Emerging Agents Signal Promising Opportunities to Expand Treatment Options for CLL


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Anthony Mato, MD, MSCE, discusses the relapsed refractory setting compared with the frontline setting and promising agents such as pirtobrutinib and zanubrutinib.

Anthony Mato, MD, MSCE

Anthony Mato, MD, MSCE

Sequencing agents for the treatment of chronic lymphocytic leukemia (CLL) is fast becoming an area of active investigation as the development of Bruton tyrosine kinase (BTK) inhibitors with encouraging efficacy emerge, according to Anthony Mato, MD, MSCE. The covalent BTK inhibitor ibrutinib (Imbruvica) and acalabrutinib (Calquence) are approved options for patients with CLL and noncovalent BTK inhibitors have shown early signals of clinical promise.

“BTK is a very relevant target even in 2022,” Mato said. “[There are] lots of options and sequencing will be the name of the game when you think about both resistance and intolerance. The noncovalent [agents and degraders] are the most exciting area [of development] specifically for BTK as a target.”

Mato delivered the presentation “Evolving Story of BTKi +/- CD20” given at the 40th Annual CFS®, which highlighted the shifting treatment paradigm. In an interview with OncLive® during the meeting, Mato, director of the CLL program at Memorial Sloan Kettering Cancer Center, discussed the relapsed refractory setting compared with the frontline setting and promising agents such as pirtobrutinib (LOX0-305) and zanubrutinib (Brukinsa).

OncLive®: Please provide an overview of your presentation.

Mato: BTK has been a key target for CLL since 2014 when ibrutinib was approved. Over the years we’ve noted some limitations [such as] intolerance—a fair number of patients can discontinue due to an adverse event—[and] resistance because these drugs are continuous.

Long-term data for ibrutinib from the RESONATE-2 trial [NCT01722487] is quite excellent; [however, there are] limitations that can be associated with the class [of drug]. [There are also] novel agents, our next-generation agents, such as acalabrutinib and zanubrutinib [which are] both covalent BTK inhibitors, as well as the emerging class of BTK inhibitors, the noncovalent inhibitors, namely pirtobrutinib and nemtabrutinib. I ended by trying to fit in the different BTK inhibitors on the sequencing algorithm and preview what’s next [in development] including BTK degraders.

How do you decide between ibrutinib, acalabrutinib, and zanubrutinib when treating patients?

In the frontline setting we have no head-to-head data and the only agents that are approved are ibrutinib and acalabrutinib. A lot of the choice depends on the experience of the provider, the comorbidities of the patient, [and] whether you’re weighing the value of long-term efficacy data vs the possible improvement in adverse events. There are a lot of factors that go into the decision. Unfortunately, [with] the absence of head-to-head data in the frontline, it's still a little bit of a gray zone; the zanubrutinib data look promising, but it’s not yet approved.

In the relapsed or refractory setting, the choice is a bit more straightforward at least when thinking about a next-generation BTK inhibitor vs ibrutinib. [There are] 2 head-to-head studies suggesting at least equal efficacy and likely better tolerability [in terms] of cardiovascular events. The next-generation agents [are options] in the relapsed or refractory setting. In the frontline setting, [there are some who are] leaning toward the next-generation agents, as well.

What has been seen so far with noncovalent BTK inhibitors and how do they differ from the traditional covalent inhibitors?

Noncovalent BTK inhibitors may represent a very important future direction in CLL. They do what they say: form a noncovalent vs a covalent reversible vs irreversible bond with the target BTK [and] they have a different binding mode, they bind to a different area on BTK, which is relevant for overcoming the covalent BTK inhibitor resistance mutations.

What’s been seen so far is very promising and the [agent] that’s most developed is pirtobrutinib; more than 250 patients with CLL have been treated with that molecule. The results look good [and the] response rate was approximately 70%, at the last update approximately 68%, but that will be updated at the American Society of Hematology [meeting].1 The responses are durable, and the median progression-free survival was not reached at the last update.

[Pirtobrutinib] seems to overcome the issue of AEs [and there was] a discontinuation rate of approximately 1% due to AEs. Overall, it is well tolerated, [there are] durable remissions in a very relevant patient population, and it is not approved, but very excited to have that as an option in the clinic if it should come.

How are sequencing decisions going to be made as more data become available for all these agents?

It’s a tough situation because although we have lots of choices, lots of available options, we also must think about the fact that there aren’t a lot of head-to-head comparisons [or] prospective trials that study sequencing specifically, and this is where real-world data will likely fit in. [It is a] complex situation, but it’s nice to have options and certainly things have evolved very nicely over the past 5 years.


  1. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study. Blood. 2021;138(suppl 1):391. doi:10.1182/blood-2021-147599

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

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.
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