ASH 2013 - New Orleans, LA, US

Encouraging early results with GS-9973 for CLL and NHL

Dr Jeff Sharman- US Oncology, Eugene, Oregon

We know that B-cell cancers have abnormal signalling through the B-cell receptor. Those are the surface antibodies, you make antibodies to fight flu and E.coli, salmonella, when they’re attached to the B-cell that is the B-cell receptor. In each of these cancers they abnormally activate the B-cell receptor signalling in some way and the key enzymes that transmit that signal very early on are SIK, BTK and PI3 kinase. So drugs that block any of these signalling enzymes have proven to have significant clinical activity and they are, in some cases, nearing approval or just getting up off the ground.

So the signalling pathway that transmits signals downstream of the B-cell receptor starts with SIK, goes to BTK and then further downstream hits PI3 kinase. So the thought was that if you interfere with this pathway at any of those locations it could have the same effect. What we reported was the preliminary very early results of 27 patients with chronic lymphocytic leukaemia and a very similar number of patients with non-Hodgkin’s lymphoma having been treated with the drug for an average of two to three months. So it’s a very early study, very early results.

What we’ve seen so far is that one of the class effects in chronic lymphocytic leukaemia with any of these drugs, BTK, PI3 kinase, SIK, is that lymphocytes go up and lymph nodes shrink. So what we think is happening is that the lymphocytes are leaving the lymph nodes and going into the circulation. So we saw that very robustly in this clinical trial sample so far and a lot of people have looked at that phenomenon as an indicator of efficacy.

Which category of patient were you looking at?

That’s chronic lymphocytic leukaemia and so it’s not a surprise when you treat patients with CLL for their cancer to actually suddenly go up. These are relapsed and refractory patients.

What do you make of these responses you had?

It’s early and in the case of ibrutinib and idelalisib, the BTK and PI3 kinase inhibitors respectively that have gone the furthest, the nice feature of those diseases is that the responses tend to be slow but durable. So with those drugs you don’t even get to a maximum response rate with ibrutinib and CLL oftentimes until eighteen months of therapy. So the responses continue to improve over time with these drugs so reporting data at the two to three month timeframe, it’s very early to make judgements as to how effective this drug will be in the long term but the early results are encouraging.

Is this a potential benefit of targeting something so upstream in the disease?

Many pharmaceutical companies right now are beginning to look at combining inhibitors at multiple steps along the B-cell receptor signalling pathway. In fact, this drug GS-9973 has been combined already with idelalisib, a further downstream PI3 kinase inhibitor. Those data have not been reported, it’s still very early with that study and drug compound but I believe that some people are believing that multiple inhibitors of the same pathway may be more effective.

Is there a risk of encountering problems when targeting upstream mechanisms?

In all experimental drug studies, particularly when you begin to combine agents that haven’t been combined before, there is chance for unexpected side effects, both good and bad. We’ve seen that in a variety of cancers and until you actually begin to do the study oftentimes preclinical models don’t give you sufficient signal.

Can you put this into clinical context?

Ibrutinib has been designated breakthrough therapy by the FDA meaning that it’s expected to be approved really quite soon. Indeed, it has been approved in mantle cell lymphoma already and many are expecting CLL approval within the next few months. Idelalisib will be reporting results of a large phase III study here on Tuesday; those results are eagerly anticipated and the published abstract is very encouraging. So these are drugs that will be entering clinical management of patients with these diseases very soon.

So GS-9973, I again would say this is an early molecule. We’re reporting two to three month data and the beauty of ibrutinib, if you will, or idelalisib is that those results are now out two to three years. So we have a little while to go before we know the full impact of this but we’re starting off very encouraging.

I think the take home message is once again we have a new target in the B-cell receptor signalling pathway and that’s SIK so now we can target SIK, PI3 kinase, BTK and all of them have similar effects on patients with CLL and how well this works in the long term remains to be seen. Patients continue to have relapsed refractory disease and even patients on ibrutinib do progress over time in many cases. So the take home message is we have an additional target that may be clinically relevant if this trend in this data continues. I think it’s an exciting time for patients with CLL; we’re lucky in this disease that there are multiple targets and that means that there’s going to be a wealth of drugs available for patients with CLL who may in some cases desperately need them.