We know that the B-cell receptor pathway is chronically activated in CLL, not genetically by mutations but it seems to be chronically activated by the microenvironment. A key nexus in that pathway is the Bruton’s tyrosine kinase or BTK and CC-292 is a highly specific covalent inhibitor of BTK. So this phase I study was initiated to determine its activity in relapsed refractory CLL patients.
Why is it so important in CLL?
CLL has a very heterogeneous disease course but about half the patients do have a steadily progressive disease that needs treatment fairly early on and even those who have more indolent disease, we still know that even older patients most often die of their CLL rather than of other causes.
How did BTK rise to the top as a potential target?
It was in this B-cell receptor pathway, as I mentioned. The other fact is that there is a genetic human disease called Bruton's agammaglobulinemia in which BTK is mutated and absent. There we see a failure of B-cell development and lack of immunoglobulins. So that clearly indicated the importance of BTK in B-cell development, suggesting that it may also be important in B-cell malignancy.
In the study we treated approximately 80 CLL patients at increasing doses, initially on a daily dosing schedule, but then we moved to a twice daily dosing schedule. We observed them for toxicity and efficacy and we found this drug was quite well tolerated. It has mostly what we call grade 1/2 side effects which are low grade and generally benign with some diarrhoea and fatigue mostly. The efficacy was quite high, especially at the higher dose levels. The twice-daily dosing allows us to give a lower single dose which reduces the side effects even more and was also more potent. We saw a 60% response rate in this highly refractory population of CLL patients.
How does the response rate manifest itself?
You get a rapid reduction in lymph nodes. Sometimes the white count will actually go up initially and this is a pattern of response that we see quite commonly in any of the drugs that inhibit the B-cell receptor pathway kinases. You get rapid nodal response but the white count will go up, plateau at a certain level, generally after 1-2 months, and then come down over time. So that is what we saw with this drug. But the other notable thing is that usually patients feel much better as soon as you start this drug or any of the drugs in this class, which we don’t know exactly why that is but it may relate to some influence on hormone production or cytokine production.
You were looking at relapsing patients with CLL, does this mean you have a treatment where you wouldn’t have any?
Potentially, yes, but I would note that we have a large number of molecules that are similar. There are other BTK inhibitors, there are inhibitors of PI3 kinase and there are other kinase inhibitors coming down the pipe which are all looking quite potent in CLL. So in the situation where five years ago we had little or no highly effective, well-tolerated treatment, we now have quite a few drugs in development and we’re expecting that some may be approved as early as this coming year.
What advice do you have for clinicians in regards to the clinical potential?
It’s truly transformative and so we may be able to start to abandon some of the more toxic chemotherapies or antibodies in favour of… Some of these may be used as single agents, particularly for older patients with other medical problems but I think for the younger, healthier patients we’ll try to combine them to get very deep remissions and hopefully maybe we can start to consider whether it’s possible to achieve cure with combinations of multiple of these agents.
Is there a possibility of selecting patients before they have to be treated?
That’s definitely a research question of great interest, particularly for patients with higher risk markers that suggest they will progress to treatment. It tends to be a hard study to do, we need to enrol many, many patients and give half of them the drug and the other half not to really know if it’s benefitting patients. There is some argument about whether treating earlier is better because there’s a little bit of scientific data that sometimes treating earlier might eliminate the sensitive cells and leave some of the resistant ones behind. But we don’t know if that’s the case at all and in particular if you use one of these highly active drugs maybe they’ll get rid of the resistant cells early on. So this is why we really need to do the studies, to understand whether it will be useful to use these earlier than we have historically.
Are there any dilemmas in implementing active surveillance?
Those are exactly the dilemmas. Right now active surveillance, or what we often call watch and wait, is really the standard for people who don’t have symptoms and don’t have problems with their blood counts or their lymph nodes. So moving away from that, when that’s been validated to be safe with older therapies, really requires that we get good evidence for both safety and efficacy.
What is your take home message for clinicians?
BTK inhibitors are profoundly effective in CLL and are likely to move into multiple potential phases of therapy. We’ll be looking to learn how best to combine them with other classes of drugs like antibodies and other inhibitors in the coming years.
