Anthony Mato, MD, MSCE, hematologic oncologist, director, CLL Program, Memorial Sloan Kettering Cancer Center, discusses recent data on the emerging class of noncovalent BTK inhibitors in chronic lymphocytic leukemia (CLL), and their potential advantage over currently approved covalent BTK inhibitors.

There are currently 3 FDA-approved covalent BTK inhibitors for the treatment of patients with CLL—ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Although these agents remain effective and viable options, the development and use of noncovalent BTK inhibitors may transform the treatment landscape and become the new standard of care in CLL, Mato begins. 

Treatment discontinuation due to adverse effects [AEs] and resistance mutations are commonly associated with the continuous administration of covalent BTK inhibitors. However, the mechanism of action and high selectivity of noncovalent agents can overcome these limitations while still preventing BTK activity, Mato explains. These agents target and noncovalently bind the target BTK molecule at a different site than covalent molecules, he adds.

Noncovalent BTK inhibitors have shown promising early efficacy and tolerability signals in clinical development, Mato continues. Data on pirtobrutinib (Jaypirca) are the most robust, he states. In the phase 1/2 BRUIN trial (NCT03740529), pirtobrutinib monotherapy was administered to patients with CLL who had previously been treated with BTK inhibitors, Bruin says. Extended follow-up was presented at the 2022 ASH Annual Meeting, and showed that the agent elicited clinically meaningful and durable response rates in this population. Moreover, pirtobrutinib continues to be well-tolerated, with a low rate of AEs and treatment discontinuation, Mato states.

Pirtobrutinib received approval for the treatment of patients with mantle cell lymphoma (MCL), and currently has an FDA orphan drug designation for CLL. Regulatory approval is currently being pursued. Although the agent has not yet been approved in CLL, its future use in clinical practice is highly anticipated, Mato concludes.

Editor’s Note: This interview was conducted prior to the 2022 ASH Annual Meeting.

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Anthony Mato, MD, MSCE, discusses recent data on the emerging class of noncovalent BTK inhibitors in chronic lymphocytic leukemia and their potential advantage over currently approved covalent BTK inhibitors. 

Dr. Mato on the Potential Use of Noncovalent BTK Inhibitors in CLL  

Dr Anthony Mato reviews the extended follow-up results from the phase 1/2 BRUIN Study that evaluated the use of pirtobrutinib in patients with lymphoma.

Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory CLL/SLL: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Anthony Mato, MD, discusses data from the following presentation:

Updated results from the phase 1/2 BRUIN study of the noncovalent BTK inhibitor (BTKi) pirtobrutinib in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]. (

Covalent BTKi have low oral bioavailability and short half-life, which may lead to suboptimal BTK target coverage in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, noncovalent BTKi, was developed. Preliminary results from the phase 1/2 BRUIN study showed that pirtobrutinib was well tolerated and demonstrated promising efficacy in patients with CLL/SLL regardless of prior therapy, number of prior lines of therapy, or 

This abstract discusses updated results from the phase 1/2 BRUIN study of pirtobrutinib in patients with previously treated CLL/SLL.

BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in patients with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles.

The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D), and the primary objective of phase 2 was overall response rate (ORR). Secondary objectives included duration of response, progression-free survival (PFS), overall survival, safety and tolerability, and pharmacokinetics. Efficacy evaluable patients included all dosed patients who underwent their first response evaluation or discontinued therapy. Safety was assessed in all patients (CLL/SLL and non-Hodgkin lymphoma).

 C481 mutations; 51 (28%) and 64 patients (37%) had 17p deletions and 

The efficacy population consisted of 252 patients with CLL/SLL.

The ORR was 68% (95% CI 62-74) among the 252 efficacy-evaluable patients with 137 partial responses (54%), 32 partial responses with lymphocytosis (13%), and 62 with stable disease (25%).

Responses deepened over time with an ORR of 73% among the patients with at least 12 months follow-up.

ORR was similar in patients who discontinued prior BTKi due to progression (68%), or adverse events or other reasons (70%). ORR was 75% in patients with 

At a median follow-up of 9.4 months for all BTKi pretreated patients, median PFS was not estimable (95% CI: 17.0 months-not estimable). In patients who received prior BTKi and BCL2 inhibitor therapy, median PFS was 18 months (95% CI: 10.7 months-not estimable).

