Emerging BTK-Directed Therapies Continue to Advance the Management of CLL

Michael Choi, MD

In an interview with OncLive^®, Michael Choi, MD, highlighted several key considerations for the treatment of chronic lymphocytic leukemia (CLL) discussed in his presentation at a recent OncLive^® State of the Science Summit™ on hematologic malignancies. He provided insights on the continued development of therapies for patients who become resistant to or experience progression on available agents including noncovalent BTK inhibitors, and detailed potential advantages of the novel drug class of BTK degraders. He also noted the challenges that have been observed with attempts to integrate CAR T-cell therapy into the current CLL armamentarium.

“Hopefully not too many of our patients will need [another therapy] beyond covalent BTK inhibitors and venetoclax [Venclexta], but if they do, we’ll be ready for it,” Choi, who is a hematologist/medical oncologist and associate professor of medicine at University of California San Diego (UCSD) Health, in California asserted during the interview.

OncLive: What are treatment considerations for patients with CLL who discontinued a prior covalent BTK inhibitor due to progression or intolerance?

Choi: We’re fortunate that there have been a lot of advances in treatment strategies for our patients who are starting to have problems with the covalent BTK inhibitors and the big clinical problem would be if somebody’s losing their remission and starting to have progression. Fortunately, there’s been excellent clinical data coming out with noncovalent BTK inhibitors. Pirtobrutinib [Jaypirca] has had impressive data coming out of phase 1 and 2 trials recently published in the New England Journal of Medicine.

Although [pirtobrutinib] is not FDA approved, the treatment has been endorsed by the NCCN. This is now viewed as something that we can have for patients who maybe don’t have other good options if they’re progressing on another BTK inhibitor. It looks like these drugs have a good safety profile, and the adverse effects [AEs] are not that different from other BTK inhibitors. In fact, the cardiovascular event rate with pirtobrutinib appears to be lower to date. So far, we’re seeing that most patients can [achieve and sustain] remission for at least a year to a year and a half based on the published data so far. We’ll see over time if that continues to extend.

If patients are progressing on pirtobrutinib, of which there are few, it looks like there are a lot of things coming down the pipeline for those patients. [This includes] BTK degraders, which are now in trials and showing good activity; bispecific antibodies [are under evaluation]; and CAR T-cell therapy is something that the field has been looking at for approximately a decade. There are continuing advances with different CAR T constructs, different targets, and combinations with BTK inhibitors.

How do BTK degraders differ from BTK inhibitors in their mechanism of action, and what potential role could these agents play within the CLL treatment paradigm?

We’ve become very familiar with BTK inhibitors over the past few years. BTK degraders take the idea that we could turn off the B-cell receptor signaling pathway by inhibiting BTK one step further. [They allow us to] take advantage of the ubiquitin-proteasome pathway and degrade BTK entirely. If we can do this with a high level of specificity, then we should be able to overcome point mutations that may affect the binding of the inhibitors.

There have been a few different degraders in [development] in trials [such as NX-2127 and NX-5948]. Data presented at the 2023 ASH Annual Meeting shows that these are working as intended, that the AE profiles look similar to that of BTK inhibitors, and that we are seeing remissions with these drugs.

At UCSD, we are currently [evaluating BGB-16673] and are starting to see some partial responses for patients who have had a disease that’s been refractory to [many other agents] in the past. That is very encouraging. I’m also excited by [BTK degraders] because they are truly kind of a new approach—[this drug class is] not [built upon] a slight variation on our [existing] inhibitors but is altogether [an approach with] new chemistry and pharmacology. That opens the door to other targets and other ways that we can treat our patients in the future.

What could the approval of lisocabtagene maraleucel (Breyanzi; liso-cel) potentially mean for patients with CLL, and why has CAR T-cell therapy been more difficult to integrate into the CLL armamentarium compared with other hematologic malignancies?

Many of my patients ask when CAR T cells are going to be approved as an option to treat them. It’s a good question and it’s not for lack of efficacy—the trials have shown that CAR T-cell therapy works for patients with CLL. We’re often reminded that the very first CAR T-cell therapies to show efficacy were given to patients with CLL and some of those patients are still in remission 10 years later. [However], the [absence of an approval] for patients with CLL is due to a few [factors]. First, there is an increased risk of toxicity with CAR T-cell treatment compared with a BTK inhibitor. For many of our patients, that risk is not justified or needed unless we see signs that they are becoming resistant to existing drugs. The positioning of CAR T-cell therapy may be in later lines of therapy for patients with CLL right now.

There are still some things to improve on with the activity of CAR T-cell therapy. Patients with CLL have deficiencies in their immune system that may be distinct vs patients with other types of cancer and we will have to look at different strategies to overcome this. Some groups have already seen that they can improve the efficacy of a CAR T-cell treatment by combining it with ibrutinib [Imbruvica] or with a BTK inhibitor. That might be one strategy. With each trial and new generation of CAR T-cell therapy, slight improvements are being made. Hopefully, we get to a point where it’s an option that’s available for our patients who need it.