Mantle Cell Lymphoma Podcast

Bruton Tyrosine Kinase Inhibitors in Mantle Cell Lymphoma: Mutations and Mechanisms of Resistance

Peter Martin, MD; Anita Kumar, MD


May 31, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Peter Martin, MD: Hello. I'm Dr Peter Martin from the Lymphoma Program at Weill Cornell Medicine and the Meyer Cancer Center in New York City. Welcome to Medscape's InDiscussion series on mantle cell lymphoma. Today, we will be discussing Bruton tyrosine kinase (BTK) inhibitors in mantle cell lymphoma, a topic that on the surface is pretty straightforward. Everyone treating mantle cell lymphoma agrees that BTK inhibitors have a role, and they're approved for treatment of previously treated mantle cell lymphoma. The reality, however, is far more exciting. Today, we'll be dipping a toe into that world. First, let me introduce my guest, Dr Anita Kumar. Dr Kumar is an expert in lymphoma and mantle cell lymphoma at Memorial Sloan Kettering. Anita, welcome to InDiscussion.

Anita Kumar, MD: Thank you so much, Peter, for having me. It's great to be here with you.

Martin: I think all of our listeners will have seen your name on a variety of topics recently — minimal residual disease in diffuse large B-cell lymphoma and Hodgkin lymphoma. But from our years of working together over the past decade, I know you've been interested in mantle cell lymphoma for a long time, and I'm wondering how that interest came about and whether it had anything to do with the rise of BTK inhibitors.

Kumar: That's a great question. When I started off at Memorial Sloan Kettering, I was focused on Hodgkin lymphoma and spent a lot of time thinking about disease bulk in Hodgkin lymphoma. But in my clinical practice, I had a chance to see a variety of both Hodgkin and non-Hodgkin lymphomas. When I started as a faculty member, there was an opportunity to develop a new frontline study for mantle cell lymphoma. And as you mentioned, it was really an exciting time. Although chemotherapy had been a mainstay of treatment in mantle cell lymphoma, we were at the dawn of the development of a number of novel biologically targeted therapies with bortezomib, lenalidomide, and then the development of the BTK inhibitors. So it was really an exciting time to get involved in the field of mantle cell lymphoma.

Martin: I have a lot of questions I'm excited to get to, mostly around frontline use of the BTK inhibitors. But for the sake of all of our listeners, maybe we can quickly go over some of the actually approved indications for mantle cell lymphoma. Can you walk us through the trials of the initial three covalently bound BTK inhibitors that got each of those approved?

Kumar: Yes. The first BTK inhibitor on the block, so to speak, was ibrutinib, and that became FDA approved for the treatment of relapsed or refractory mantle cell lymphoma based on the very exciting data at the time from a phase 2 study, PCYC-1104. That study was published in 2013 and included 111 patients with mantle cell lymphoma who had received, in most cases, multiple prior lines of therapy. The overall response rate associated with single-agent ibrutinib was 66%, the complete response (CR) rate was 17%, and the median progression-free survival was around 14 months. So in comparison to other treatments at that time, such as bortezomib or lenalidomide, this was remarkably efficacious and an exciting development in the field of mantle cell lymphoma. Then came the development of the second-generation BTK inhibitors, acalabrutinib and zanubrutinib. Acalabrutinib was approved based on a phase 2 study, ACE-LY-004, which was published in 2017 and included 124 patients. The overall response rate reported in that study was somewhat higher, 81%, with a CR rate of 40% and a median progression-free survival of 22 months. And then a study on zanubrutinib was published in 2020, the phase 2 experience, BGB 3111-206, and that included 86 patients. The overall response rate was also very promising, 84%, with a CR rate of 78% and median progression-free survival of 33 months. So, until just a few weeks ago, those were the three covalent BTK inhibitors that had been approved for relapsed or refractory mantle cell lymphoma.

Martin: The efficacy data differ in each of those trials. You can make the argument that there might be some differences in terms of study design or patient population that might explain some of it. There may also be differences in the drugs that account for some of it, but it is hard to know in those studies. In addition to some differences in efficacy data, there are also some differences in safety profiles. Do you think that in the absence of phase 3 trials in mantle cell lymphoma, it is reasonable to select one or the other under certain circumstances?

