Matching-Adjusted Analysis Shows Acalabrutinib/Obinutuzumab Offers PFS Benefit Vs Zanubrutinib in CLL/SLL Without 17p Deletions

Adam S. Kittai, MD

Patients with treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) without 17p deletions experienced superior efficacy following treatment with acalabrutinib (Calquence) plus obinutuzumab (Gazyva) compared with zanubrutinib (Brukinsa) monotherapy, according to findings from a matching-adjusted, indirect comparison of the phase 3 ELEVATE-TN (NCT02475681) and SEQUOIA (NCT03336333) trials presented at the 2023 International Workshop on CLL.¹

Post-matching, patients in ELEVATE-TN who received acalabrutinib plus obinutuzumab (effective sample size [ESS] = 124) achieved an investigator-assessed 36-month progression-free survival (PFS) rate of 95% (95% CI, 90%-97%) compared with 84% (95% CI, 79%-88%) among patients who received zanubrutinib in SEQUOIA (n = 241; HR, 0.41; 95% CI, 0.23-0.74). Notably, patients who were treated with acalabrutinib monotherapy (ESS = 105) did not achieve a significant difference in terms of investigator-assessed 36-month PFS rate compared with those who received zanubrutinib, at 86% (95% CI, 78%-91%) vs 84% (95% CI, 79%-88%), respectively (HR, 0.91; 95% CI, 0.53-1.56).

“Currently, we have 2 second-generation BTK inhibitors that are [FDA] approved for the treatment of CLL: acalabrutinib and zanubrutinib,” Adam S. Kittai, MD, assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center–James in Columbus, said during the presentation. “There is no phase 3 clinical trial planned that will compare these 2 drugs. Ultimately, when you don't have a phase 3 clinical trial planned, it's difficult to know what drug to use, especially when these 2 drugs have such a similar mechanism of action. The point of this project was to do a comparison between these 2 drugs to help inform providers when the appropriate use of these drugs might be, how the toxicity differs between them, and whether efficacy differs between them.”

ELEVATE-TN randomly assigned patients with treatment-naïve CLL in a 1:1:1 manner to receive acalabrutinib plus obinutuzumab (n = 179), acalabrutinib monotherapy (n = 179), or obinutuzumab plus chlorambucil (n = 177). At a median follow-up of 58.2 months (range, 0.0-72.0) for the overall population, both acalabrutinib plus obinutuzumab (HR, 0.11; 95% CI, 0.07-0.16; P < .0001) and acalabrutinib monotherapy (HR, 0.21; 95% CI, 0.15-0.30; P < .0001) offered a substantial benefit in terms of investigator-assessed PFS compared with obinutuzumab plus chlorambucil. Among patients with 17p deletions and/or TP53-mutated disease, acalabrutinib plus obinutuzumab (HR, 0.19; 95% CI, 0.08-0.45; P < .0001) and acalabrutinib monotherapy (HR, 0.21; 95% CI, 0.09-0.50; P < .0001) were again superior to obinutuzumab plus chlorambucil in terms of investigator-assessed PFS.²

SEQUOIA randomly assigned patients in a 1:1 manner with CLL/SLL without 17p deletions to receive zanubrutinib (n = 241) or bendamustine plus rituximab (Rituxan; n = 238). Updated findings from the trial showed that, at a median follow-up of 43.7 months (range, 0-60), the median PFS was not reached in the zanubrutinib arm compared with 42.2 months (95% CI, 38.4-49.8) in the bendamustine plus rituximab arm (HR 0.30; 95% CI, 0.21-0.43; P < .0001).³

To conduct the comparative analysis between the 2 trials, study authors performed an unanchored, matching-adjusted, indirect comparison to minimize the differences between the respective study populations. First, they applied Cox regression analysis to ELEVATE-TN investigator-assessed PFS data and identified the following prognostic and/or predictive variables: age; ECOG performance status; Binet stage; bulky disease; β2; macroglobulin; cytopenia; 11q deletions; trisomy 12; IGHV status; and TP53 mutation. Then, individual patient data from those who received acalabrutinib in ELEVATE-TN were weighted according to the prognostic/predictive variables to match aggregate findings among patients treated with zanubrutinib in SEQUOIA.¹

The efficacy analysis examined investigator-assessed PFS in all patients without 17p deletions who underwent randomization using the most recent study data cutoffs, which were October 2021 for ELEVATE-TN and October 2022 for SEQUOIA. The median follow-up was 58 months vs 44 months, respectively. Investigators performed a sensitivity analysis to determine if adding all possible variables impacted investigator-assessed PFS, irrespective of whether they were found to be predictive or prognostic of investigator-assessed PFS.

