Patient Selection for Treatment With Ibrutinib in CLL

Steven Coutre, MD: Ibrutinib was approved several years ago for patients with CLL who’ve had prior treatment. It also was approved for initial treatment if patients had deletion 17p, but that’s uncommon at presentation. Because of the RESONATE-2 trial, it very recently received approval for initial treatment of patients with CLL. So, that really broadens our ability to use the drug in patients as upfront therapy. With an FDA approval, of course, it’s much easier to obtain it for a patient from an insurance perspective. And so, in our practice, where we’re largely doing clinical trials, that’s not as relevant. But, for a patient treated in the community, it’s all about what they’re able to obtain as well. And I think we’ve seen, with the approval in the frontline setting, that it’s quite easy to access the drug for an appropriate patient.

I think in our treatment algorithm overall, ibrutinib is really being integrated in, whether in the context of a trial or in standard practice for pretty much all patients. It gives you another very good option, when you’re making that decision about what’s most appropriate for that individual patient that you’re making a decision about.

We’re often asked about when to use ibrutinib, and sometimes you get a comment about saving the best for later. That’s an issue that’s very important. There’s a recent publication describing how patients do after they’ve progressed with ibrutinib. But, it’s very important to realize that the patients who were the subject of that study were patients from our very early clinical trials, those who have had many, many prior therapies—for some, every therapy you could think of—and patients with very advanced disease. That’s a very different patient population than someone receiving ibrutinib as initial treatment or even in second-line therapy. So, when you hear people say, “Those patients didn’t do well, they died in a matter of months,” that’s not the right answer, because it’s really looking at a different group of patients.

The relevant question, and what we’re most interested in, is how do patients who are receiving ibrutinib early in their care, either frontline or perhaps after an initial chemoimmunotherapy regimen, how do they do? And, admittedly, we have limited data so far. In the RESONATE-2 trial, there are only three patients who came off ibrutinib because of progressive disease. And, although follow-up of them is still short—measured in months, not years—none of those patients have gone on to subsequent treatment yet, which is quite interesting.

Now, we have a limited experience from our very first trial, where we included a group of 31 patients over 65 who received ibrutinib as initial therapy. And one patient progressed at 8 months. No other patient has progressed. I have a few patients on that trial who have been receiving ibrutinib for more than 6 years now. So, I think one of the real values of the RESONATE-2 trial will be to address this very question: how do you do if you have to stop ibrutinib, either because of an adverse event or because of progression?

What would I do? I’d give them venetoclax. The nice thing is now we’re developing other drugs, and another one’s been approved, venetoclax. Of course, idelalisib is on the market, but there are safety issues there. That’s clearly the direction we would go. In fact, we do that now. We have a trial for ibrutinib or idelalisib progressing patients with venetoclax, and they respond perfectly well since it’s a different mechanism of action. You could certainly give chemoimmunotherapy if you wanted. And there’s no reason to expect that those patients would respond any differently.

The value of the RESONATE-2 trial is not the fact that it’s better than chlorambucil. If it wasn’t, they might as well shut down the company. So, that was no surprise, and chlorambucil is not a very good comparison anyway. The real value is going to be to see how those patients do as they continue on ibrutinib. That’s going to give us the data that everybody wants to know: how long do we have to continue it?

Physicians often ask what do we do after ibrutinib. What if a patient progresses? And, fortunately, that’s not been all that common. There are some published data on that, but one has to be very careful about interpreting that data because that study involved heavily pretreated patients who were receiving ibrutinib. In many cases, they had exhausted all prior conventional therapy and had quite advanced disease. That’s a very different patient receiving ibrutinib than someone receiving it as initial therapy, or even as second-line therapy after say an FCR regimen. So, those patients didn’t do well. And that’s not a surprise, because they didn’t have other treatment options. But, for someone receiving it earlier, I would argue two things. First, we do have other treatment options for them, including newer oral drugs as well. And second, I think it’s a very different patient population, so the progression is going to be much less common. Those patients will respond to subsequent therapies, whether they are traditional chemoimmunotherapy or other novel targeted agents. The idea that you want to hold back your best for later, if you’re calling ibrutinib your best, I think you have to move beyond. There’s nothing wrong with using your best therapy initially.