Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 4

Clinical Trials of BTKi in B-Cell Lymphomas

Drs Shadman and Cohen discuss clinical trial data utilizing acalabrutinib in B-cell lymphomas.

Mazyar Shadman, MD, MPH: In CLL [chronic lymphocytic leukemia], starting from the relapsed setting with the TRANSCEND trial, acalabrutinib was the investigational arm. The standard arm patient received idelalisib and rituximab or bendamustine and rituximab. The study showed that acalabrutinib was superior, and that led to the approval of acalabrutinib for the relapsed CLL. Then we had the ELEVATE TN study. This compares acalabrutinib in 1 arm, acalabrutinib and obinutuzumab, and chlorambucil and obinutuzumab in the first line. That study led to the approval of acalabrutinib for first-line use.

Any comments on any of these studies? Anything we should be following with longer follow-up?

Jonathon Cohen, MD, MS: In the relapsed study, it wasn’t a surprise that acalabrutinib outperformed the experimental arms. But recognizing that at the time there weren’t other agents out there that we have to compare, we have to take that for what it is, and it certainly brought acalabrutinib into the forefront as an option. I found the ELEVATE TN data to be very exciting but also challenging to apply. We had the ALLIANCE trial, which compared rituximab and ibrutinib vs ibrutinib monotherapy vs BR [bendamustine, rituximab], showing that outcomes for patients who received ibrutinib and those who received rituximab-ibrutinib were virtually identical. In the ELEVATE TN trial, there was a statistically significant improvement in outcomes for patients who received obinutuzumab as opposed to acalabrutinib monotherapy.

In my own practice, I have applied those data, and when I have a newly diagnosed patient, I’ll have a conversation with them about the data. It looks as if there is a significant but marginal improvement using obinutuzumab. Most patients have wanted to go ahead and receive it, and I’ve been comfortable doing that. I have used it. But if I have a patient who says I don’t want IV [intravenous] therapy, I’m also very comfortable not using it. I recognize that it’s difficult to reconcile those. What have you been doing? If you’re going to use acalabrutinib up front, are you combining it with obinutuzumab?

Mazyar Shadman, MD, MPH: I haven’t been using CD20 antibodies with BTK [Bruton tyrosine kinase] inhibitors in general, but I agree that ELEVATE TN is something that makes you think. It has small numbers and is probably not powered, but it sounds like the PFS [progression-free survival] difference with the longer follow-up is there. Maybe those curves are getting even more separated. Another factor that has been important is COVID-19 and some emerging data that exposure to CD20 may negatively impact the efficacy of vaccines. In the big picture overall, I’ve been trying to avoid CD20 antibodies. But you’re right: looking at the data, it’s something to think about. With ibrutinib, for example, we have the iLLUMINATE study, which combined ibrutinib with obinutuzumab, but the control arm was chlorambucil and obinutuzumab. There was no ibrutinib monotherapy. It’s hard to say if the difference in the ELEVATE TN is because obinutuzumab is a better antibody than rituximab because we never had a control arm with ibrutinib. That’s something to monitor with longer follow-up. It’s a very good point.

Jonathon Cohen, MD, MS: I agree. And your point about COVID-19 is a great 1. I had hoped that this was going to be a few weeks to months of adjustments, but it looks like it’s going to be a long-term consideration, so that’s a good point. Like you, I’ve been trying, when possible, to not incorporate CD20-direct therapy unless I feel it’s critical. That’s an important consideration.

Mazyar Shadman, MD, MPH: Staying on acalabrutinib, we talked about TRANSCEND-CLL-004, the second-line or relapsed label, and ELEVATE TN. More recently we have the ELEVATE-RR or ELEVATE relapsed/refractory. That was a very important study, comparing acalabrutinib head-to-head with ibrutinib in the relapsed setting. Did you want to say a few words about that study?

Jonathon Cohen, MD, MS: Yes. One of the things that had been a challenge in our world, for a couple of years at least, was that we had these 3 BTK inhibitors. We thought that they had similar efficacy. We thought there were differences in toxicity, but we didn’t have a lot of head-to-head data. The ELEVATE-RR trial did provide some head-to-head comparison between ibrutinib and acalabrutinib, and there were some differences in the rate of several toxicities, including atrial fibrillation and bleeding. This is clinically meaningful. As you pointed out, it does suggest that the toxicity profile is more favorable for patients who receive acalabrutinib.

One thing that’s worth mentioning is that there was still a decent number of patients who received acalabrutinib in that setting who had to discontinue therapy after toxicity. It’s important. There may have been a conception in the past that patients who received ibrutinib were at risk for toxicity, but now we have these newer agents, and we don’t have to worry about toxicities as much. This study does show that although it’s probably better tolerated, there still are patients who have to discontinue therapy. It suggests that these patients are going to need ongoing follow-up and ongoing management over a long period of time and that you can’t just assume they’re not going to develop any toxicities. I was really happy to see that study and the results. That helps me when I’m thinking about how to best to manage patients.

Mazyar Shadman, MD, MPH: Yes, and just to remind the audience that the study was a noninferiority study. For the primary end point, it wasn’t designed to show that acalabrutinib is superior to ibrutinib from the efficacy standpoint. The study did show that acalabrutinib wasn’t inferior but secondary end points of lower rates of atrial fibrillation or flutter, fewer or lower rates of grade 3 or more infections, or Richter transformation. Then there was another end point of overall survival, which we haven’t seen in this presentation. But acalabrutinib is a drug that’s not inferior to ibrutinib from the efficacy standpoint for CLL but does provide a better safety profile with lower rates of toxicities.

Because you’ll be talking about the similar study that compared zanubrutinib with ibrutinib, it’s worth mentioning that ELEVATE-RR focused on high-risk patients or included patients with del17p or del11q, so those are the differences between the 2 studies.

Jonathon Cohen, MD, MS: You’ve done a nice job of summarizing the data. For me the take-home is that it’s not so much the difference in efficacy as much as there are likely some differences in tolerability that need to be taken into account when you’re deciding how to treat an individual patient. Because we have the longer tack record with ibrutinib, we do have longer-term follow-up with some of the initial studies. Also, ibrutinib has been the more common combination partner for novel combinations and other combinations that have been investigated. We’ll see that there’s a role for ibrutinib in some instances, especially if we were to identify that a particular combination is effective in 1 disease.

This transcript has been edited for clarity.