BTK Inhibitors Revolutionize Treatment in B-Cell Malignancies, But Require AE Awareness

Shuo Ma, MD, PhD

BTK inhibitors have emerged as a major treatment option for patients with B-cell malignancies, according to Shuo Ma, MD, PhD, who added that although these agents have improved outcomes, it is very important to be mindful of the associated toxicities that come with treatment. Newer-generation agents are being developed to address that challenge and overcome known resistance mechanisms.

“BTK inhibitors have been a great addition to our treatment options for [patients with] B-cell malignancies; these agents have really improved quality of life for our patients. Patients can take these inhibitors and continue their normal lifestyle,” said Ma. “However, we do need to understand the potential risk [of this approach] when selecting treatment. We must carefully monitor [them] to ensure they can continue [treatment] in a safe manner.”

Although the first-generation BTK inhibitor ibrutinib (Imbruvica) has shown great efficacy and received approval for use in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, and marginal zone lymphoma (MZL), it poses a serious risk to patients with cardiac comorbidities, noted Ma. Second-generation BTKs, such as acalabrutinib (Tecentriq) or zanubrutinib (Brukinsa), were developed to be more selective with less off-target effects, and ongoing trials are examining this further.

In an interview with OncLive, Ma, an associate professor at the Feinberg School of Medicine of Northwestern Medicine, discusses the evolving role of BTK inhibitors in B-cell malignancies, ongoing research efforts examining their use, safety concerns to be aware of with the agents, and next steps for research.

OncLive: Could you start off by providing an overview of how BTK inhibitors are being used to treat patients with B-cell malignancies?

Ma: BTK inhibitors, as we know, have really been emerging as a major treatment option for various B-cell malignancies. This started in 2013, when ibrutinib was initially approved for MCL; it was later approved for CLL, and then Waldenström macroglobulinemia and MZL. It has been studied in other malignancies, as well.

In recent years, we have had newer BTK inhibitors emerge, [such as] acalabrutinib (Calquence) and zanubrutinib. Many ongoing clinical trials are studying those different BTK inhibitors across different B-cell malignancies. They have really revolutionized our treatment of [patients with] various B-cell malignancies.

Could you expand on how you use these agents in practice?

Ibrutinib and acalabrutinib are approved for both frontline and relapsed CLL. In terms of how we're using these agents in a clinical setting, they are really [becoming] 1 of [our] major first-line treatment options. Over that past several years, many very large, randomized clinical trials have compared BTK inhibitor-based therapies with the conventional immunochemotherapy. [BTK inhibitors] have shown significant benefit in terms of the progression-free survival, even when compared with the best immunochemotherapy [regimens that] we have. The BTK inhibitor-based therapies are really starting to become a mainstream frontline treatment. In the relapsed setting, targeted therapies are gradually replacing our conventional treatments. BTK inhibitors and BCL-2 inhibitors are really becoming the mainstream treatment for the relapsed setting, as well. In general, for CLL, BTK inhibitors play a major role.

For other lymphomas, [they're more so used] in the relapsed setting. In MCL, ibrutinib, acalabrutinib, and zanubrutinib are approved for use in the relapsed/refractory setting. [These agents have] not been approved for use as frontline treatment and are not being currently used as a standard treatment. However, ongoing clinical trials are exploring [how they can be] incorporated into the frontline or maybe as a maintenance therapy or consolidation approach.

For MZL, ibrutinib is also approved in the relapsed/refractory setting. Similar to MCL, the agent is not being used as the standard of care for the frontline setting, but trials are exploring this option. For Waldenström macroglobulinemia, ibrutinib is currently the only agent approved for use, so it is being used either in the frontline or the relapsed setting. The other 2 BTK inhibitors, acalabrutinib and zanubrutinib, are both being studied in a clinical trial setting [for this disease, as well].

What factors do you consider when selecting among the available BTK inhibitors?

Currently, first-generation BTK inhibitors are represented by ibrutinib, while the second-generation BTK inhibitors are represented by acalabrutinib and zanubrutinib. The latter 2 are referred to as second generation because they are more selective for BTK. The main mechanism of action for ibrutinib is to inhibit the BTK enzyme. However, beyond BTK, ibrutinib also affects some other tyrosine kinases, such as TAG and EGFR. Some of the other targets are probably responsible for some of the adverse effects (AEs) that we see with ibrutinib.

The hope with the newer-generation BTK inhibitors it to try and limit the off-target effects by being more selective. Theoretically, we're hoping for less AEs because these agents are more selective; however, that still needs to be demonstrated on a clinical trial. To this end, ongoing clinical trials are now comparing ibrutinib versus acalabrutinib or ibrutinib versus zanubrutinib in different B-cell malignancies.

