Building on Current Understandings of BTK Inhibition in CLL, MCL

BTK inhibitors have shown widespread utility in B-cell malignancies, explained Nilanjan Ghosh, MD, PhD, who added that a growing body of evidence is helping the field to optimize the use of each agent.

For example, in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), wherein ibrutinib (Imbruvica) and acalabrutinib (Calquence) are approved as continuous therapy, the field is investigating the use of minimal residual disease (MRD)-adapted treatment to determine the actionability of MRD and optimal duration of BTK inhibition.

To that end, in the ongoing phase 2 CAPTIVATE trial (NCT02910583), patients are receiving ibrutinib ​(Imbruvica) plus ​venetoclax (Venclexta) in patients with treatment-naïve CLL/SLL. After 12 cycles of combination therapy, patients are randomized to continued ibrutinib monotherapy or placebo based on MRD assessment.

Furthermore, in mantle cell lymphoma (MCL), wherein zanubrutinib (Brukinsa) is also approved, the field is beginning to understand the differences between each of the 3 agent’s safety profiles.

“If we extrapolate from the Waldenström macroglobulinemia data, zanubrutinib appears to have a more favorable safety profile compared with ibrutinib,” said Ghosh.

In an interview with OncLive, Ghosh, director of the Lymphoma Program and a physician with Levine Cancer Institute, discussed the role of BTK inhibitors in B-cell malignancies and ongoing research with each agent.

OncLive: What are the current indications for BTK inhibitors in B-cell malignancies?

Ghosh: Three BTK inhibitors are FDA approved: ibrutinib, acalabrutinib, and zanubrutinib. Ibrutinib is approved in CLL/SLL in the previously untreated and relapsed setting, in MCL after 1 prior therapy, in marginal zone lymphoma (MZL) after 1 prior therapy, and in Waldenström macroglobulinemia. Acalabrutinib is approved in CLL/SLL in the previously untreated and relapsed/refractory setting, and in MCL after 1 prior line of therapy. Zanubrutinib is approved in MCL after 1 prior line of therapy.

How did the available BTK inhibitors compare with one another, and how do you navigate among these options?

There are similarities and differences. All three of the approved BTK inhibitors bind covalently at the C481 site of BTK. That’s how they inhibit BTK. It appears that acalabrutinib and zanubrutinib are more selective for BTK compared with ibrutinib. That can translate into [different] adverse effect (AE) profiles. In CLL/SLL and MCL, we don’t have head-to-head comparisons between these BTK inhibitors, so it’s probably not [judicious] to look at the AEs of individual studies. Although, we do have [data] with zanubrutinib versus ibrutinib in Waldenström macroglobulinemia.

In general, it does appear that the rate of atrial fibrillation and some other cardiovascular AEs could be higher with ibrutinib compared with the next-generation BTK inhibitors. That may be related to their selectivity for BTK. We don’t know for sure, but the randomized trials will come and then we’ll have a better idea.

That being said, I have many patients who have been on ibrutinib for 5 years and are tolerating it just fine. In general, if you have patients on ibrutinib who are having problems tolerating it but are still deriving clinical benefit from it, I would switch to another BTK inhibitor like acalabrutinib or zanubrutinib so they can still derive maximum benefit from BTK inhibition. If someone progresses on ibrutinib or acalabrutinib, I’m not switching [to another BTK inhibitor] knowing that the mechanism of action is very similar.

A lot of data with BTK inhibitors have recently come out. Could you discuss some of the key trials that caught your eye and the results that have been presented so far?

Two phase 2 studies were conducted with zanubrutinib. One study was done in Australia which included patients with relapsed/refractory MCL, and the other study was done in China and primarily included patients with MCL. If you look at the MCL cohort in the Australian study plus the other study, the overall response rate was around 84% and the median PFS was approximately 17 to 19 months.

The most common AEs were cytopenias, rash, and infections. Hypertension was also reported [and is common] with most of the BTK inhibitors. However, the rate was around 12%. Additionally, atrial fibrillation, even though it has been reported with BTK inhibitors, was not seen in the MCL study. That does not mean that you don’t get atrial fibrillation with zanubrutinib, but in this particular study they had not seen atrial fibrillation within their duration of follow up. In the pooled analysis of patients with non-Hodgkin lymphoma, investigators reported a low rate of atrial fibrillation with zanubrutinib.

At the 2020 European Hematology Association Congress Virtual Congress, the CAPTIVATE study was presented with ibrutinib and venetoclax in patients with newly diagnosed CLL/SLL. In the study, there’s a lead-in with ibrutinib and then patients receive the combination with venetoclax. What’s interesting is that there are 2 different cohorts. There’s a fixed-duration cohort, and there’s an MRD-adaptive cohort. Patients who are MRD negative [after receiving the combination] are randomized to ibrutinib versus placebo. Patients who are MRD positive are randomized to continue ibrutinib or ibrutinib plus venetoclax. We don’t have data from all those separate cohorts.

[Single-institution data] on the combination of ibrutinib and venetoclax has been already published in the New England Journal of Medicine, by Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center. These data showed really exciting clinical activity with this combination. In the larger CAPTIVATE study, we do see that the MRD-negative rate in the peripheral blood was 75%. In fact, the MRD-negative rate in the bone marrow was 72%. This is one of the first studies that shows that the peripheral blood may reflect what is in the bone marrow. It would be great if patients don’t have to go through a bone marrow biopsy to see if they’re MRD negative.

