Treating CLL With BTK Inhibition: Next Steps

Alan Skarbnik, MD: As the field is moving forward, we understand that depth of response may be important for long-term outcomes for these patients. We’re trying to combine different agents with different mechanisms of action here. There are a number of trials going on. Some preliminary data have been presented at previous ASH meetings as well. What are your considerations?

Jennifer R. Brown, MD, PhD: We’re not curing anyone with single-agent BTK [Bruton tyrosine kinase] inhibitors, or with antibody therapy, or with venetoclax. If we want to strive toward cure, I think combinations are where we need to go. It’s also statistically the case that if you have non cross-resistant drugs for which the mechanisms of resistance are probably distinct—which so far seems to be true with BTK inhibitors and BCL-2 inhibitors, although the data are very limited—you’re much less likely to develop resistance if you treat with both drugs than if you treat with just 1. It’s much easier for the disease to have a mutation against 1 than mutations against both. So I think that’s driven a lot of the excitement and interest, particularly with BTK and BCL-2 inhibitor combinations.

The initial was CLARITY with ibrutinib/venetoclax in the relapsed setting in patients who had not had prior BTK inhibitors. About 25% of them had a prior PI3 kinase inhibitor, I believe. But that had about a 40% MRD [minimal residual disease] undetectable rate in the marrow, which looked quite encouraging. That’s since moved up front. MD Anderson Cancer Center has data, and there’s also CAPTIVATE data where it looks like ibrutinib and venetoclax can achieve very, very high levels of undetectable MRD in the frontline setting. We don’t really have any follow-up on that beyond the initial response data.

We’ve also been combining acalabrutinib with venetoclax and obinutuzumab at our institution, and we’ve reported very preliminary data on that at ASH. Again, the undetectable MRD rates looked quite high. The goal of many of these therapies is to achieve time-limited therapy. This would allow patients to reach a deep remission and stop therapy, because that has a lot of benefits, right? You don’t get resistance because of continuing on the drug. You reduce costs. You reduce adverse events. Patients like it. You know, they’re not patients if they’re off drug. They’re back to their life, right? I think psychologically it’s beneficial, too. So, that is hopefully where we can move for the majority of the patients, I would think.

A really key question, though, that we don’t have an answer to, which I view as a driving question for the field for randomized trials is, for example, is time-limited therapy with venetoclax/obinutuzumab equivalent in PFS [progression-free survival] to acalabrutinib or acalabrutinib/obinutuzumab continuous therapy? And, in which patient populations? And then, is a BTK/BCL-2 combination better than either alone, or with an antibody? We don’t actually know. We have no randomized data, right?

Alan Skarbnik, MD: Yes. And [the] CLL17 [trial] is opening with that question in mind. Venetoclax is given with obinutuzumab, versus ibrutinib, versus the combination of the 3 in trying to look into what the best approach will be. It will take a couple of years for us to have that data at hand. Hopefully, we’ll have some answers.

And also, in consideration of the combination of these drugs, it seems like leading with the BTK inhibitor decreases the TLS [tumor lysis syndrome] risk of the addition of venetoclax during the second or third month. So, perhaps we’ll be able to modify the process of ramping up the venetoclax in these patients to be a less cumbersome process down the road. Do you think that will be feasible?

Jennifer R. Brown, MD, PhD: I hope so. I think that we need to get data and it needs to be evaluated. You don’t want there to be a couple of outlier patients who then could have problems. We’ll see. Most of those trials are collecting systematic data on the reduction in TLS risk parameter, such as from high to moderate to low. I don’t know if they’re collecting data on actual laboratory changes when they escalate venetoclax, which of course, is what the initial risk model was based on. But it really would be ideal if we could simplify our venetoclax escalation, even in other contexts.

Alan Skarbnik, MD: Yeah, because a lot of patients don’t want to do that just because of sometimes being admitted to the hospital and the risks associated with it.

Jennifer R. Brown, MD, PhD: I mentioned earlier about the very young, fit, patients with mutations for whom we already have a plateau on the survival curve with FCR [fludarabine, cyclophosphamide, and rituximab]. There are 3 different trials that have added ibrutinib to an FC [fludarabine/cyclophosphamide] antibody-type combination to try to improve that. MD Anderson Cancer Center has done it in patients who have mutations, with essentially 100% undetectable MRD at 1 year. Our group has done it with ibrutinib/FCR in patients with and without mutations, and the undetectable MRD rate was 85%.

So, I think that these regimens, particularly for young and fit patients, remain as very valid and good options. If you’re looking at someone aged in their 40s or age 50 who needs to get through multiple decades of life, it’s not necessarily the case that we can do it with just ibrutinib or venetoclax sequential therapy. We can buy them 10 or 15 years with a regimen like this, or maybe forever.

Alan Skarbnik, MD: It could be more. That would be fantastic. Hopefully, these patients can be cured.

Jennifer R. Brown, MD, PhD: Exactly.

Well, this has been extremely informative. Thank you, Dr Skarbnik, for this insightful discussion. And thank you to our audience for watching this Targeted OncologyTM presentation on precision medicine. We hope you found this discussion to be useful and informative. Thank you.

Alan Skarbnik, MD: Thank you, Dr Brown, for having me. It was a pleasure being here.

Transcript edited for clarity.