PFS was similar in patients with CLL/SLL with 

C481 mutations and wild-type who progressed on a prior BTK inhibitor.

No dose-limiting toxicities were reported, and maximum tolerated dose was not reached.

96% of patients received ≥1 pirtobrutinib dose at or above RP2D of 200 mg daily.

1% (n=6) of patients permanently discontinued due to treatment-related adverse events.

Fatigue (23%), diarrhea (19%), and neutropenia (18%) were the most frequent treatment-emergent adverse events seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (8%).

Treatment-related hemorrhage and hypertension occurred in 8% and 7% of patients, respectively.

Pirtobrutinib demonstrates promising efficacy and safety in patients with CLL/SLL previously treated with BTK inhibitors.

 C481 mutation status, the reason for prior BTKi discontinuation (progression versus intolerance), or other classes of prior therapy received (including covalent BTK inhibitors, BCL2 inhibitors, and PI3K-delta inhibitors).

Favorable safety and tolerability are consistent with the design of pirtobrutinib as a highly selective and noncovalent reversible BTK inhibitor.

Anthony Mato, MD, discusses updated efficacy and safety results from the phase 1/2 BRUIN study of the noncovalent BTK inhibitor, pirtobrutinib, in patients with previously treated CLL/SLL that was presented at the American Society of Hematology 2021 Annual Meeting.

Rapid Readout: Pirtobrutinib, A Highly Selective, Noncovalent (Reversible) BTK Inhibitor In Previously Treated CLL/SLL: Updated Results From The Phase 1/2 BRUIN Study

People have many questions about MRD [minimal residual disease]. One of the questions is, what tests do I use? What compartment do I use? At what time point do I use this type of testing, or am I using it at all to make a clinical decision? 

 stands for minimal residual disease. It will have a growing importance in the future. Are you using it at all in clinical practice? If so, what tests, what compartment, and at what time point?

 I’m a bit conservative in this as well, so I tend to follow the prescribed regimen. MRD still doesn’t necessarily have a lot of data in terms of how to make decisions and tailor therapy if you’re MRD positive or MRD negative. We know it has prognostic value, but because it doesn’t necessarily change what I would do. I still don’t test it in routine clinical practice.

One circumstance where I might occasionally use it after a discussion with a patient is if somebody finishes a year of venetoclax-obinutuzumab combination based on CLL14 and they get anxious and concerned that they’ll be stopping therapy. Then I discuss with them the possibility of testing MRD. At that point, because the MRD rate is 70% in that setting, it helps me reinforce the point that it’s OK to stop. However, if it’s positive, then we have a discussion on whether it’s worth it to continue for another year, knowing that we don’t have any information that continuing venetoclax for an extra year helps improve progression-free survival in the context of positive MRD at that time point. That’s 1 circumstance where I have used it outside a clinical trial. And I use flow-based MRD. I’ve occasionally used clonoSEQ assay for patients who have progressed through multiple therapies and are concerned about their subsequent therapeutic approach, but that’s also a very rare situation. For the majority of my patients, I haven’t been necessarily testing for MRD.

I agree. In clinical practice, I use it at the same decision point as you do after the completion of venetoclax-based therapy, particularly in high-risk patients. I’m using both flow and next-generation sequencing. I’m trying to get a feel for both. Although on our trials, we have pretty much given up on flow cytometry because it’s impossible to standardize across sites and switched more to the clonoSEQ assay, mostly because I’m trying to make decisions for MRD based on deeper levels of remission than just 10-4. Our stopping rules are either at 10-5 or 10-6 in the peripheral blood, and I can’t get that with flow cytometry, so I’ve walked away from it for the most part.

 It’s still an evolving concept, and that’s another … 10-6 is even less than with flow cytometry, so we’d still need even more data before we make daily decisions in the clinic.

In the context of clinical trials, when we start to compare these regimens, like ibrutinib-venetoclax or venetoclax-obinutuzumab or whichever, at 10-4, they’re all going to have such high rates of MRD or undetectable residual disease. Maybe only 1 of the ways to distinguish 1 from the other, the doublets vs the triplets or whichever of the venetoclax-based therapies, might be to use the clonoSEQ, where we can nuance the proportion of patients who are at 10-5 or 10-6. We won’t get that from flow, which is another reason I’ve walked away from that a bit.

Circumstances for which MRD testing may be considered for patients with chronic lymphocytic leukemia.

