Head-to-Head Trials of BTKi in Chronic Lymphocytic Leukemia


Shared insight on and reactions to head-to-head comparison trials between novel BTK inhibitors in the setting of chronic lymphocytic leukemia.


Sonali M. Smith, MD: What we’ve talked about so far have been BTK [Bruton tyrosine kinase] inhibitors in the initial setting and the relapsed and refractory setting, focusing on some recent data. Now comes the hard part, which is how do you select between the different BTK inhibitors, and are there any data that might help us with any of those head-to-head comparisons? I’m going to ask Ryan to address this.

Ryan W. Jacobs, MD: I’ll stick with the FDA-approved options between ibrutinib and acalabrutinib to talk about choosing between the two. We were stuck with cross-trial comparisons for a while, comparing trials like ASCENDto ibrutinib in relapse studies. We, of course, wanted a prospective study that looked at these 2 agents compared head to head. That is what we got with ELEVATE-RR. Not surprisingly, I would say, with its noninferiority design, it showed noninferiority in terms of outcomes. The progression-free survival [PFS] was almost exactly the same for this group of patients with relapsed chronic lymphocytic leukemia [CLL]. Of note, they were high-risk patients in particular, they either had 11q or 17p abnormalities. PFS was not different, but was the toxicity profile different? Because we had a sense with the more selective kinome that acalabrutinib would perhaps have less toxicity. That was shown in the trial. Notably, the key secondary end point of lower rates of atrial fibrillation, all grade, was seen. It was about 15% with ibrutinib compared to 9%. There were various other toxicities that seemed to favor acalabrutinib, less diarrhea, both in all grades and in grade 3 plus. There were fewer arthralgias, and seemed to be lower rates of bleeding.

Then when you look at the big picture, how many patients are discontinuing treatment due to toxicities, that also favored acalabrutinib. Twenty two percent of patients on that study with over 4 years of follow-up discontinued treatment on the ibrutinib arm vs only around 15% on the acalabrutinib arm. So we seem to have an answer there in terms of maintaining the great efficacy that ibrutinib had established with BTK inhibition, but having a favorable toxicity profile and being able to give it with antacids and proton pump inhibitors. For the time being it seemed to be that acalabrutinib was the right choice for our patients with CLL in terms of the FDA-approved options if we were going to treat with a BTK inhibitor.

Sonali M. Smith, MD: Certainly, having a more restricted target on the kinome map, I think, has been supporting the improved toxicity profile. We just heard about acalabrutinib vs ibrutinib. I’m going to ask Susan to talk to us a bit about zanubrutinib vs ibrutinib.

Susan M. O’Brien, MD: [ALPINE] is another randomized trial in the relapsed setting. [It has a] bit of a different design and patient population than you heard from Ryan in the ELEVATE-RR, but both are relapse trials. These patients were all-comers with relapsed [CLL], randomized to receive zanubrutinib twice a day or ibrutinib once a day, standard dosing. What this showed was that the response rate with zanubrutinib was somewhat higher than with ibrutinib. One thing to note was that the response rate did not include PRL, or [partial response] with lymphocytosis. However, if you do include the PRL, the response rate is still higher with zanubrutinib, although the response rates come a bit closer together. However maybe more importantly, if we look at the PFS, the PFS appeared to be longer with zanubrutinib than with ibrutinib. As with the ELEVATE-RR trial, we saw significantly reduced atrial fibrillation rates with zanubrutinib in comparison to ibrutinib. But one somewhat different thing is we did not see any difference in hypertension between the two, as we did in the ELEVATE-RR trial. But this trial, the end point again is a little different, showing rather than noninferiority, showing a somewhat prolonged progression-free survival with zanubrutinib.

Sonali M. Smith, MD: Sameer and Nicole, I’m going to ask you to talk a bit about how you compare these BTK inhibitors in the front line and relapsed/refractory settings. I have a couple of questions. First, for Nicole, how did the population included in the head-to-head ELEVATE-RR and ALPINE studies compare?

Nicole Lamanna, MD: As Susan just noted, they are slightly different populations. Obviously, in the acalabrutinib study, the median number of prior therapies was 2. I think in the ALPINE study it was only 1. They were higher risk, about 45% or so were 17p and P53. Whereas in the ALPINE study they were all-comers. So, slightly different populations for sure. I think when I look at those data I’m not going to directly compare that study to the other study. You can look at it in comparison to ibrutinib, and I think that’s fair, each agent in comparison to ibrutinib. But I’m not going to be looking at acalabrutinib vs zanubrutinib in that setting, or trying to extrapolate differently in that sense.

Sonali M. Smith, MD: How do the follow-up duration and the other end points compare between the 2 trials?

Nicole Lamanna, MD: Yes, obviously ALPINE, being a younger study in general, does not have the same mature follow-up that we have with the other study with acalabrutinib. I think all of us are going to be looking forward to longer-term data to see if that PFS holds up over time between zanubrutinib and ibrutinib.

Sonali M. Smith, MD: Sameer, can you comment on the treatment discontinuation and toxicities in these head-to-head comparisons?

Sameer A. Parikh, MD: Yes, I think as we look at the toxicity profile, it appears that the second-generation BTK inhibitors in both studies have a better tolerability profile. Specifically, with respect to cardiovascular issues, it looks like the risk of atrial fibrillation is lower with second-generation BTK inhibitors. In the ALPINE study, it looks like, again, more patients discontinued treatment due to toxicity in the ibrutinib arm compared to progression of disease, which speaks to the tolerability issues that we have come to know with ibrutinib, with discontinuation in the long term. But again, I think we need to see longer-term data on how these progression-free survival curves mature with longer-term follow-up. Because, as Nicole pointed out, the median follow-up in the ALPINE study is just short of about 2.5 or 3 years. I think we really need to see longer-term data.

Sonali M. Smith, MD: But do you think that the discontinuation and the toxicities play into your selection?

Sameer A. Parikh, MD: Yes, I think they do. And it’s unfortunately very hard to predict which patient will experience what type of toxicity as we are about to begin treatment. But overall, if I know that a second-generation BTK inhibitor is likely to lead to less treatment discontinuation, I’m more likely to pick that as my BTK inhibitor of choice. Increasingly there are combination therapies, and I know we are going to talk about those that are being explored in the treatment of CLL. So long-term continuous BTK inhibitor-based treatment may not be what we would do. In which case, I think it would not be as big of a question as to which BTK inhibitor to choose.

Sonali M. Smith, MD: That’s a great point.

Transcript edited for clarity.

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