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Indirect Comparison Shows Zanubrutinib Outperforms Acalabrutinib/Venetoclax in Frontline CLL

Talha Munir, MBChB, PhD, discusses findings from an Indirect comparative of zanubrutinib vs acalabrutinib plus venetoclax in treatment-naive CLL.

CLL | Image Credit: © Motion Pics - stock.adobe.com

CLL | Image Credit:
© Motion Pics - stock.adobe.com

As the treatment landscape for chronic lymphocytic leukemia (CLL) continues to evolve, indirect comparative analyses can inform frontline therapeutic decision-making in the absence of head-to-head phase 3 trials, according to Talha Munir, MBChB, PhD.

Findings from a matching-adjusted indirect comparison (MAIC) evaluating continuous zanubrutinib (Brukinsa) vs fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta) in treatment-naive patients with CLL who do not harbor 17p deletions or TP53 mutations were presented at the 2025 ASCO Annual Meeting. The analysis leveraged individual patient data from the phase 3 SEQUOIA trial (NCT03336333) and reconstructed data from the phase 3 AMPLIFY trial (NCT03836261) to assess progression-free survival (PFS) outcomes across comparable baseline populations.

After adjusting for key baseline characteristics—including age, sex, ECOG performance status, Rai stage, IGHV mutation status, and 11q deletion status—zanubrutinib demonstrated superior PFS compared with acalabrutinib plus venetoclax (HR, 0.23; 95% CI, 0.12-0.48; P < .0001). The 36-month PFS rates were 88.5% vs 76.5%, respectively.

“We were able to show in this analysis that continuous therapy with zanubrutinib, when evaluated via indirect comparison, was superior in terms of both PFS and overall survival [OS],” Munir, a consultant hematologist at Leeds Teaching Hospitals NHS Trust, explained in an interview with OncLive®.

In the interview, Munir detailed the rationale behind conducting indirect comparisons, expanded on findings from the MAIC, and discussed other considerations for first-line treatment selection in CLL.

OncLive: What was the clinical rationale for conducting the MAIC between zanubrutinib and acalabrutinib plus venetoclax in first-line CLL?

Munir: The main reason for doing this comparison was that we now have 2 paradigms of [frontline] treatment for CLL: one is continuous therapy, and the other is [fixed-duration] therapy. The AMPLIFY trial looked at the combination of [acalabrutinib] with venetoclax, and we’ve had the data from SEQUOIA for a long time with continuous zanubrutinib. Now, we're not going to see any phase 3 comparative data, and what we want to inform people about whether an indirect comparison [could show if] one therapy could be superior [to] the other.

What was the methodology used for the MAIC, including which baseline variables were selected and how the data reconstruction was approached?

An MAIC is always going to be fraught with some issues, because we are comparing data from different trials. The methodology involved looking at patient-level data from [SEQUOIA] and then comparing it to the publicized data from [AMPLIFY]. What we tried to do was identify clinically important variables and match between the patients recruited in the [SEQUOIA] and [AMPLIFY] studies. Once we made that comparison, we arrived at an effective sample size that provided the best possible comparison between the 2 patient groups from the 2 trials. As a result, we were able to make PFS and OS adjustments and reach conclusions through this indirect comparison.

What were the key findings from the analysis, and how consistent were those results across different end points or subgroups?

The findings we were able to establish [were] that we had a common anchor in the trial, which was a standard treatment in the control arm—[bendamustine and rituximab]. Based on this anchor, and using an effective sample size of 125.6 patients from [SEQUOIA] compared with [AMPLIFY], we found that zanubrutinib was superior in terms of PFS and OS. Hence, we were able to show in this analysis that continuous therapy with zanubrutinib, when evaluated via indirect comparison, was superior.

Were there any additional relevant data regarding the safety and tolerability of continuous therapy vs fixed-duration treatment, particularly with respect to hematologic toxicity?

In terms of the safety analysis, we did not observe major differences [between groups] at this moment in time. Obviously, with continuous therapy, there is the potential to accumulate toxicity over time, but there were no significant differences between the 2 study groups. The only caveat to all of this data is that this was not a phase 3 study—this was an indirect comparison—so there are always going to be some limitations in the interpretation of the results.

Given the absence of more head-to-head data, what do you consider the key clinical factors when selecting between these two treatment approaches?

[In the absence of available clinical data] comparing continuous with fixed-duration therapy, one has to [consider all relevant] patient characteristics when choosing therapies. This kind of information gives [patients some reassurance] that they’re not necessarily losing out with continuous therapy, and if they are going to be using fixed-duration therapy, the outcomes might be slightly inferior compared with what might be seen with continuous therapy. It helps us to individualize therapy for each patient. [That’s] always an incredibly useful thing to enable.

Does this analysis open up any future avenues of investigation, or are there other questions you'd like to see answered to clarify the optimal use of these regimens?

Obviously, we would like to see a head-to-head phase 3 trial comparing continuous therapy and fixed-duration options. There are a number of trials that may be looking at this question, but one of the trials that we will be reporting out soon [will] look at different regimens compared with continuous therapy. However, the field of CLL is moving so quickly that these large phase 3 trials may be quite delayed in reporting out. Hence, to get an optimal answer, we may be waiting for some years before we get to that point. [We’ll] look forward to seeing if any of those questions can be answered.

Reference

Munir T, Yang K, Xu S, Williams R, Shadman M. Comparative efficacy of zanubrutinib (ZANU) versus fixed-duration acalabrutinib plus venetoclax (AV) for first-line treatment of chronic lymphocytic leukemia (CLL): A matching-adjusted indirect comparison (MAIC). J Clin Oncol. 2025;43(suppl16). doi:10.1200/jco.2025.43.16_suppl.e19032


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