Expert on Role for Ibrutinib, Chemo, and Novel Combos in First-Line CLL

Steve Coutre, MD, discusses how he determines which CLL treatment option is best for which patient, the advantage of treating patients with ibrutinib over chemoimmunotherapy, and new oral agents currently being investigated in the space.

Steve Coutre, MD

The field of chronic lymphocytic leukemia (CLL) has evolved in recent years, with drugs like ibrutinib (Imbruvica) providing a well-tolerated and effective oral therapy for the frontline setting. Now, said Steve Coutre, MD, researchers are investigating the use of combinations in this space, with the hope of pairing an effective oral therapy like ibrutinib with a regimen that provides the advantage of a defined treatment endpoint.

In an interview withTargeted Oncology, Coutre, professor of medicine, Stanford University School of Medicine, discusses how he determines which treatment option is best for which patient, the advantage of treating patients with ibrutinib over chemoimmunotherapy, and new oral agents currently being investigated in the space.

TARGETED ONCOLOGY:In frontline management of CLL, what is the argument for ibrutinib and tyrosine-kinase inhibitors (TKIs) over chemoimmunotherapy?


Things have evolved in recent years. We now have drugs like ibrutinib which are very different from our traditional chemotherapy or chemoimmunotherapy regimens and they allow the use of an oral therapy that is well tolerated and is very effective. That’s an important issue when you think about the fact that the majority of patients with CLL are diagnosed when they’re 70. Most patients don’t need treatment right away, so when they do need treatment, they’re usually in their mid-70s and the tolerability of therapies is quite important.

We have drugs like ibrutinib, and I’m sure there will be more similar oral drugs, that will eventually move to frontline, and in comparison we have our traditional chemoimmunotherapy. Those regimens, although they’re fairly well tolerated, are still harder than taking a pill, and they do have toxicities, infection and such. For people who have a lot of comorbidities, that’s a significant issue.

We also have antibody therapies, for example, obinutuzumab (Gazyva) with chlorambucil, is also approved frontline, so that is kinder and gentler as well, certainly a little more difficult than taking a pill. But, it’s probably not as effective, or certainly the durability isn’t as long, as the oral therapies.

So, on the one hand you have a pill you can take and go about your business and hopefully will have little impact on your quality of life, but right now you do have to take those continuously. We haven’t explored stopping therapy yet. With our more traditional chemoimmunotherapy regimens or immunotherapy or antibody therapy, they’re given for a defined period of time — 6 months or so. So that’s the trade-off, and then of course the other issue that always comes up is cost, the financial impact.

TARGETED ONCOLOGY:When an oncologist is trying to decide which of these options is best, what are the considerations they should take?


We have very well-defined guidelines for when to start therapy, so assuming we follow those, then there is not really an algorithm, per say. I always like to think of it as you’re looking at each patient as an individual. There might be medical comorbidities that really have a significant impact on your decision — somebody who’s too frail, let’s say, and you don’t think they can tolerate these chemotherapy regimens. There, an oral therapy, like the TKIs, might be most appropriate.

On the flip side, some patients, really because of financial constraints, it’s better for them to have a defined course of therapy, something that might very well be fully reimbursed, whereas an expensive oral therapy might not be fully covered by their insurance, so that’s a significant consideration.

It’s not as simple as just making a medical decision, I think you have to look at the whole picture and have that discussion with your patient and decide what’s best for that individual.

TARGETED ONCOLOGY:Are there any new oral agents on the horizon now?


We had idelalisib (Zydelig), another B-cell receptor pathway inhibitor, but because of safety issues, particularly recent ones with infections, it’s not likely to ever get an approval for up-front therapy.

We have venetoclax (Venclexta), a BCL2 inhibitor, also an oral therapy, approved now, but just for relapsed 17p deletion patients, but I’m sure that with more trials, a drug like that may make its way into the frontline as well.

I think even more importantly, really where we are going is combining some of these drugs, not so we can give two or more expensive drugs indefinitely, but really trying to see if we can get a better response, a better depth of response, and start addressing the issue of actually stopping therapy. To have the advantage of an oral, well-tolerated therapy, and perhaps to have the added advantage of a time-limited therapy, I think that’s really what we’re most interested in.

TARGETED ONCOLOGY:Are there any trials looking at these combinations?


Sure, you’re just starting to see them. Many of them will start with a combination of an antibody and one of these drugs, so you have trials with ibrutinib and obinutuzumab, for example, or venetoclax and obinutuzumab. The German CLL study group in particular has really moved ahead quite aggressively with this. You’ll see trials that use a combination of perhaps 3 drugs, you might use obinutuzumab and ibrutinib initially, reduce the lymph nodes, reduce the circulating lymphocytes and then add in venetoclax over several months and try to get a better overall depth of response. I think there will be a lot of creative ways of doing this and we’ll see what turns out to be the best.

TARGETED ONCOLOGY:In terms of selecting between chemoimmunotherapy and ibrutnib, is there a patient population that should always receive ibrutinib?


That’s an easy question. Patients with 17p deletion should always receive ibrutinib, since our chemoimmunotherapy largely is ineffective or has very poor efficacy in this group, even if patients initially respond. I think without a doubt, anyone that has that abnormality should receive one of these novel agents.

Fortunately, that abnormality is quite uncommon at the time of diagnosis, maybe 5% of patients, so it’s not going to be a big issue as far as up-front therapy, but certainly, it’s a reason why all patients before they start therapy, if you’ve made that decision that they need treatment, should have that tested. You should do at the very least a Fluorescence in Situ Hybridization (FISH) test to see if that’s present because it’s a predictive factor, it’s something that will influence what you choose to treat that patient with, so all patients should receive one of these drugs. Right now the only one that has an indication for initial therapy is ibrutinib.

TARGETED ONCOLOGY:Can you talk a little bit about the RESONATE-2 trial and what impact that had?


The RESONATE-2 trial was the randomized phase III trial for previously untreated patients. Patients had to be over the age of 65, but again, that’s a typical CLL patient. They were randomized to chlorambucil versus ibrutnib monotherapy. They were allowed to cross over if they didn’t respond or responded and didn’t progress with one of the regimens. Many of the patients did eventually cross over from chlorambucil.

Not surprisingly, it showed a significant benefit to the use of ibrutinib, both in terms of progression-free survival, but even overall survival with fairly short follow-up, so you saw a survival advantage, you changed the natural history of the disease compared to chlorambucil alone.

Of course, people will say, well that’s chlorambucil. We had already essentially moved beyond that by combining it with rituximab (Rituxan) or obenotuzimab, but I think the more important aspect of that trial is not the fact that it was superior to chlorambucil, it was to see how patients who received ibrutinib as initial therapy do over time, what’s the natural history of their disease when you get treated up front. That is going to be very different than looking at all of our other patients in the trials— the ones who are heavily pre-treated, the relapse patients, the ones that got ibrutinib approved in the first place—and asking the question of how they do if they progress on ibrutinib or if they stop it. I think is a very different question than looking at this up-front population.