Investigators noted that there were no differences between treatment arms for matched variables following the matching process. Moreover, differences observed between treatment arms in terms of nonmatched variables were minor.

Meanwhile, the safety analysis evaluated the incidence of adverse effects (AEs) and reported the odds ratios of AEs among patients who received acalabrutinib plus obinutuzumab (ESS = 123), acalabrutinib monotherapy (ESS = 103), and zanubrutinib (n = 240). Investigators used the ELEVATE-TN data cutoff of September 2020 since it most closely matched the median follow-up of the SEQUOIA data cutoff of October 2022; the median follow-up times were 47 months vs 44 months, respectively. In this case, the sensitivity analysis only assessed the impact of matching on characteristics considered relevant for safety, which consisted of age, ECOG performance status, and cytopenia.

Post-matching findings from the safety analysis showed that patients who received acalabrutinib plus obinutuzumab did not experience significant differences in the odds of suffering from most types of AEs compared with patients who were treated with zanubrutinib monotherapy, except for any-grade neutropenia with acalabrutinib plus obinutuzumab (odds ratio [OR], 2.19; 95% CI, 1.33-3.60) and any-grade arthralgia (OR, 2.33; 95% CI, 1.37-3.96). All other AEs examined had reduced or similar odds of occurrence with acalabrutinib plus obinutuzumab vs zanubrutinib, with the most pronounced reductions being observed in terms of grade 3 or higher atrial fibrillation or flutter (OR, 0.30; 95% CI, 0.03-2.95), grade 3 or higher hemorrhage (OR, 0.37; 95% CI, 0.12-1.19), and grade 3 or higher hypertension (OR, 0.46; 95% CI, 0.17-1.20).

In the acalabrutinib monotherapy vs zanubrutinib monotherapy comparison, the odds of any-grade hypertension were significantly lower with acalabrutinib monotherapy (OR, 0.44; 95% CI, 0.20-0.99) than with zanubrutinib. The ORs for any-grade atrial fibrillation or flutter (OR, 1.69; 95% CI, 0.66-4.36) and any-grade arthralgia (OR, 1.38; 95% CI, 0.75-2.53) both favored zanubrutinib over acalabrutinib. All other ORs favored acalabrutinib monotherapy, although investigators determined these differences insignificant.

“Ultimately, you have to treat the patient in front of you,” Kittai said. “Certain patients might prefer acalabrutinib and some prefer zanubrutinib, for whatever reason. What this study does is puts us at ease in terms of [clinicians] that treat CLL to know that the efficacy of these drugs is broadly similar.

“We have very different ways of analyzing research. We should approach research in these very different ways to try to answer questions that otherwise can't be answered. That being said, I would love to have a randomized phase 3 clinical trial of acalabrutinib vs zanubrutinib, but I don't think it's ever going to happen. [Therefore], at least we have this analysis to compare trials. [These types of analyses have] broad applications in hematological diseases, solid tumors, and internal medicine in general, where we don't have data.”

References

1. Kittai A, Allan J, James D, et al. A matching-adjusted indirect comparison of ELEVATE-TN versus SEQUOIA: acalabrutinib with and without obinutuzumab versus zanubrutinib in treatment-naïve chronic lymphocytic leukemia. Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, Massachusetts. Abstract 1550098.
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Five-year follow-up of ELEVATE-TN. J Clin Oncol. 2022;40(suppl 16):7539. doi:10.1200/JCO.2022.40.16_suppl.7539
3. Shadman M, Munir T, Robak T, et al. Zanubrutinib vs bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 154.