MRD Testing in CLL

Because we’re talking about combinations, the world is leaning toward the novel-novel combinations or the triplets. Where do you stand on where ibrutinib-venetoclax will fit into your treatment landscape, given that it may likely be an option in the near future? Will you use it? Who will you use it for? I’m curious.

 This is a very interesting question. I still haven’t made up my mind on this. The most obvious population that could be a good candidate for this doublet-doublet therapy is patients with high-risk CLL [chronic lymphocytic leukemia] or patients with deletion 17p or 

 mutations. We know that the venetoclax-obinutuzumab combination is associated with inferior efficacy in this particular group of patients as opposed to the whole CLL cohort. For patients with high-risk CLL with 

 abnormalities, the median PFS [progression-free survival] has been reached, and it stands at about 4 years. That’s still a very impressive result for a time-limited therapy; nevertheless, it’s less effective.

On the other hand, we also know that BTK inhibitors are likely less effective in this group of patients as well based on the PFS data that we have. This will be the first group of patients where I’d be interested in using this regimen, in particular with patients who are interested in time-limited therapy. The question will then become what to use next after these patients progress and have already been exposed to the 2 most effective classes of drugs that we have in this situation for deletion 17p disease.

My answer is that it depends on the mode of progression. If I find a 

 mutation, then maybe next would be something like pirtobrutinib or repeated venetoclax. If we find a 

 mutation, then the next approach will be BTK inhibitor or the CAR [chimeric antigen receptor] T-cell approach, which is emerging. It’s still not approved for therapy of CLL, but hopefully we’ll have that as standard of care at some point. A clinical trial is still available. In regard to patients who have standard-risk CLL, I’m still not certain. What this regimen provides is an all-oral combination treatment. In my practice, it might replace BTK inhibitor single-agent because of this opportunity for time-limited therapy. I’m not sure which patients would be the best candidate. What do you think, Anthony?

I’m similar in thinking to you. My major issue with the novel-novel combinations is the comparisons. I’ve learned this term recently about relative contributions and how to assess them. When individual drugs are better than the control arm, I don’t know how to judge the combination, so that’s my major concern. What will limit my adaptation of the regimen is essentially that, relatively speaking, the comparison is placebo. The other concern I have is what you just brought up: the resistance pattern. Right now, I’m working with a younger patient who’s under 30 who’s being treated with triplet therapy in the context of a clinical trial and is progressing. I’m trying to sort out what to do next. It’s complex, particularly because the relapse is mostly nodal and it’s hard to assess what you asked for—the 

 mutations—to make that decision in real time outside getting a lymph node out. We’re starting to grapple with these questions in practice. It’s not only theoretical, so that’s a bit of a concern.

Regarding the deletion 17p population, I agree that the data look good, although there were fewer than 30 patients treated with the deletion 17p on the CAPTIVATE fixed-duration trial. The comparison in my mind is the CLL14 results with deletion 17p, where only 17 patients were treated. We’re dealing with tiny numbers of patients and trying to make these broad conclusions about which would be better. I’d use it only in a 17p deleted patient who absolutely mandated a fixed-duration schedule. Otherwise, a continuous BTK inhibitor is still a reasonable option.

 I completely agree. Of the therapies that we have that have been tested extensively, BTK inhibitors are probably the most extensively tested effective option and remain a very appropriate therapy for these patients. You mentioned triplet therapy. Do you think that has legs, or do you think that’s not the future? I found it a bit difficult in terms of tolerability in older patients of mine.

I don’t think it’s the future, and I don’t think the current trials comparing triplet therapies in the United States with ibrutinib-obinutuzumab are going to be very informative. The data I’ve seen so far from OSU [Ohio State University] on IVO [ibrutinib, venetoclax, obinutuzumab] look about as effective as ibrutinib-venetoclax but with more adverse effects, so I haven’t been a widespread promoter of triplet trials. I believe there’s a trial—maybe you can correct me on this—where acalabrutinib-venetoclax is being compared with AVO [acalabrutinib, venetoclax, obinutuzumab] vs chemoimmunotherapy. If that’s the case, it might be helpful to have that information when it’s finally published. It seems as if the acalabrutinib team are good about comparing the contribution of the CD20 vs not, so that will be very helpful.

