Long-Term Experience With BTK Inhibitors for CLL

Alan Skarbnik, MD: Changing gears a little bit, as we’re talking about acalabrutinib and ibrutinib, ibrutinib has more long-term follow-up at this point. As you know, the drug was the first to market, and acalabrutinib is a much younger sibling, or cousin. What are the data for the long-term follow-up for ibrutinib?

Jennifer R. Brown, MD, PhD: Well, the longest-term follow-up is actually from the phase 1b/2 single-arm study, which is out to about 7 or 8 years now. At that point in the relapsed setting, only about 20%, 25% of patients are still on the drug. The median PFS [progression-free survival] was about 50 months—4 1/2 years overall. This was shorter in patients with a 17p deletion, for which it was only about 2, 2 1/2 years. And then, the median PFS was shorter in patients with a complex karyotype—about 33 months. Regarding the patients with an 11q deletion, the results were about at the average for that specific population. There was a small frontline cohort on that study—only about 30 low-risk patients—but their PFS is still quite high. The PFS is above 90%, although the majority of patients or about half are off the drug, mostly for various toxicities that we’ve already discussed and we can discuss more that tend to accumulate in patients on ibrutinib for a long time.

The first randomized trial was RESONATE, and that now has more than 5 years of follow-up data. But the median PFS was reached some time ago—at about 44 months. This was a relapsed population with 2 to 3 prior therapies, and about a third of them had a 17p deletion. Half of the patients had a TP53 mutation. So, it’s a very high-risk population. That’s obviously a very nice PFS for that randomized trial.

We don’t have that kind of long duration data with acalabrutinib, or certainly not from a randomized trial. We only have about 2 1/2-year follow-up data. So that is an issue. It influences me more in drug selection for the higher-risk patients—the patients with a 17p deletion, for example, or even obscure diseases like PLL [prolymphocytic leukemia]. For people who you’re more worried about, if there are longer-term data, it provides some comfort, although I feel pretty comfortable that acalabrutinib is a highly effective drug. So, I’d be more influenced about the patient’s age and the comorbidities and still be willing, in many cases, to choose acalabrutinib.

The other issue we should address is that some doctors have had an idea that maybe you can treat people for 6 or 12 months with a BTK [Bruton tyrosine kinase] inhibitor and get them into remission and then stop therapy. Maybe the cost is too much. Maybe the patient has a minor adverse event. I never do that. That’s just not a good idea. A patient’s disease can flare. It can breed resistance. They might lose the ability to go back on the drug, and it really can’t be recommended in my view.

Alan Skarbnik, MD: Yeah, I agree. We know that there is selected pressure, and the main issue with resistance in BTK inhibitors is the acquired BTK C481S mutation. It seems that patients who have interruptions of the drug may breed a little bit more of that. It’s driven by the use of BTK inhibitors. Usually, you don’t find this particular mutation prior to use of the drug. But, I do fear that it will drive more resistance as well. And accordingly, with this stop-and-go approach—which there’s no data to support—there’s also no data to support, as of yet, reducing the dose off the bat with ibrutinib. I’ve seen people starting with 140 milligrams and trying to build up afterward. It’s not the indicated dose. You should only decrease the dose if there are CYP3A4 interactions. Or, for the opposite: You start at the right dose and the patient has significant adverse events. There’s a whole algorithm of how to decrease the dose based on that.

We do know that it’s important to front-load the dosage and try to get the significant BTK inhibition off the bat. That has less detrimental issues in terms of efficacy down the road, if you decrease the dose based on adverse events. Of course, there are data from MD Anderson Cancer Center on doing the full dose during the first month. It’s phase 1. And then, decreasing the dose afterward. In terms of BTK inhibition, it should be stable. But I wouldn’t favor the opposite, which I’ve seen a number of doctors doing. That can drive different outcomes for these patients.

Jennifer R. Brown, MD, PhD: I’ve seen that as well, but I still try to resist reducing the dose even later. The MD Anderson Cancer Center data are favorable, but they were based on about 10 patients and there’s no clinical outcome, right?

Alan Skarbnik, MD: Yes.

Jennifer R. Brown, MD, PhD: I really think what we need is a clinical test for BTK occupancy, so that we can actually titrate the dose to a particular patient’s needs.

Alan Skarbnik, MD: Yeah, I agree with that. It’s “preclinical data,” quote, unquote.

Transcript edited for clarity.