Dr Shadman on the Framework of a Meta Analysis of BTK Inhibitors in R/R CLL

There's no data in form of a prospective, randomized trial comparing zanubrutinib vs acalabrutinib, and that has resulted in a number of analyses recently done by our group and others, indirectly comparing the efficacy…of the 2 drugs."

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center and physician at Seattle Cancer Care Alliance, discussed the rationale and methodological framework behind a network meta analysis aimed at evaluating the comparative efficacy of BTK inhibitors in relapsed/refractory chronic lymphocytic leukemia (CLL).

Currently, 3 covalent BTK inhibitors—ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa)—are approved for the treatment of R/R CLL. Although head-to-head trials are available comparing acalabrutinib vs ibrutinib and zanubrutinib vs ibrutinib, no direct comparative data exist between acalabrutinib and zanubrutinib. As a result, indirect treatment comparisons have emerged as a method to evaluate these therapies when direct prospective data are lacking. One such approach is the network meta analysis, which uses statistical modeling to integrate both direct and indirect evidence across randomized controlled trials.

The network meta analysis described by Shadman and colleagues aimed to assess the relative efficacy of the 3 BTK inhibitors, in addition to chemoimmunotherapy, in the R/R CLL setting. A systematic literature review was conducted to identify relevant phase 3 trials, including the ALPINE trial (NCT03734016) of zanubrutinib vs ibrutinib; the ELEVATE-RR trial (NCT02477696) of acalabrutinib vs ibrutinib; and the ASCEND trial (NCT02970318) of acalabrutinib vs chemoimmunotherapy. These trials were chosen based on similarity in design, patient population, and end point reporting, which facilitated a more robust comparative framework.

Using this approach, the meta analysis evaluated efficacy outcomes—such as progression-free survival and overall response rate—across the 4 treatment strategies: ibrutinib, acalabrutinib, zanubrutinib, and chemoimmunotherapy. This methodology enabled estimation of relative treatment effects in the absence of head-to-head trials, offering a clinically relevant comparison of available BTK inhibitors in the relapsed/refractory CLL landscape.

Shadman emphasized that although such indirect comparisons cannot replace randomized controlled trials, they offer valuable insight into relative therapeutic performance and support evidence-based decision-making in clinical practice. Network meta analyses provide an essential tool to bridge evidence gaps where direct trial data remain unavailable, he concluded.