ASCO 2015

Ibrutinib combination regimen shows substantial benefits in relapsed CLL

Dr Asher Chanan-Khan - Mayo Clinic, Jacksonville, USA

Ibrutinib seems to be an extremely interesting drug in the context of chronic lymphocytic leukaemia. Can you paint in for me some of the reasons why it’s interesting and why potentially you were looking at it in the first place?

Ibrutinib is certainly a very unique drug and is a game-changer in the treatment of CLL. There are two aspects that will be very, very attractive to you. First is the biology of how it works and the second piece is, of course, the efficacy in how good it has been for patients. Looking at the biology, the leukaemia cell likes to have signals from its environment and the environment provides these signals that give survival, longevity of life to the cancer or the leukaemia cells. Think of it as a very electrical kind of signal so once the signals come down to the core of the cell it allows these cells to develop biological processes that sustain them. Now, ibrutinib clips or interrupts these signalling pathways that the cell has with its outside and that interruption leaves the cell or renders the cell very susceptible to death.

Now it is, therefore, quite specific but you already had relatively targeted therapy with rituximab and bendamustine. What were you trying to do in this study that you’ve now published?

This particular study was designed to see if a targeted therapy like ibrutinib can be effectively combined with existing other therapies or chemo-immunotherapy. So this is a unique study, unique combination, because you have a very nicely, as you pointed out, immunotherapy component to it, which is rituximab, a chemotherapy component to it, which is bendamustine, and then the newest very specific signalling inhibitor that is mixed together. So it’s a very unique combination for the first time in CLL.

So could you tell me what you did in the study?

This is a phase III double blind randomised study where chemoimmunotherapy, or bendamustine Rituxan, was compared with both that combination with ibrutinib and it was controlled with a placebo. Basically the idea was to see whether ibrutinib can enhance the progression free survival.

Right, so standard therapy plus or minus ibrutinib?

Absolutely, in a placebo controlled fashion.

What happened?

We found that… the primary endpoint of the study was can these patients have a durable and longer remission induced by the chemo-immunotherapy? We found clearly yes, ibrutinib substantially added to the progression free survival benefit to these patients and it reduced the risk of relapse or death by 80%. It reduced the risk of death by itself by about 37%. It was so effective that on the interim analysis it was deemed that those patients who have progressed on the placebo arm or the control arm were allowed to go on to receive ibrutinib. 31% of those patients actually did that.

Was there a downside, though, in terms of any toxicity?

There was no significant or untoward or unanticipated side effects. Clearly bendamustine, rituximab and ibrutinib have their own toxicity profiles and what we saw in this study was there is no untoward effect of the triple combination. So it was very effective, anticipated side effects and great results.

What, then, are the immediate clinical implications for patients who are relapsing or refractory to standard therapy with bendamustine and rituximab?

Very, very important. So every research at this scale and with so many countries and investigators and patients involved should mean… or the anticipation it should have a gain, it should have an impact on what the patients are going to see in their treatment paradigm. What has happened as a result of this study is that, first thing, we have been able to confirm in a second phase III trial that ibrutinib is actually a very effective drug for CLL patients. This is in continuation with a previous phase III study that was reported by Dr John Byrd. So this study, again in a randomised fashion, proves that ibrutinib is effective, that’s number one. Number two is the fact that it prolongs progression free survival and enhances the chance of going into remission. Those are very, very important points. In the present management period for relapsed CLL, where it’s not a curable disease, the goal is to prolong remission duration. This study proves that if patients are being treated for relapsed disease with chemotherapy or chemo-immunotherapy they need to be given ibrutinib with the combination.

How do you choose your patients, though, because patients with chronic lymphocytic leukaemia vary quite a lot?

Absolutely, great point. This is a heterogeneous disease. We select patients’ therapies based on their genetics, their ability to tolerate, their age, their personal goals – what do they want to achieve. A 70-80 years old may have a different tolerability or preference of treatment versus a 35 years old. So there are multiple factors that go into this end selection of therapy. But one thing is clear, whether it be young, old, genetically aggressive disease or less aggressive disease, ibrutinib seems to be effective in all.

Could you, do you think, use the drug earlier, initially with this triple therapy?

Ibrutinib has made an impact in the relapsed CLL. The encouraging news of its tolerability, ease of giving and the durability of response plus the fact that you can give this therapy for so many years without cumulative toxicity causes us to ask the question should it be the number one treatment to start with. Those clinical trials are on-going.

Could you give it as a monotherapy or perhaps with just one extra drug?

Again, that also is a question that is being explored. There are two important aspects, can it be given? Yes. Tolerability, toxicity-wise, yes, it can be given as a single agent, it has been, it’s prescribed right now.  Should it be given? If you are aiming to cure this disease, if you are aiming to push patients into complete remission, undetectable disease, then one thing we know about ibrutinib that perhaps in the relapsed setting, that chance is less. So combinations with other drugs, newer drugs, is a very, very important question that we need to answer.

Briefly, then, what are the clinical take home messages for cancer doctors all over the world coming out of this?

That what we saw as an initial signal of efficacy and tolerability of ibrutinib in relapsed CLL patients is now endorsed with a large phase III second trial. The second thing is the toxicity signal was not alarming or not unanticipated. Third, if they are going to give chemo-immunotherapy with BR to patients for their treatment of relapsed CLL then the standard has now changed from this particular trial into a chemo-immunotherapy, BR, plus ibrutinib.