Role of Non-Covalent BTK Inhibitors in Mantle Cell Lymphoma Treatment: Part 4

In this expert roundtable series, Kami Maddocks, MD, The Ohio State University, Columbus, Ohio, leads a 5-part roundtable panel discussion on updates in mantle cell lymphoma with Jia Ruan, MD, PhD, Weill Cornell Medicine, New York, New York, and Krish Patel, MD, Swedish Cancer Institute, Seattle, Washington.

In the fourth video of the series, the members of the panel review the available data and discuss the role of non-covalent BTK inhibitors in the treatment of patients with mantle cell lymphoma (MCL).  

Transcript:

Kami Maddocks: Welcome to Oncology Learning Network. My name is Kami Maddocks from the Ohio State University James Comprehensive Cancer Center, and I will be moderating today's discussion on mantle cell lymphoma. I am joined today by a distinguished panel of experts in treating mantle cell lymphoma. 

Let's move on to discussion topic number 4, which is non-covalent BTK inhibitors. Earlier this year, in January, we saw the approval of the first non-covalent BTK inhibitor, pirtobrutinib, for patients who've had 2 prior therapies and been exposed to covalent BTK. Maybe we could just start, Dr Patel, if you could tell us a little bit about what is a non-covalent BTK inhibitor, and the rationale, and some of the data supporting that.

Krish Patel: The current covalent BTK inhibitors that we're all used to work by binding irreversibly to Bruton's tyrosine kinase. So non-covalent BTK inhibitors are reversible binders. They may also bind at a different site than the covalent BTK inhibitors, and so may be able to bind and inhibit BTK even when covalent BTK inhibitors can no longer work, because of the acquisition of point mutations that affect binding of covalent BTK inhibitors. Put another way, non-covalent BTK inhibitors may still work in patients where covalent BTK inhibitors are no longer able to inhibit Bruton's tyrosine kinase.

In mantle cell, it's not entirely clear how non-covalent BTK inhibitors work, so we don't tend to see as common mutations in BTK, but at least one of the non-covalent BTK inhibitors, pirtobrutinib, has been studied and identified to potentially lock BTK in a non-functional state through its binding, so it may actually stop BTK-signaling in a different way than covalent BTK inhibitors. 

That non-covalent BTK inhibitor pirtobrutinib has been studied in a very large phase 1 clinical trial of patients with B-cell lymphomas, including mantle cell. We've seen data on an initial 90 patients who had enough for us to have some early conclusions about pirtobrutinib. Essentially what we saw in that trial is in patients who had had mantle cell lymphoma previously treated with a covalent BTK inhibitor, we see a high overall response rate with the potential for durable responses. The median progression-free survival looks relatively short, but for the patients who are responding, that median duration of response is now close to about 18 months, or a year and a half. That data was updated from the BRUIN MCL trial this summer and I expect we'll see more updates. 

I think the other exciting thing about pirtobrutinib is it's a very selective BTK inhibitor, and so the toxicity profile is also very favorable, with a very low number of either treatment discontinuations due to adverse events, or dose reductions. I think this is a very important option for us. And as you mentioned, based on these data, is now approved on an accelerated basis for relapsed/refractory mantle cell.

Kami Maddocks: Great. With the approval of pirtobrutinib and the prior approval of CAR T-cell therapy, could you walk us through when you're approaching a patient in that progressing on covalent BTK inhibitor therapy, how do you look at treatment here, deciding between CAR T-cell therapy or pirtobrutinib. Or do you consider a role for both?

Jia Ruan: I think it's a very important question. I don't think that we have definitive answers. We're kind of just learning the ropes with newer agents, really. I think overall, I am enthusiastic about it because it affords a very good option for our patients. I think that especially for people that previously we were wondering how well they can tolerate CAR T, or can we generate enough high cell number for the CAR T-cell therapy? I do think that the non-covalent BTK inhibitor provides...it's a great rescue in that case. I'm also very impressed with how well-tolerated this medication is for our patient.

The other question that I have is that we were thinking about, especially for those patients who are on the pirtobrutinib non-covalent BTK inhibitor, how do we position our next plan if they're going into complete remission, versus just partial remission? Because the complete remission rate for those patients who previously had BTK inhibitor [treatment], it's not the majority. That's something to keep in mind, to monitor those patients very, very carefully. 

I'm eager to see if there's data specifically to discuss or provide some kind of guidance in terms of pirtobrutinib after CAR T. I do think that the previous trials included some of those patients, not the majority of the patients, under clinical trial and vice versa, those patients who move on to pirtobrutinib prior to CAR T and how that's affecting their overall survival or subsequent survival.

Krish Patel: I might just add to that. I think you both highlighted that most patients who are fit enough to get CAR T-cell therapy are probably going to see both therapies. I think about them really as complementary tools. We talked about the fact that when patients have disease progression on covalent BTK inhibitors, it can be very challenging. 

I think many of my patients, even who are opting for CAR T-cell therapy, because it's a finite treatment and potentially they can be off therapy for a while, are probably going to get pirtobrutinib in that time frame when we're trying to get the CAR T process started, collect the cells, manufacture them. Increasingly what we have done at our institution is recognizing that some patients have a very good response and can maintain that is potentially to even continue the pirtobrutinib and keep the CAR T cells, so that patients are potentially maximizing benefit from both therapies.

One of the things about the BRUIN trial that I think I'm a little cautious about is that there were very few patients who had had prior CAR T-cell therapy in that initial cohort. While pirtobrutinib may be active in patients post CAR T-cell therapy, we know much less about that scenario. So if patients are responding to pirtobrutinib, even if it's being given for so-called bridging, if they're responding really well, I think it's maybe important to potentially continue that and then have the CAR T-cell in waiting if we start to run into the earliest signs of trouble.

Kami Maddocks: Dr Patel, when you were talking very nicely summarizing the BRUIN study results, you mentioned the selectivity and safety of this drug. Is this something that you think about potentially switching a patient on a covalent BTK who's having toxicity? I think when we primarily used ibrutinib, or when ibrutinib was still approved, it made sense I felt like to switch from ibrutinib to [acalabrutinib] (acal) or [zanubrutinib] (zanu) when people were having toxicity. Now that we have acal and zanu, would you still switch from 1 to the other, or do you think more of switching to pirtobrutinib if there's toxicity with those?

Krish Patel: That's a really good question. I think it depends on which BTK inhibitor the patient is having toxicity on as you were mentioning. For example, if they're on ibrutinib, we know that some of the toxicities that are, I think, worse with ibrutinib can get better or not reoccur on acal or zanu. That might be my preference, if they're toxicities that are really occurring on acalabrutinib or zanubrutinib, I think those 2 drugs are probably more similar than different. 

It's not entirely clear to me that pirtobrutinib would be less toxic in that setting. I think it's potentially an option for patients that have toxicity on acalabrutinib and zanubrutinib, but perhaps I'd also maybe try dose adjustment of the covalent BTK inhibitor before switching to pirtobrutinib. But I think for patients who maybe have tried all of the second-generation covalent BTK inhibitors, a switch to pirtobrutinib would be a good option as well.