Second-Generation BTK Inhibitors Set the Stage for Future Advances in CLL Management

Cyrus M. Khan, MD

With BTK inhibitors expanding beyond first-generation ibrutinib (Imbruvica), the sustained efficacy and improved safety profiles of the second-generation BTK inhibitors zanubrutinib (Brukinsa) and acalabrutinib (Calquence) have set a new precedent for the treatment of patients with chronic lymphocytic leukemia (CLL), according to Cyrus M. Khan, MD.

Of note, in November 2019, the FDA approved acalabrutinib for the treatment of treatment-naive and relapsed/refractory patients with CLL and small lymphocytic lymphoma (SLL); these indications were supported by findings from the phase 3 ELEVATE TN (NCT02475681) and ASCEND (NCT02970318) trials, respectively.1 Furthermore, the FDA approved zanubrutinib in January 2023 for the treatment of patients with treatment-naive or relapsed/refractory CLL/SLL.2 This regulatory decision was based on data from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials, respectively.

“There are many [ongoing] clinical trials, and if patients have relapsed/refractory [CLL], [it may be] best to look for a clinical trial they can go on because that is how we will get new treatments approved,” Khan said during an interview with OncLive®. “One of the more exciting treatments that hopefully will be approved in the future is bispecific T-cell engagers, [including] epcoritamab-bysp [Epkinly], glofitamab-gxbm [Columvi], and others. They’re showing promising utility in relapsed/refractory CLL, so hopefully we’ll eventually get those drugs approved in the future.”

In the interview, Khan discussed how zanubrutinib and acalabrutinib fit into the CLL treatment paradigm, the clinical implications of data with these BTK inhibitors, approaches to treatment decision-making, and updates from the 2025 ASCO Annual Meeting.

Khan is an assistant professor of medicine at the Drexel University School of Medicine and the assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute in Pittsburgh, Pennsylvania.

OncLive: How does zanubrutinib fit into the CLL treatment paradigm?

Khan: [Zanubrutinib fits into the paradigm] in a multitude of ways. It can be used as a frontline treatment, but it can also be used as relapsed/refractory treatment, provided the patient has not already progressed on a BTK inhibitor [in the] frontline [setting]. In the second-line as well as frontline settings, the data [with zanubrutinib] compared with ibrutinib, [showed that zanubrutinib demonstrated] more efficacy with lesser toxicity [than ibrutinib]. We also saw lower rates of atrial fibrillation, atrial flutter, and the bleeding risk that’s associated with the BTK inhibitors as a general class.

The other good aspect of zanubrutinib is that you can use it either once daily or twice a day. This allows for flexibility in dosing, which is its main benefit. It also now has availability in other disease states and lymphomas. [In particular,] it is available in follicular lymphoma in the relapsed setting, Waldenström macroglobulinemia in the relapsed setting, and marginal zone lymphoma. That gives us more confidence to use it because now we can use it in a multitude of disease states. When we got used to how to use the drug, we learned that it’s a versatile BTK inhibitor.

What is acalabrutinib’s role in the CLL treatment paradigm?

Acalabrutinib is a second-generation BTK inhibitor. We also have data [with this agent] both in the frontline and relapsed/refractory setting, provided patients haven’t progressed on a BTK inhibitor in the frontline [setting]. One of the differentiating factors [between acalabrutinib and other BTK inhibitors] is that the [one of the arms of the ELEVATE-TN] trial that led to the approval of acalabrutinib in the frontline setting added the anti-CD20 antibody obinutuzumab [Gazyva] to [acalabrutinib]. [Therefore, in clinical practice,] there’s flexibility [to choose] whether [acalabrutinib is used as a] single agent or in addition to obinutuzumab. We have seen deeper responses [with the addition of obinutuzumab], and perhaps adding obinutuzumab can speed up remission, which can be useful for patients who sometimes present with autoimmune complications that can be associated with CLL.

Acalabrutinib was also compared head-to-head with ibrutinib in the second-line setting [in ASCEND, which] showed that although the efficacy was similar [between these 2 agents regarding] progression-free survival, the adverse effect [AE] rates were lower [with acalabrutinib], particularly atrial fibrillation, atrial flutter, and bleeding risk.

What are the clinical implications of the findings from the phase 3 ELEVATE-RR trial (NCT02477696), which assessed the detailed safety profiles of acalabrutinib vs ibrutinib in patients with previously treated CLL?

We knew for many years from smaller studies, real-world analyses, and our own practice that typically acalabrutinib was safer to use than ibrutinib. [However,] there was never a head-to-head comparison. We didn’t know whether [acalabrutinib] was more efficacious, less efficacious, or [equally as efficacious as ibrutinib]. However, now there are phase 3 data from this head-to-head comparison. [Acalabrutinib] is safer, and [this gives us] more confidence using it in patients in the relapsed and frontline settings, although the data [from ELEVATE-RR] were in the relapsed setting.

How does ibrutinib—a first-generation BTK inhibitor—compare with second-generation BTK inhibitors?

The only [BTK inhibitor] we had in the first generation was ibrutinib. We were fortunate when ibrutinib [was FDA approved for patients with relapsed/refractory CLL in 2014 and first-line CLL in 2016]. Nevertheless, technology and science progress, and we have become better.

Now we know that compared with ibrutinib, [acalabrutinib] efficacy is [slightly improved]; however, we go more by the safety profile [in clinical decision-making]. We saw with ibrutinib that some patients were having atrial fibrillation and atrial flutter. There were even ventricular arrhythmias, which can be dangerous, and we saw a long-term hypertension risk. [Additionally,] we saw a bleeding risk. There were also more of the nuisance AEs, like myalgia, arthralgia, etc.

The idea for the development of second-generation drugs was that they [should] more tightly inhibit the BTK site without as many off-target effects as ibrutinib. Preclinically, we thought that would lead to fewer AEs. Now we’ve proven that is the case.

When we use second-generation BTK inhibitors, patients have fewer problems. When patients have atrial flutter, bleeding risk, and even the arthralgias, myalgias, etc., we can continue the treatment and [patients can] continue to get the benefit of BTK inhibition in CLL. We primarily feel that patients will receive benefit from BTK inhibitors longer if we use second-generation drugs.

In your practice, how do you approach BTK inhibitor selection for patients with CLL, and what data do you base your decisions on?

[These decisions are] individualized. In both the frontline and second-line settings, we discuss each treatment option with the patient to see what they’re thinking. Sometimes we can make an informed decision based on the patient’s comorbidities and social situation. However, sometimes patients can be treated with any therapy, because if they’re doing well, they can tolerate any [available] treatment. [Overall,] we discuss the pros and cons of each treatment with the patients and decide based on whichever [we both think is best], so it’s a shared decision.

What were some updates seen with BTK inhibitors at the 2025 ASCO Annual Meeting?

[One main question in the field is] what to do after BTK mutations develop. We have data with pirtobrutinib [Jaypirca], as well as data with other BTK inhibitors in development that can work for BTK C481 mutations and other mutations. There’s a lot of work being done to see how we can further improve upon what we currently have, and what we can do when the patients progress on the current crop of BTK inhibitors. There are also more real-world analyses coming out investigating BTK inhibition and what happens afterwards. How [should we] use CAR T-cell therapy in patients with CLL post-BTK inhibitor progression? How do we know BCL-2 inhibitors work post-BTK inhibitor progression?

References

1. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed July 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed July 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma