The MONARCH series of trials are testing a cyclin dependent kinase 4/6 inhibitor called abemaciclib in the treatment of hormone receptor positive metastatic or advanced breast cancer. The MONARCH 1 trial, which was the first trial and the one that I’m discussing, looked at single agent abemaciclib in the treatment of hormone receptor positive metastatic breast cancer. Abemaciclib and its two other cousins are inhibitors of this cyclin dependent kinase 4/6 which are enzymes that are important in the cell cycle in entry into S phase where cells are dividing. These enzymes, if you block their activity you actually can block entry into S phase or block dividing cells by allowing a tumour suppressor to suppress cell cycle.
It’s actually very interesting because the oestrogen receptor plays a big role in cell cycling and so fairly elegant preclinical work showed the importance of these cyclin dependent kinases, 4 and 6 in particular, on entry into the cell cycle through their interactions with cyclin D1 and also showed that this was particularly important in hormone receptor positive or luminal-like disease. Interestingly, it also seems to be important in HER2 positive disease and that’s another area of ongoing study.

Abemaciclib in particular is a little different from its cousins, palbociclib and ribociclib, now both approved in the treatment of hormone receptor positive metastatic breast cancer with hormone therapy, in that it is a much more potent inhibitor, fourteen-fold, of CDK4 rather than CDK6. That may be important in terms of both its mechanism of action, its activity and its toxicities.

What are your findings so far?

MONARCH 1, the study itself was based on very encouraging data from a phase I dose finding study. In that phase I dose finding study abemaciclib demonstrated impressive single agent activity. Some of the patients in that phase I study continued on their hormone therapy and in those patients the response rate was 30%. It was a little bit lower but still in the mid-20s in patients who didn’t take hormone therapy and took only abemaciclib. This is strikingly different from the other two CDK4/6 inhibitors where the single agent response rates were under 10%.

So based on that encouraging activity MONARCH 1 was designed as a single agent trial to see what abemaciclib could do in patients who were relatively heavily pre-treated. They had to have received at least one line of chemotherapy and they could have received up to two and one of those lines had to include a taxane. They could have received any number of hormonal therapies but they could not have received a prior CDK 4/6 inhibitor. We enrolled in that trial 132 women who had received one to two, and one patient received three, lines of prior chemotherapy and these patients had a lot of cancer, they had big disease burden so most of the patients had visceral disease at the time that they went on abemaciclib. Their other choices for treatment at that time would have been other chemotherapy regimens. It was particularly interesting because of what the choices are for these women and providing differential choices. This is an oral therapy and it doesn’t require IV administration.

Abemaciclib also has some other differences from the other CDK 4/6 inhibitors in that it’s dosed continuously, you take it every day. Palbociclib and ribociclib are given three weeks on, one week off, repeated every month because of the bone marrow suppression resulting in neutropenia. Abemaciclib doesn’t cause as much neutropenia; actually even though it’s dosed continuously the rate of neutropenia grade 3 or greater is less than half that seen with the other two agents. But differentially it causes diarrhoea and there are cases of grade 3 diarrhoea. If you give anti-diarrhoeal therapies you can control this very well so as we learned more and more about the drug, using the drug treating patients, we were able to give anti-diarrhoeal therapy at the first sign of diarrhoea, we were able to control it and patients really only had grade 1 diarrhoea after that time.

So the study itself that enrolled these 132 women showed an overall response rate of 19.7%, close to 20%, a little bit lower than what we saw in the phase I trial but a much larger number of patients. The response rate, however, was very durable. Progression free survival was 6 months, that’s also strikingly different from what we see in an overall population in this later line setting treated with chemotherapy – there’s more toxicity and progression free survival is often less than 6 months. So we’re very pleased with that data. There was the grade 3 diarrhoea although, as I mentioned, fairly easy to control and didn’t result in patients going off study which was encouraging. Then for the purpose of this presentation we were also able to look at overall survival which was about 22 months in this patient population. To me that’s also very encouraging because if you look at patients who were receiving their first line of chemotherapy in a study that I did called CALGB40502, published in the JCO a couple of years ago, the median survival for patients was a little over two years who were getting first line chemotherapy. These patients already had received first line chemotherapy and yet their survival was close to what we saw in that setting. So that was encouraging as well, having more treatment options plays a really big role for these patients and hopefully in the long term we’ll be improving survival as well as improving reasonably well tolerated treatments.

The other thing that we’re able to show in this presentation was a little bit more about one of the non-important toxicities that we noticed with abemaciclib. We noticed this early on in treating patients, that it looked like their creatinine was going up but their renal function, their kidney function, was fine. It turns out actually that abemaciclib can block tubular secretion of creatinine through the kidneys and you actually can do alternative testing to show that the renal function is completely normal and that when you clear the abemaciclib the creatinine level returns to normal. Creatinine is not that high, it just goes up a little bit just because you’re blocking clearance and it’s meaningless on a clinical basis. I see this clinically to a lesser degree with the other CDK 4/6 inhibitors and some other oral medications that we use like the tyrosine kinase inhibitors but it was particularly interesting and we were able to study it in an interesting way in patients who were receiving abemaciclib.

What is your take home message?

To me the quick take home message is that this CDK 4/6 inhibitor is a little different from the other two. It stands on its own, it has a differential toxicity that we can manage now, it’s very well tolerated overall and it has single agent activity which suggests to me that this agent may even demonstrate further activity in combination with hormone therapy. So that’s very exciting.

So two main take home messages: one is that we hope to have approval of abemaciclib some time in the not too distant future and that that approval will give us another treatment option for our patients. We don’t yet know what the activity of abemaciclib is after progression on a CDK 4/6 inhibitor but I think it will be very interesting to see that.

Second, we’re looking with bated breath for the results of MONARCH 2 which is looking at abemaciclib with fulvestrant versus fulvestrant alone. Those data we hope to see presented at ASCO this year. There has already been a press release showing that they achieved their progression free survival endpoint.