Actually today I am going to present during the Presidential Symposium later this afternoon the results of the MONARCH 3 trial that is a phase III randomised study comparing single agent endocrine therapy versus combination of endocrine therapy plus a CDK4/6 inhibitor, abemaciclib, as an initial therapy for ER positive HER2 negative advanced breast cancer patients. The study is going to be reported with a median follow-up of eighteen months and these are the results of the interim analysis that will be presented today.
Can we have just a quick breakdown of the patients involved in this trial?
The patients who were involved in the study were menopausal patients with ER positive HER2 negative advanced breast cancer. They did not receive any prior systemic therapy for metastatic disease but they could have received adjuvant or neoadjuvant endocrine therapy assuming that the time elapsing between the end of adjuvant endocrine therapy and the start of the trial treatment was at least one year.
How was the assignment to each arm of the trial?
Patients were randomised in two arms, in one of the two arms, either the experimental arm – a combination of abemaciclib plus a non-steroidal aromatase inhibitor given at standard doses – or the control arm, placebo plus a non-steroidal AI at standard doses. We recruited 493 patients into the study and the primary trial endpoint was a comparison in terms of progression free survival between the two different treatment groups.
And was the endpoint met?
The endpoint was met because actually we presented the data supporting clearly the superiority of the combination therapy. We had a 46% reduction in the risk of disease progression when patients received the combination therapy. This difference is clinically relevant and is also statistically significant.
Do we think that this PFS improvement might translate to OS in the near future?
We don’t know if this is going to translate into overall survival improvement. This is a big question that has been raised in all these types of trials and I would say more generally in all the metastatic breast cancer trials. It’s important to remember that the vast majority of the metastatic breast cancer trials, including the CDK4/6 inhibitor trials, have not been powered to detect survival improvements. So we will see, we need to wait at least another four to six years before we will have the survival analysis but personally I do not think that this is really the most relevant point to judge on the activity of these treatments, not because the survival is not an important endpoint, of course it is. The problem is that survival is not a sensitive endpoint so you may have a trial where you do not show a survival improvement but this does not mean that the drug is not an active drug. It’s difficult to demonstrate a survival improvement in the context of a first line therapy metastatic breast cancer trial.
Speaking of activity, abemaciclib came with some toxicity from this trial.
Yes, adding abemaciclib to endocrine therapy definitely also is associated with some toxicity. You increase the risk of neutropenia. It’s not a severe neutropenia in the sense that actually only one patient of our trial had a neutropenic fever during treatment with abemaciclib. It corresponds to 0.3% of the trial population treated with abemaciclib. The other problem is diarrhoea; you may observe diarrhoea in the vast majority of patients, almost 85% of patients had some diarrhoea. Severe diarrhoea, grade 3, is less than 10%, 9.5%, grade 2 diarrhoea is 27%. The good point is that diarrhoea can be managed because if the patient is properly informed and the physician starts treatment with loperamide quickly you can manage diarrhoea in such a case, the duration of this problem is going to be in the range of a few days and in most of the cases you do not require any dose adjustment or any treatment interruption.
How does that compare to other CDK4/6 inhibitors as a class toxicity?
It’s very difficult to make cross comparisons between different trials. It’s quite clear that all the three are active, the hazard ratio of the three trials is nearly the same. They clearly reduce substantially the risk of disease progression. Now the big challenge is going to be mainly when we should start with up-front therapy, with CDK4/6 plus endocrine therapy, or when we could start with endocrine therapy alone and then keep the CDK4/6 inhibitor as a second line therapy. In this record, our study, for the first time it’s suggesting that perhaps patients who have a good prognosis such as those with bone metastases only or those patients who relapse many years after the end of adjuvant endocrine therapy, in these patients it may be possible that endocrine therapy alone can still be considered an active treatment option. In such a case we may suggest that the CDK4/6 inhibitor could be considered for the second line therapy after disease progression to endocrine therapy alone.
There’s a molecular comparison, you mentioned the potency of abemaciclib earlier.
Yes, when you compare the three CDK4/6 inhibitors in terms of potency in targeting CDK4 and 6 it’s quite clear that abemaciclib is fourteen times more potent on targeting CDK4 than CDK6. This has implications in terms of the safety profile because neutropenia is less frequently reported with abemaciclib because of this lesser selectivity in targeting CDK6. CDK6 inhibition is associated with neutropenia; abemaciclib is targeting more CDK4 and this can explain why we have less neutropenia with abemaciclib.
Could future doses be built around tailoring either the dose of abemaciclib up or down, depending on neutropenia and diarrhoea, or maybe even supplementing it with one of the other CDK4/6 inhibitors depending on the toxicity profile the patient has?
Yes, of course. The difference in safety profiles may be potentially a clinical information for the physician and for the patient so the selection of one of the different CDK4/6 inhibitors can be done also based on these types of differences in safety profile. Certainly it’s not the only information that you can use but, for instance, if I would have a patient where I know that there is difficulty in checking so regularly the blood counts probably I would not go for a CDK4/6 inhibitor that is inducing neutropenia very frequently. Conversely, in a patient where I know that there is some sensitivity in terms of gastrointestinal problems I would probably not go with abemaciclib I would probably select the other CDK4/6 inhibitors.