CDK inhibitors?

There are two key issues to consider. One is can we assume that the second and third line therapies that were tested in the pre-cyclin dependent kinase era still will hold in patients who progress on a CDK inhibitor? The second question which is a derivative of this first one is what is the biology of patients who progress on CDK inhibitors because we know precious little about that.

So let me start with the biological piece first since we generally assume that biology is critical in terms of what drugs we use. We are learning more about the fundamental basis of cancer in general and particularly resistance to both hormonal therapy and CDK inhibitors but we’re just scratching the surface. Since patients are being treated with either aromatase inhibitor or fulvestrant along with the CDK inhibitor, when they progress the mechanisms of resistance could be diverse. They could be more general hormonal therapy resistance mechanisms or they could be specific to CDK inhibitors. So much of our knowledge base now comes from laboratory experiments in cells that are exposed to either endocrine therapies or CDK inhibitors and then, of course, from studying the tissues of patients. More commonly now we can learn a lot from blood samples, we can look at the tumour genomics.

What we know so far is that in endocrine therapy resistance one of the prime mechanisms is activation of growth factor pathways. Growth factor receptor pathways are highly convoluted and interactive with a lot of intersecting pathways so when you say growth factor pathways it actually could mean many potential targets. The one that has been clinically validated and is approved for therapy is interruption of the mTOR node of that pathway which is a convergence area of growth factor signalling. That was the first class of drug to be approved back in 2012, the mTOR inhibitor everolimus which we now use, and there are emerging new drugs, particularly the PI3 kinase inhibitors. Very recently data from the SOLAR-1 trial which was testing alpelisib, which is an alpha selective PI3 kinase inhibitor, did in fact show that this significantly prolonged progression free survival when added to fulvestrant compared to placebo. This was specifically in patients who are known to have activating mutations in the alpha subunit of a PI3 kinase, specifically in the PIK3CA gene. These patients derived a significant prolongation of PFS and most likely this drug is going to be approved in the US and eventually in other parts of the world, although this is still under review.

So the question is what is the best therapeutic strategy? Should one use, for example, stay on endocrine therapy and switch the partner to everolimus where we do have data? And will that apply specifically in patients who have progressed on CDK, might the biology be different? Again we simply don’t know that but we make that assumption and it is one of the commonly used drugs we use in the next line setting.

The other common approach we use, of course, is chemotherapy and of the chemotherapy drugs capecitabine is probably the most commonly used. We do have a little bit of data that there is activity with capecitabine after progression on CDK inhibitors, as reported, for example from the PALOMA-3 trial of fulvestrant and palbociclib. But, again, we do not have large scale data on that. So nevertheless that remains an option. Then, of course, the other appealing option is going to be the new class of PI3 kinase inhibitors.

Now, in the SOLAR-1 trial they did enrol a small number of patients who happened to have progressed on a CDK inhibitor but as the trial was running the CDK inhibitors were just been uptaken so only a small number of these patients exist. But the trend there, and it’s too small for statistical analysis, does show that these patients do respond. They may have a slightly shorter overall progression free survival than patients who may not have been exposed to CDK inhibitors but we need to await more data. But I would say for now as a practical standpoint, since we do need to manage these patients, I would say that we would use the same algorithms, either everolimus potentially moving on to chemotherapy if the response to endocrine therapy was extremely short because we know that these patients generally don’t have long responses to endocrine based therapies, or if the PI3 kinase inhibitors are approved using those as we build up our knowledge.

Just to finish I would say that the biology of what makes patients resistant to CDK inhibitors specifically is very interesting. We are starting to get some insights into that from predictive biomarkers that were done particularly in the PALOMA-3 study but this was also done in the MONALEESA-7 study and in the MONALEESA-2 study so we will be having more data come out.  One of the early hints that was presented at AACR by the group from the Royal Marsden is that overexpression of cyclin E, which is a bypass pathway through CDK2, is potentially a marker of resistance to CDK inhibitors and may eventually allow us to choose patients that maybe shouldn’t be treated with CDK4/6 inhibitors or for which we need to develop other therapies.

But there are other mutations that are being seen in these trials. We know that mutations in the ESR seem to predict resistance, more to endocrine therapy, particularly to aromatase inhibitors but possibly also to fulvestrant. We also see activation of other growth factor receptor pathways such as the fibroblast growth factor receptor pathways, FGFR1, 2, 3 and 4, although again this may not be specific to CDK inhibitors, it may be to endocrine therapy since patients are receiving both. The ones that seem to be unique, though, to CDK4/6 do appear, as I mentioned, to be cyclin E and then also loss of the retinoblastoma gene which is essential for the proper function of CDK4/6 inhibitors since it’s a substrate for CDK4/6. Loss of that really takes away your ability to control that entire pathway. It doesn’t seem to be a frequent aberration but it has been shown now in several studies that it does emerge upon the development of resistance to CDK inhibitors.

So this is why it’s essential for modern day studies to acquire both tissue and serial blood samples from patients so that we can learn more about the so-called evolutionary genomics of patients becoming resistant, to learn about these mechanisms. Many of the mechanisms may be non-genomic, they may involve epigenetic changes, histone modifications, chromatin remodelling and we need to learn much more about those pathways as well through multi-omic studies. So the field is moving rapidly thanks to the inclusion of these biomarker studies and we need to really continue that pattern of discovery as we test new drugs.