AACR 2014

"Exciting" implications of bemacyclib study in the treatment of breast cancer

Dr Amita Patnaik - South Texas Accelerated Research Therapeutics, San Antonio, USA

Can you tell us a little about the importance of cell cycle inhibition?

We’ve now determined through a number of preclinical as well as clinical studies that the cyclin dependent kinases, specifically 4 and 6, seem to have a greater importance in specific types of cancer. To give you just a few examples, breast cancer, non-small cell lung cancer and a number of others that seem to have higher levels of expression of the cyclin dependent kinases. But not only is cyclin dependent kinase important but there are other regulators that normally suppress cyclin dependent kinases such as p16 which can actually be lost in solid tumours. So if one loses the element of tumour suppression that may actually cause dysregulation of the pathway. Thus blocking the pathway at the level of cyclin dependent kinase may have utility in a number of different types of cancer.

What about this new agent, bemacyclib?

Bemacyclib is a highly selective cyclin dependent kinase 4 and 6 inhibitor. It seems to have nanomolar-potency against cyclin dependent kinase 4 and 6. The unique aspect of this particular molecule is that structurally it is actually the most dissimilar of the three that are currently in development and while the others have to be given on an intermittent schedule bemacyclib can be dosed daily and continuously without interruption. It also, uniquely amongst the compounds that are currently in development, is dosed twice daily as opposed to the others which are dosed once daily. This intricate dose and scheduling which has been developed through detailed pharmacology and pharmacodynamic type studies may have lent or informed our ability to derive a dose and schedule which has been associated with single agent activity.

What makes CDK4 and CDK6 particularly pertinent to cancer?

Cyclin dependent kinases may have a role in regulating the function of normal cells so it’s very important to be able to target the very specific kinases that are most important in cancer.

Can you tell us more about your study of patients with metastatic breast cancer?

This study in fact represents an expansion cohort that was performed after a phase I dose escalation study which we reported at ASCO last year which was geared towards identifying safety, tolerability and a dose that could be taken forward. Having seen preliminary hints of anti-tumour activity in the phase I study we thereafter decided to embark upon expansion cohorts in very specific tumour types including breast cancer but also other cancers including lung.

What did the study entail and what did you find?

Patients with advanced metastatic breast cancer unselected for prognostic markers, so patients were allowed to participate as long as they had metastatic disease and had received standard of care therapies. So it just so happens that the most common subtype of breast cancer or metastatic breast cancer is hormone receptor positive and that’s what we saw a prevalence of in our subset of patients as well.

What are the indications of efficacy and responsiveness?

It’s important to remember that our agent has been dosed as a single agent in the study and the efficacy signals are very promising from the standpoint of this early study. Of course this data has to be corroborated from the standpoint of confirmatory studies but response rates are being seen in the order of magnitude of 25% in hormone receptor positive patients, but highly refractory patients who have received up to seven prior lines of therapies.

So you looked at patients with very few remaining options?

That is correct. Our patients were in fact reflective of a typical phase I patient population. So those who had progressed on standard of care therapies and would not necessarily have been expected to have this level of benefit with a single agent therapy. So in that regard the results were surprising and very promising.

What are the clinical implications?

I think the implications are exciting for the field of metastatic breast cancer. As you know, it is still a field that is in desperate need of newer therapies. There are no curative approaches for this particular disease and thus it is very important to have newer therapies that allow patients not only to live better but to live longer.

What should physicians take from this?

The results are exciting but they’re still preliminary. We’re seeing activity in the setting of highly refractory patients with a single agent drug that is producing response rates of 25%. These results have to be corroborated in future clinical trials.

Do you think this is going to be an effective new class of drugs?

There are currently no drugs that are approved that block CDK4 and 6 so this is a unique mechanism. There may very well be a number of molecules that demonstrate activity but bemacyclib seems to be uniquely positioned from a number of considerations, from the standpoint of single agent activity in very heavily pre-treated patients and the fact that it’s safe and can be dosed continuously without interruption.