A new matching adjusted indirect comparison of the efficacy of zanubrutinib vs acalabrutinib in relapsed or refractory chronic lymphocytic leukemia (CLL) based on data from the phase III ALPINE and ASCEND trials was presented by Shadman et al at the 28th Annual International Congress on Hematologic Malignancies. The analysis suggests a progression-free survival and complete response advantage for zanubrutinib over acalabrutinib, as well as potentially improved overall survival.
Zanubrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK); acalabrutinib is an irreversible and selective BTK inhibitor.
“The CLL landscape is evolving rapidly, and this matching adjusted indirect comparison provides timely comparative effectiveness data for physicians, and reinforces zanubrutinib’s role as a foundational CLL treatment via a robust evaluation of the efficacy in the ASCEND and ALPINE studies; the presented analysis not only accounts for differences in key patient characteristics, but also clarifies the impact COVID-19 may have had on study outcomes,” said study author Mazyar Shadman, MD, MPH, Associate Professor of Hematology and Oncology, Lymphoid Malignancies and Immunotherapy, Fred Hutch Cancer Center and University of Washington. “Head-to-head randomized clinical trials are the gold standard when it comes to evaluating the potential impact of individual treatments for patients. Matching adjusted indirect comparisons are intended to be hypothesis-generating, provided they are conducted with appropriate rigor to minimize potential biases.”
Key Details
In this matching adjusted indirect comparison, individual patient-level data from ALPINE was matched against the aggregate data from ASCEND. An unanchored matching adjusted indirect comparison was used due to the lack of a common comparator arm between the ALPINE and ASCEND trials. Given the differences in the timing of the studies, with respect to the onset of the COVID-19 pandemic, the analysis adjusted for the impact of COVID-19 in the ALPINE study.
In a previously published matching adjusted indirect comparison of zanubrutinib vs acalabrutinib by Kittai et al in the American Journal of Hematology, there were significant limitations that precluded a robust efficacy comparison, including the exclusion of data from the final analysis of ALPINE, lack of adjustment for the impact of COVID-19 on the outcomes, lack of adjustment for key differences in patient characteristics, the effective sample size, and the exclusion of complete response rate and overall survival from the analysis.
Zanubrutinib is the only BTK inhibitor to demonstrate progression-free survival superiority vs ibrutinib in relapsed or refractory CLL, as observed in the ALPINE trial. Acalabrutinib has demonstrated improvement in progression-free survival vs rituximab plus idelalisib/bendamustine in relapsed or refractory CLL in the ASCEND trial, and has also demonstrated progression-free survival noninferiority vs ibrutinib in patients relapsed or refractory CLL with chromosome 17p or 11q deletions in the ELEVATE-RR trial.
The matching adjusted indirect comparison suggests that investigator-assessed progression-free survival was improved for zanubrutinib vs acalabrutinib in both the unadjusted population (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.55–1.07), as well as the base case-adjusted population (HR = 0.68, 95% CI = 0.46–0.99). Additionally, the odds ratio for complete response favored zanubrutinib over acalabrutinib in the unadjusted (odds ratio [OR] = 2.88, 95% CI = 1.18–7.02) and base case-adjusted populations (OR = 2.90, 95% CI = 1.13–7.43). Results for the sensitivity analysis were consistent with the base case. The overall survival trend remained consistently in favor of zanubrutinib.
While matching adjusted indirect comparison analyses can be hypotheses-generating, in the absence of head-to-head data, the safety of a drug may be best evaluated using all available evidence across indications. A recent independent Mayo Clinic meta-analysis of 61 trials involving 6,959 patients who received ibrutinib plus an anti-CD20 antibody, acalabrutinib, and zanubrutinib extensively analyzed the adverse event profiles of the two therapies across several indications and reported key differences in the safety profiles of the two treatments.
