Dr Kittai on an Indirect Comparison of Acalabrutinib Plus Obinutuzumab vs Zanubrutinib in CLL/SLL

Adam Kittai, MD, discusses key findings from a matching-adjusted, indirect comparison of acalabrutinib (Calquence) with or without obinutuzumab (Gazyva) vs zanubrutinib (Brukinsa) monotherapy in treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), as seen in the phase 3 ELEVATE-TN (NCT02475681) and SEQUOIA (NCT03336333) trials.

In the ELEVATE-TN trial, patients with treatment-naïve CLL were randomly assigned 1:1:1 to receive acalabrutinib plus obinutuzumab (n = 179), acalabrutinib monotherapy (n = 179), or obinutuzumab plus chlorambucil (n = 177). In contrast, theSEQUOIA trial randomly assigned patients with CLL/SLL without 17p deletions 1:1 to zanubrutinib (n = 241) or bendamustine plus rituximab (Rituxan; n = 238).

In this comparative analysis, an unanchored, matching-adjusted, indirect comparison was conducted to minimize the differences between the respective study populations, Kittai explains. Cox regression analysis of The ELEVATE-TN study utilized an investigator-assessed progression-free survival (PFS) data identified age; ECOG performance status; Binet stage; bulky disease; β2; macroglobulin; cytopenia; 11q deletions; trisomy 12; IGHV status; and TP53 mutation status as prognostic and/or predictive variables. Data from individual patients who were treated with acalabrutinib in the ELEVATE-TN trial were weighted based on these factors to align with the overall outcomes observed in patients treated with zanubrutinib in SEQUOIA and decrease bias often associated with comparator trials, Kittai says. Following the matching process, the treatment arms did not exhibit any disparities in matched variables, and any distinctions in non-matched variables were minimal.

Results from this trial were presented at the 2023 International Workshop on CLL, and showed that acalabrutinib plus obinutuzumab produced a significant progression-free survival (PFS) benefit over the zanubrutinib regimen in patients without a 17p deletion, Kittai reports. After the matching process, the 36-month investigator-asses PFS rate was 95% in patients from ELEVATE-TN vs 84% in patients who received zanubrutinib in the SEQUOIA trial. However, patients treated with acalabrutinib monotherapy did not experience a significant difference in the investigator-assessed 36-month PFS rate vs those who received zanubrutinib. Corresponding PFS rates were 86% and 84%, respectively.

In terms of safety, the risk of experiencing most adverse effects (AEs) did not significantly vary between patients who received acalabrutinib plus obinutuzumab vs zanubrutinib monotherapy, Kittai continues. Exceptions included a higher likelihood of developing any-grade neutropenia with acalabrutinib plus obinutuzumab as well as any-grade arthralgia. When comparing acalabrutinib monotherapy vs zanubrutinib monotherapy, the odds of developing any-grade hypertension were significantly lower with acalabrutinib, he details. Although all other odds ratios were in favor of acalabrutinib, investigators determined that these differences were not significant.