When we're selecting treatment, because ibrutinib has been used for so many years, it probably has the longest track record and there are a lot of long-term survival data. For those reasons, it is still the current mainstream treatment. However, when we're looking at a particular patient who is a candidate for a BTK inhibitor, I would look at their comorbidities [when making my decision].

For example, I would examine their cardiac history because 1 of the most concerning AEs with ibrutinib is the cardiac risk, in particular the risk of atrial fibrillation and hypertension. For patients who have a history of significant cardiac disease, such as atrial fibrillation, congestive heart failure, or valvular heart disease, I would be in favor of selecting a second-generation BTK inhibitor.

Based on separate clinical trials, the reported incidences of atrial fibrillation were [found to be] lower with a second-generation inhibitor. The only randomized study we have, for which we only have preliminary data, is one that is examining zanubrutinib versus ibrutinib in Waldenström macroglobulinemia. In that study, the incidence of atrial fibrillation was significantly lower with zanubrutinib.

Could you expand on the available data supporting the use of zanubrutinib in this space?

We know that zanubrutinib is currently FDA approved for the treatment of [patients with] relapsed/refractory MCL. The data that supported that [decision] was [from] a phase 2 study [that was done] in the relapsed/refractory setting. Results demonstrated significant clinical benefit [with the agent] based on response rate.

Zanubrutinib is also being studied in other B-cell malignancies. At the 2020 ASCO Virtual Meeting, investigators reported [data] from a randomized phase 3 study with compared single-agent zanubrutinib with ibrutinib as a treatment for [patients with] Waldenström macroglobulinemia. Preliminary findings showed that the clinical efficacy of zanubrutinib is definitely comparable to that of ibrutinib. The overall response rate was very similar, with a trend toward very good partial response rate, although it has not yet reached statistical significance.

In terms of safety, there are definitely very encouraging signals that [those who receive] zanubrutinib may have a lower risk of [experiencing] several important continuous AEs, cardiac toxicities. The atrial fibrillation rate reported was significantly lower compared with [what had been observed with] ibrutinib. The 1 AE that was shown to occur a bit [more with zanubrutinib] was neutropenia. Other than that, there appears to be fewer AEs with zanubrutinib; it appears to be a very well-tolerated drug.

Other clinical trials are examining the role of zanubrutinib in follicular lymphoma. At our institution, we're participating in 1 of the clinical trials for relapsed follicular lymphoma, comparing an anti-CD20 antibody with or without zanubrutinib. Other trials are examining zanubrutinib in MZL and other B-cell malignancies, as well. Many trials are ongoing, so hopefully we'll see some data come out in the [next few] years.

What are some remaining questions with BTK inhibitors in B-cell malignancies? What is some of the research that is being down with newer-generation inhibitors?

Yes, there are several. What are we going to do for patients who develop resistance? What is the mechanism of resistance for BTK inhibitors? For some [malignancies], we have more information. For example, in CLL, we do know that certain mutations, for example, a mutation directly in the BTK enzyme itself or other mutations can confer resistance to the first-generation or second-generation BTK inhibitor. Based on that, newer, third-generation BTK inhibitors are being studied. In comparison with the previous BTK inhibitors, which have irreversible binding to BTK, the newer-generation agents have reversible binding that might [allow them] to overcome the resistance. Some new compounds are showing very promising early results.

We also need to understand the AEs [of these agents] better. For example, the bleeding risk is universal across all BTK inhibitors, but we don't really know much about the detailed mechanism of that bleeding risk. We just know it has some kind of anti-platelet effect, [the mechanism of which] is unclear. That needs to be studied. Maybe in the future, we can design newer generations of agents that hopefully will avoid hitting those targets that cause bleeding.

Since these BTK inhibitors work so well, they are being used a lot. However, the 1 thing that is a little unsatisfying for patients is that these agents are given continuously. You cannot really stop treatment, because when you do, many patients will [progress]. We need to know: Is there a point in certain diseases where we can stop treatment? What would happen? Not every patient will progress after stopping treatment, so we just don't know which patient can safely stop.

We had some experience with a patient who stopped treatment because of AEs; [this happened with] one of my patients who went into remission, continued remission for a few years. I think we need to understand more about whether there's some feasibility of stopping treatment at some point.

The financial toxicity is another thing we need to address. A long-term treatment is a very expensive treatment. It's quite a big burden on the patient and for society, as well. That's something that hopefully the industry can eventually [work on] so we can cut down on the cost.