Acalabrutinib Demonstrates Improved Tolerability, Similar Efficacy to Ibrutinib in CLL


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John C. Byrd, MD, discusses key findings from ELEVATE-RR, differences between acalabrutinib and ibrutinib, and future directions with the second-generation inhibitor.

John C. Byrd, MD

John C. Byrd, MD

Acalabrutinib (Calquence) proved to be noninferior to ibrutinib (Imbruvica) with regard to progression-free survival (PFS) in patients with previously treated chronic lymphocytic leukemia (CLL), according to John C. Byrd, MD, who added that the second-generation BTK inhibitor also demonstrated lower frequencies of common toxicities, underscoring better tolerability.

The phase 3 ELEVATE-RR trial (NCT02477696) was the first to evaluate acalabrutinib and ibrutinib head-to-head in adult patients with previously treated CLL who had the presence of deletion(17p) or (11q), and results presented during the 2021 ASCO Annual Meeting demonstrated that the independent review committee–assessed median PFS was 38.4 months in both arms (hazard ratio [HR], 1.00; 95% CI, 0.79-1.27), meeting the primary end point.

Moreover, acalabrutinib was also found to result in a significantly lower incidence of any-grade atrial fibrillation/flutter compared with ibrutinib, at 9.4% (n = 25/266) vs 16.0% (n = 42/263), respectively. The incidence of grade 3 or higher infections between the 2 agents was reported to be comparable (P = .8777), as was the incidence of Richter transformation, at 3.8% and 4.9%, respectively.

“This is the first study that I've done as a CLL investigator where, even at the end, I felt that the patients on both arms of the study really benefited because the outcome of patients in both groups was outstanding,” Byrd, a professor of hematology at Ohio State University College of Medicine, said. “We're just in a really wonderful place for CLL in that we have very effective therapies now.”

In an interview with OncLive®, Byrd, D. Warren Brown Chair of Leukemia Research, Distinguished University Professor of Medicine, Medicinal Chemistry and Veterinary Biosciences, and senior advisor, Cancer Experimental Therapeutics, at The Ohio State University Comprehensive Cancer Center–James, discussed key findings from ELEVATE-RR, differences between acalabrutinib and ibrutinib, and future directions with the second-generation inhibitor.

OncLive®: What was the rationale for a head-to-head comparison of acalabrutinib vs ibrutinib?

Byrd: BTK inhibitors have made a very significant impact in the natural history of CLL. The first [inhibitor] approved for marketing by the FDA was ibrutinib. Although [ibrutinib] has transformed treatment [in this paradigm], the drug hits a variety of other targets that cause adverse effects [AEs] that can lead to patient discontinuation.

Acalabrutinib and several other second-generation BTK inhibitors have come forward in the clinic and have [shown efficacy that is comparable to that of] ibrutinib with respect to treatment outcome. [However, these agents] appear to have a better safety profile based upon single-arm or randomized studies where they were compared with other [therapies].

For the ELEVATE-RR study, given that we [already] have an impactful therapy for CLL that targets BTK [in the form of ibrutinib], we wanted to know whether we [could reduce] the toxicity that's observed by giving a more specific drug that targets BTK and [does] not compromise efficacy.

Could you speak to the study design and the methods used to evaluate these BTK inhibitors in this population? What were the key findings from this research?

This study focused on patients with relapsed/refractory CLL with deletion 17p or 11q who had not received a prior [BCR or BCL-2] inhibitor. The randomized, unblinded phase 3 study had a noninferiority primary end point. Noninferiority studies are generally done to show that a new therapy is at least as [effective] as, but offers some advantage over, an alternative therapy. That [advantage] might [have to do with] toxicity, cost, [that the drug is] taken less frequently, or [that it is] more patient friendly.

This study moved forward with that design in mind. The study enrolled over 500 patients and had significant follow-up at the time that it [was] reported. [Results] demonstrated that ibrutinib and acalabrutinib for the duration of response or PFS was similar. The hazard ratio between the arms was 1, so the study met its end point,[showing that] acalabrutinib is as good as ibrutinib in terms of PFS.

Furthermore, the design specified that we could then look at other [components] that distinguish acalabrutinib from ibrutinib. For example, [the incidence of] atrial fibrillation was significantly higher with ibrutinib compared with acalabrutinib. Other secondary end points were examined, such as infections, Richter transformation, and overall survival [OS]. Those all favored acalabrutinib in terms of safety and outcome, but they were not significant.

[When] looking at other AEs between the 2 drugs, there was a plethora of AEs that were problematic to patient outcome, like grade 3 or 4 hypertension, or were just irritating to patients, [such as] diarrhea, bruising, rash, and interstitial pneumonitis. [These were AEs] that would cause patients to [discontinue] therapy, and indeed, discontinuations were higher in the ibrutinib arm than in the acalabrutinib arm.

Acalabrutinib itself had some distinct AE from ibrutinib; headaches and coughing were more common. The headache that occurs with [acalabrutinib] generally did not lead to treatment cessation. When we looked at everything, the PFS was the same [between the agents]. The AEs, for the most part, were more common with ibrutinib vs acalabrutinib. Something that we really care about when we look at outcome, is not only how long our patients stay in remission, but also OS. The OS was not significantly different with acalabrutinib vs ibrutinib; however, the HR favored acalabrutinib, at 0.82.

How might the results from this study help to inform selection among available BTK inhibitors going forward?

I think there are 2 places where [these data will help to] inform decisions. The first is, when giving monotherapy with a BTK inhibitor, unless you [consider] the small group where acalabrutinib is not the appropriate choice, this study really establishes that this drug is probably a better monotherapy BTK inhibitor for patients with CLL. Our goal in combination studies is that the side effects [of the agents being combined] do not overlap. It's going to be exciting to see how the combination studies with acalabrutinib roll out as compared with ibrutinib in terms of toxicity with longer term follow up.

Could you expand on any next steps for research in this area?

The next steps with acalabrutinib will be combination studies. Hopefully 1 thing that we'll see moving forward is that patients who are on proton pump inhibitors, [a subset] which had to be omitted from this study, will have a new formulation of acalabrutinib, or alternatively, another second-generation BTK inhibitor such as zanubrutinib [Brukinsa] that can be used. [Regardless,] these results lead us to [further exploring] combinations [with which] we can hopefully treat patients for a short period of time, get them off therapy, and have them be free of their disease rather than on [continuous] therapy.

Is there anything you would like to add?

Something that always gets forgotten when we're talking about positive or negative results of a trial are the very special patients who participated in the trial. The patients with this trial, and many of the other BTK inhibitor and targeted therapy trials in CLL, have really helped move things forward to where we have good therapies. The patients, the FDA, and everybody [who has] helped move these [drugs] forward, deserve recognition because we're at such a great place for the therapy of CLL right now.


Byrd JC, Himmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39(15):7500. doi:10.1200/JCO.2021.39.15_suppl.7500

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