Kumar: Yes. And that's a great question, given that we don't have head-to-head comparison data between the three different covalent BTK inhibitors. Looking across these phase 2 experiences, we can note that there are differences in terms of the response criteria that were utilized across these studies, as well as differences in the patient populations and the number of lines of therapy that had been previously received. These may impact the overall response rate estimates and the progression-free survival estimates. In general, most of us in the field feel that the efficacy is likely very similar across these three covalent BTK inhibitors. However, as you mentioned, there are key differences in terms of the adverse event or safety profiles of these three agents. We know that there are differing degrees of off-target kinase inhibition with these BTK inhibitors, and ibrutinib, the first-generation BTK inhibitor, does have greater off-target effects. It does hit some other kinases, interleukin-2–inducible T-cell kinase and other Tec kinases that drive the higher incidents of particular adverse events. Notably, there is an increased incidence of cardiovascular adverse events associated with ibrutinib, such as atrial fibrillation and hypertension. This is particularly relevant in mantle cell lymphoma because mantle cell lymphoma is typically diagnosed in older adults, with a median age at presentation of 68 years. So, many of our patients come to us with preexisting cardiovascular comorbidities and other medical issues. In my practice, in general, we favor the use of second-generation BTK inhibitors like acalabrutinib and zanubrutinib, which have been associated with fewer adverse events compared to ibrutinib, particularly higher-grade adverse events and cardiovascular adverse events. One other factor that sometimes impacts my selection of a covalent BTK inhibitor is the issue around financial toxicity with these agents. They are commercially available. However, there can be differences in terms of insurance coverage based on a patient's particular insurance provider. So oftentimes, I'll put in for consideration both the acalabrutinib and zanubrutinib and then see if one is associated with a lower copay for an individual patient. Sometimes we do factor that into our consideration with regard to the treatment.

Martin: Same here. It's interesting that this becomes part of the metric in determining which one to use. So, the newest drug just approved last week is pirtobrutinib, which is different from the other three. Can you explain how it's different and what the data are that led to the approval of pirtobrutinib?

Kumar: Pirtobrutinib is a noncovalent, reversible BTK inhibitor, and it has the ability to bind to BTK in such a way that it is able to bind to wild-type BTK and also BTK, which has acquired mutations. For example, the C481S mutation that has been well-described in chronic lymphocytic leukemia (CLL) — we see that pirtobrutinib is able to bind with similar potency to BTK with this mutation, as well as to wild-type BTK. Pirtobrutinib is a highly selective BTK inhibitor and does have some favorable pharmacologic properties that allow for continuous BTK inhibition throughout the once-daily dosing interval. The recent FDA approval was based on data from the phase 1/2 BRUIN study, which included a number of different B-cell non-Hodgkin lymphoma histologies but also a subset of relapsed or refractory mantle cell lymphoma patients who were treated with pirtobrutinib at a dose of 200 mg once daily. And in a subset of 90 patients, among which 82% had previously received a covalent BTK inhibitor and experienced disease progression after receipt, it was seen that the overall response rate was approximately 58%, with a CR rate of 20%. At the median follow-up of 12 months, the median duration of response was approximately 22 months. These are very exciting data because as you've published, Peter, outcomes for patients after they progress with a covalent BTK inhibitor have typically been quite poor, and there are limited therapeutic options for this group of patients. We do have CAR T-cell therapy as a potential option. However, there can be difficulties accessing this treatment, particularly in a timely manner, for many patients. So having an oral and very well-tolerated targeted agent for this patient population is an exciting advance for the treatment of relapsed or refractory mantle cell lymphoma.

Martin: You brought up two key points there. I think it was ASH 2014 or right around that time that ibrutinib had been approved, and somebody who I realized afterward was probably a financial analyst — not a scientist — asked me if I thought mantle cell lymphoma would become like chronic myeloid leukemia and there would be BTK mutations the same way we see BCR-ABL mutations and if we'd get a whole new series of drugs — a new series of tyrosine kinase inhibitors. And I thought at the time, no, probably not. Mantle cell lymphoma is a pretty complicated disease. Lots of different things go on. Since then, many people have now described the C481S mutations happening in mantle cell lymphoma. But for the most part, we don't really see it. I know you have been doing a lot of sequencing of your mantle cell lymphomas. Have you been seeing that mutation or other mutations arising in the context of BTK inhibitors?

Kumar: That's a really great question. There are a number of unanswered questions in terms of better understanding mechanisms of resistance to BTK therapy in mantle cell lymphoma. I think we know more in CLL, and like you said, the resistance mutations that occur within the BTK binding pocket are quite rare, actually, in mantle cell lymphoma. In our experience, sequencing patients who have received covalent BTK inhibitors, we have seen the C481S mutation, but it occurs quite rarely. And so among the grand majority of patients who progress after receipt of covalent BTK inhibitors, it continues to be a mystery and an unanswered area we are looking to further explore. Why do patients develop resistance and what are the mechanisms? I think there are a variety of different hypotheses. Certainly, we have identified some mutations in downstream components of the B-cell receptor pathway beyond BTK. So we have seen mutations, for example, in the scaffolding protein CARD11, which signals downstream of BTK. There have also been some elegant preclinical and clinical work that has described mutations in negative NF-κB regulators like TRAF2 and TRAF3 and BIRC3. That can lead to the activation of the alternative or noncanonical NF-κB signaling pathway. And we have seen those mutations in our experience at Memorial Sloan Kettering, but I think there's still a lot of work to be done in this area. Hopefully, we'll be able to better understand mutations that are relevant — a resistance to covalent BTK inhibitors but also to the noncovalent BTK inhibitor pirtobrutinib. There has been some work done at Memorial Sloan Kettering looking at mechanisms of resistance to pirtobrutinib in CLL. And one of the interesting findings was that patients with CLL who were treated with single-agent pirtobrutinib and then progressed were found to have novel mutations in BTK that developed. We do have one patient who was treated in the BRUIN study and received pirtobrutinib. That patient actually did have a C481S mutation after receiving ibrutinib for around 3 or 4 years. They had a nice response to pirtobrutinib initially and then progressed after about 8 months on therapy. At that time, a biopsy revealed an acquired BTK mutation, the T474I mutation, which has been described in CLL. So, it's going to be a really interesting area of ongoing discovery to better understand these mechanisms of resistance to both covalent and noncovalent BTK inhibitors.

Martin: I will leave that for a minute, and let's try to move to where we're headed in the future, which is the frontline setting. We all see BTK inhibitors moving up front. We saw in the SHINE trial, bendamustine and rituximab plus or minus ibrutinib in nontransplant patients provided a progression-free survival benefit. And then the TRIANGLE trial just presented, which is transplant-eligible patients being effectively randomized between ibrutinib vs a stem cell transplant. The patients had better outcomes if they received ibrutinib with or without a transplant than if they got a transplant without ibrutinib. So clearly, BTK inhibitors have a role in combination with chemotherapy in the frontline setting. But let's skip over all of that and go right to where I think we all want this to go, which is leaving the chemotherapy behind and going right to the BTK inhibitors. That's something you've been working on with the BOVen trial. Can you tell us about the BOVen trial and how you got there?

Kumar: Like you mentioned, on the horizon, we can potentially envision a chemotherapy-free era. Certainly, the exciting activity of BTK inhibitors as well as BH3 mimetics like venetoclax for the treatment of relapsed or refractory mantle cell lymphoma has allowed us to envision moving these agents into the frontline setting. It's been described in mantle cell lymphoma that if we use these targeted agents earlier on, they tend to be more efficacious and better tolerated. So I think that provides a strong rationale for us to use them earlier. There seems to be synergy with combinations, as well. We can learn a lot from the CLL experience; they seem to be a few steps ahead of mantle cell lymphoma, and CLL is certainly a disease that's biologically and clinically similar to mantle cell lymphoma. We've seen that in CLL, BTK inhibitors have eclipsed chemotherapy and now are the standard frontline approach for CLL that requires treatment. Given that whole backdrop, we were interested in thinking about a combination of the anti-CD20 monoclonal antibody obinutuzumab in conjunction with zanubrutinib, a covalent BTK inhibitor, and venetoclax, the BCL2 inhibitor. And we were interested in studying this specifically in high-risk mantle cell lymphoma patients who had evidence of p53 aberrancy. That was the area where we felt there was greatest unmet need because these patients with p53 aberrancy really had poor outcomes with standard chemoimmunotherapy and mantle cell lymphoma. There was clearly a need to think about novel treatment approaches, and looking in the relapsed or refractory setting, we saw that there was synergy with these types of combinations. So we hypothesized that this three-drug combination could represent a potentially more efficacious treatment approach for high-risk mantle cell lymphoma patients. The BOVen study specifically enrolled 25 patients with p53-mutated mantle cell lymphoma. And at this point, with the 25 patients, we have a median follow-up of 12 months, and 19 patients remain progression free and are continuing on therapy. We saw an overall high response rate of 96% with this treatment combination and a CR rate of approximately 75%. It's early days in terms of the study — our primary endpoint is 2-year progression-free survival — but we're encouraged by the early results, particularly for this group of patients who tend to have a fairly short progression-free survival and overall survival with standard treatments.

Martin: There are a handful of triplets that are being evaluated in this setting. I can't think of any that are notably better or worse than one another. BOVen clearly has the most active and best tolerated of all of the drugs in that potential triplet. So it's exciting. But eventually we're going to have to take one of these triplets. Now at the National Cancer Institute, they even have the ViPOR regimen, which has five drugs. How do we practically figure out which one of these drugs goes into a phase 3 trial? Do you want to talk about that and maybe even mention some of the ongoing phase 3 trials that might help move us a little bit closer to this?