 I agree. That will be a great study in combination with your trial that compares acalabrutinib-venetoclax vs venetoclax-obinutuzumab. That’s a randomized study as well. Those 2 studies will help us answer a lot of questions. What’s the right approach to frontline therapy of CLL? That’s interesting. Because we started the conversation with prognostic markers, while the CAPTIVATE regimen, or the doublet therapy with novel-novel, hasn’t been approved, is BTK inhibitor your go-to regimen for the majority of patients with 

 abnormalities? Or do you still consider venetoclax?

I still consider both, largely because the venetoclax data for deletion 17p are based on CLL14, with only 17 patients in that arm. It’s too small of a number for me to give up on a particular therapy that has generally been excellent for patients, so I’m not willing to do that. The long-term follow-up data from NCI [National Cancer Institute] with deletion 17p look really good. But at the same time, that’s a highly select patient population who are able to participate in a trial there. We need studies comparing these modalities—either 

 in that population or fixed duration vs continuous therapy—to give us the answer about what to do. I still offer both on and off study.

Considerations for using novel fixed-duration regimens and triplet therapy to treat patients with chronic lymphocytic leukemia.

Future Directions Treating CLL With Novel Therapy-Based Regimens

Anthony Mato, MD, MSCE, hematologic oncologist, director, CLL Program, Memorial Sloan Kettering Cancer Center, discusses the potential utilization of CAR T-cell therapy in earlier lines of therapy in chronic lymphocytic leukemia (CLL).

CAR T-cell therapy is an important investigational treatment modality in terms of immunotherapy for CLL as it is building upon the success observed with allogeneic stem cell transplant, Mato says. However, with agents such as BTK inhibitors, venetoclax (Venclexta), and non-covalent BTK inhibitors either approved or in developing in CLL, the question of how the field should sequence CAR T-cell therapy remains unanswered, Mato explains.

Moreover, the clinical trials evaluating CAR T-cell therapy in CLL have utilized the therapy in later-line settings for patients who have been through multiple classes of prior agents, Mato continues. Going forward, it will be important to design clinical trials to evaluate whether patients are suited for earlier implementation of CAR T-cell therapy, as opposed to sequencing it after patients have received multiple therapies, Mato concludes.

Anthony Mato, MD, MSCE, discusses the potential utilization of CAR T-cell therapy in earlier lines of therapy in chronic lymphocytic leukemia. 

Dr. Mato on the Potential for Early Utilization of CAR T-Cell Therapy in CLL 

Anthony Mato, MD, MSCE, hematologic oncologist, director, CLL Program, Memorial Sloan Kettering Cancer Center, discusses recent advances made in the treatment of patients with chronic lymphocytic leukemia (CLL).

In the past few years, a significant amount of data has emerged regarding the treatment of patients with CLL, Mato explains. For example, long-term follow-up data with ibrutinib (Imbruvica) and venetoclax (Venclexta) continued to demonstrate efficacy with the agents for patients with CLL.

Additionally, next-generation agents, such as the covalent BTK inhibitor acalabrutinib (Calquence), have been integrated into clinical practice. Data also emerged regarding non-covalent BTK inhibitors like pirtobrutinib (LOXO-305), demonstrating encouraging efficacy in patients with relapsed/refractory CLL, Mato explains.

The field is also developing a greater understanding of where CAR T-cell therapy may fit into treatment sequencing in CLL, as well as how to optimize doublet and triplet therapies of novel agents, Mato says. Notably, the advances made in CLL underscore a shift away from chemotherapy in the field, Mato concludes.

Anthony Mato, MD, MSCE, discusses recent advances made in the treatment of patients with chronic lymphocytic leukemia. 



Dr. Mato Discusses Advances in the Treatment of Patients With CLL 

Anthony Mato, MD, director of the Chronic Lymphocytic Leukemia Program, University of Pennsylvania, discusses how oncologists can manage adverse events associated with ibrutinib (Imbruvica) and idelalisib (Zydelig) for the treatment of patients with chronic lymphocytic leukemia (CLL).

Recognizing that toxicities can be a reason for discontinuation of treatment is important, Mato explains. The more often that community oncologists administer agents such as ibrutinib and idelalisib, the more likely they will become more familiar with managing the associated toxicities.

If it is unacceptable or medically difficult for a patient to continue medication due to its side effects, there are alternative strategies, Mato says. Researchers will begin exploring other B-cell receptor antagonists that may have improved efficacy with minimal toxicity.

Anthony Mato, MD

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