It’s going to be interesting to see the data from the MRD cohort and the fixed-duration cohort. The lead-in with ibrutinib can lower the tumor lysis risk which can be associated with venetoclax. The 3 months of lead-in with ibrutinib led to a decrease in tumor lysis risk. That may lead to less hospitalizations for patients who may need to start venetoclax.

The combination has a little bit more diarrhea and a little bit more neutropenia. Some patients did have to be dose reduced. In general, this was a relatively well tolerated combination. We’ll have to wait and see what the future holds with the study.

Another study which caught my eye was the phase 3 ASPEN study with ibrutinib versus zanubrutinib in Waldenström macroglobulinemia. This the first randomized study that has read out in this space, comparing 2 different BTK inhibitors. The primary end point of the study was the proportion of patients who achieved a very good partial response (VGPR) or better by independent review committee (IRC). However, we didn’t see a significant difference in the VGPR rate or VGPR or higher response rate with zanubrutinib versus ibrutinib.

However, when you look at longer follow up and investigator-assessed responses, zanubrutinib had a higher VGPR rate compared with ibrutinib. However, this was an exploratory end point. The primary end point was IRC-assessed [responses] at an earlier time point that was not statistically different, you could say that the study was negative. However, zanubrutinib was found to be better than ibrutinib. In the study, we saw fewer discontinuations and drug holds and fewer adverse effects. We saw a lower rate of atrial fibrillation, hypertension and bleeding, and diarrhea, which is very significant. Zanubrutinib was associated with a higher rate of neutropenia; though, this did not translate into neutropenic infections. There’s a study of acalabrutinib versus ibrutinib coming down the road, so we’ll get to see more [comparative data]. This was the first glimpse of comparing 2 BTK inhibitors head to head.

How has zanubrutinib impacted the treatment landscape in MCL?

Zanubrutinib was recently approved. It’s a competitive space. A lot of patients have already seen ibrutinib. We don’t know much about the differences between zanubrutinib and acalabrutinib. In general, the field has more experience with acalabrutinib. Zanubrutinib is clearly a very good drug with equal efficacy [to the other BTK inhibitors] and a good safety profile.

We don’t necessarily know how different zanubrutinib is from acalabrutinib. Therefore, it is an option. How it’s been used, I’m not very sure. I have not used it much in my practice, but we didn’t really participate in the trial. The trials in relapsed/refractory MCL were conducted primarily outside of the United States in China and Australia. We did have a good experience with zanubrutinib in an MZL study. Overall, zanubrutinib is a well-tolerated drug and will be used.

Are there any other unanswered questions regarding the use of BTK inhibitors in B-cell malignancies?

There are many unanswered questions. BTK inhibitors have played a really central role in the treatment of CLL/SLL and have really great efficacy in that disease. Once BTK inhibitors were approved, chemoimmunotherapy slowly faded away. Then there were these large randomized studies comparing [BTK inhibitors] with chemoimmunotherapy, showing superiority. What we don’t know is whether a combination of a BTK inhibitor with venetoclax for a fixed duration is better than sequencing a BTK inhibitor with other treatments. That’s sort of the next area of research.

In MCL, [BTK inhibitors] are used in relapsed/refractory disease, and we know that the results are better if we use them earlier versus later. High-risk patients, such as those who have a p53 mutation or deletion or those who have blastoid morphology, typically do very poorly with standard treatments. If you move BTK inhibitors to the frontline space, how does that compare with standard treatments [in this patient population]. Trials are ongoing [in that regard]. The PCYC 1143 trial is looking at ibrutinib and venetoclax for high-risk or older patients in the frontline setting.

In MZL, we don’t know how BTK inhibitors compare with lenalidomide (Revlimid)-based therapy with a CD20 antibody. Is it better to give a BTK inhibitor first, or is it better to give a lenalidomide-based regimen first?

Additionally, ibrutinib has nice central nervous system (CNS) penetration, and even though it’s not technically approved in this setting, we know that it does have activity in primary secondary CNS lymphomas. What about acalabrutinib and zanubrutinib? They have not been as well studied in that space. There are so many areas we still need to research and explore.

What research efforts are ongoing with BTK inhibitors?

We’re learning a lot about MRD in the academic setting. We order blood and bone marrow biopsies for MRD testing, but what we have not done too much is MRD-adaptive therapies. The importance of MRD will become evident when it becomes actionable. Hopefully, we’ll see the results from CAPTIVATE at the 2020 American Society of Hematology Virtual Meeting.

There’s also a study of zanubrutinib, obinutuzumab (Gazyva), and venetoclax where treatment could be stopped 2 cycles after they were MRD negative. If someone was MRD negative at cycle 6 or 8, they would get 2 more cycles, and then stop treatment. That would be stopping treatment earlier than in fixed-duration studies where it’s either in the frontline setting, 1 year, or 2 years in relapsed setting when you’re combining with venetoclax without really paying that much attention to MRD.

Perhaps these MRD-based studies [can indicate] whether patients can stop treatment early or continue more intense treatment. These are very cool things to look at and may define the applicability of MRD in the treatment setting. Sequencing trials are being planned as well, which are going to be very interesting to look at. Then there are these newer generation BTK inhibitors, which have a different mechanism of action compared with ibrutinib, acalabrutinib, and zanubrutinib, which may allow us to use a BTK inhibitor, even when somebody progressed previously. These trials [with LOXO-305 and SNS-062] are very interesting to look at.