Kumar: I agree with you. There are a lot of exciting combinations. Dr Ruan's data from ASH this past year showed exciting activity with acalabrutinib, lenalidomide, and rituximab, and there are a number of active combinations. I think the phase 3 studies that will be most informative are the BeiGene-sponsored phase 3 study, which is going to compare bendamustine and rituximab to zanubrutinib and rituximab in older mantle cell lymphoma patients. This will be a very important, potentially practice-changing study in the field. And then the United Kingdom randomized phase 2 ENRICH study is comparing ibrutinib and rituximab to rituximab and chemotherapy. For older mantle cell lymphoma patients, this will also be a trial that will help us to better understand whether these chemotherapy-free combinations are better than established chemoimmunotherapy regimens.

Martin: And then now we have also the bispecific antibodies that are moving forward. In a way, designing a study to move into the next phase 3 trial is hard until you see where all of the phase 2 trials land. But if we keep doing that, we'll never have a new standard of care. It's kind of a catch-22 where you want things to keep getting better. They keep getting better faster than we can possibly test them. It's challenging. It's a good position, but it's a new one to be in, I think.

Kumar: Absolutely. It's going to be interesting to try to weigh the importance of the initial efficacy of the therapy against the toxicity of the different agents and also access to these different therapies. Like you said, CAR T-cell therapy is very exciting and highly efficacious. But logistically, it can be very challenging to access CAR T-cell therapy, which is available only at specialized centers. And from your data from Flatiron, we can see that despite national and international guidelines that supported autologous stem cell transplant at the time, only around 20%-25% of patients who were younger with mantle cell lymphoma received an upfront autologous stem cell transplant. This gives us a good hint that access and logistics and therapies that can be easily administered within the community and allow patients to maintain a good quality of life are very important considerations when thinking about what treatments will represent the next wave of most attractive therapies for our patients with mantle cell lymphoma.

Martin: That's a great point. We're really good at developing regimens that only we can give, which is not good for the bulk of people with mantle cell lymphoma in the United States or the world, for that matter. Thank you very much, Anita. Today, we spoke with Dr Anita Kumar about mantle cell lymphoma. In summary, we learned that the three covalent BTK inhibitors are very interesting. And now we have the additional noncovalent pirtobrutinib, which we'll all get more experience with in the near future. The mechanisms of resistance are complicated and not entirely understood. Despite the recognition that BTK mutations play a role, they don't play their only role in BTK inhibitor resistance. And then we're also seeing the BTK inhibitors move into the frontline setting, clearly with chemotherapy but also excitingly in doublets and triplets, as in the BOVen regimen that Dr Kumar is involved in leading at Memorial Sloan Kettering. Thank you, everyone, for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on mantle cell lymphoma. This is Dr Peter Martin for InDiscussion.


Long-term Follow-up of MCL Patients Treated With Single-Agent Ibrutinib: Updated Safety and Efficacy Results

Acalabrutinib in Relapsed or Refractory Mantle Cell Lymphoma (ACE-LY-004): A Single-Arm, Multicentre, Phase 2 Trial

Treatment of Patients With Relapsed or Refractory Mantle-Cell Lymphoma With Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

The Potential of Pirtobrutinib in Multiple B-cell Malignancies

Pirtobrutinib in Relapsed or Refractory B-cell Malignancies (BRUIN): A Phase 1/2 Study

Postibrutinib Outcomes in Patients With Mantle Cell Lymphoma

Genetic Heterogeneity in Primary and Relapsed Mantle Cell Lymphomas: Impact of Recurrent CARD11 Mutations

NF-κB Signaling and Its Relevance to the Treatment of Mantle Cell Lymphoma

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

Ibrutinib Plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma

Efficacy and Safety of Ibrutinib Combined With Standard First-line Treatment or as Substitute for Autologous Stem Cell Transplantation in Younger Patients With Mantle Cell Lymphoma: Results From the Randomized Triangle Trial by the European MCL Network

Zanubrutinib, Obinutuzumab, and Venetoclax With Minimal Residual Disease-Driven Discontinuation in Previously Untreated Patients With Chronic Lymphocytic Leukaemia or Small Lymphocytic Lymphoma: A Multicentre, Single-arm, Phase 2 Trial

A Phase II Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma

Phase 2 Trial of Acalabrutinib-Lenalidomide-Rituximab (ALR) With Real-time Monitoring of MRD in Patients With Treatment-Naïve Mantle Cell Lymphoma

A Phase III Study of Zanubrutinib Plus Rituximab Versus Bendamustine Plus Rituximab in Transplant-Ineligible, Untreated Mantle Cell Lymphoma

A Study Looking at Ibrutinib for Older People With Mantle Cell Lymphoma (ENRICH)

Treatment Outcomes and Roles of Transplantation and Maintenance Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts

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