Indirect comparison study shows PFS advantage of Zanubrutinib vs. acalabrutinib/acalabrutinib in CLL

A matched-adjusted indirect comparison (MAIC) analysis of zanubrutinib versus acalabrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) showed that zanubrutinib had significant progression-free survival (PFS) and complete response (CR) benefits over acalabrutinib. The results of the MAIC study have been published.

After matching prognostic and predictor variables on baseline characteristics of the Phase 3 ALPINE (NCT03734016) and ASCEND (NCT02970318) trial populations, in the unadjusted population, zanubrutini bRelated to significant improvement in investigator-assessed PFS compared with acotinib (HR, 0.77; 95% CI, 0.55-1.07; P=0.1213) and in the base case adjusted population (HR, 0.68; 95% CI, 0.46-0.99; p=0.0448). Additionally, overall survival (OS) results were likely to favor zanubrutinib postmatching in the unadjusted population (HR, 0.60; 95% CI, 0.37-0.97; p=0.0354) and in the base-case adjusted population (HR, 0.60; 95% CI, 0.35-1.02; p=0.0575).

The CLL landscape is evolving rapidly, and this MAIC provides physicians with timely comparative effectiveness data and strengthens the role of zanubrutinib as a baseline treatment for CLL with a robust assessment of efficacy in the ASCEND and ALPINE studies; this analysis not only explains differences in key patient characteristics, but also sheds light on the impact that COVID-19 may have on study results. The ALPINE trial showed that, to date, zanubrutinib is the only next-generation covalent BTK inhibitor to achieve superior PFS results to the first-generation BTK inhibitor ibrutinib in patients with relapsed/refractory CLL. ALPINE data supports 2023 FDA approval of zanubrutinib for patients with CLL or small lymphocytic lymphoma (SLL).

In addition, in theASCEND trial, the second-generation covalent BTK inhibitor acotinib improved PFS outcomes compared with rituximab plus idelalisib or bendamustine in this patient population. The ASCEND data supports the 2019 FDA approval of acotinib for adult patients with CLL or SLL. However, the phase 3 ELEVATE-RR trial (NCT02477696) showed that acotinib was non-inferior to ibrutinib in patients with relapsed/refractory disease with 17p or 11q deletions. No trials have directly compared zanubrutinib with acotinib in patients with relapsed/refractory CLL. Therefore, the researchers conducted MAIC to determine the relative efficacy of these two drugs.

The researchers matchedALPINE's individual patient data (IPD) with ASCEND's aggregated data and compared these data using an unanchored MAIC approach because the two trials lacked a common comparator group. ALPINE's data are adjusted to account for the impact of COVID-19 due to the timing of the trial relative to the epidemic. Base case analysis population adjustment included all variables identified as prognostic factors or predictors of treatment efficacy. We obtained pseudo-PFS and OS IPD from the acotinib arm of ASCEND by reconstructing Kaplan-Meier curves from published ASCEND data.

Researchers collected IPD from 327 patients in ALPINE and 155 patients in ASCEND, with a median follow-up of 39 months. ASCEND IPD data have a median follow-up period of 36 months. After performing a sensitivity analysis of scenarios to account for the impact of matching on different sets of variables, and then matching, reweighing, and adjusting the variables, the ALPINE intention-to-treat population was screened to include only patients with existing data on selected baseline characteristics and to exclude patients with SLL, for a total of 308 patients. Population adjustment brought the effective sample size of ALPINE to 184.8 patients, equivalent to 60% of the initial screening population.

The primary outcomes of this analysis were investigator-assessed PFS and OS, which were compared between the two studies using a weighted Cox proportional hazards model, and CR using a weighted logistic regression model.

In theASCEND population, 21.9% of patients were 75 years or older, the majority of patients (69.7%) were male, and 37.4% had an ECOG performance status (PS) of 0. The majority of patients (84.5%) were from Europe. Regarding genomic status, 16.2%, 17.4%, 25.2%, and 25.2% of patients had IGHV mutations, 17p deletions, 11q deletions, and TP53 mutations, respectively. In addition, 32.4% and 49.0% of patients had complex karyotype and bulky disease, respectively. A total of 77.4% of patients had β2-microglobulin levels greater than 3.5 mg/L, and 58.1% had Rai to stage II disease or Binet A/B disease. Overall, 25.8%, 11.0%, and 10.3% of patients had received 2, 3, and at least 4 prior therapies, respectively; this consisted of anti-CD20 antibodies (83.9%), alkylating agents other than bendamustine (85.8%), prior therapies including (30.3%), and purine analogues (70.3%). Patients had a median absolute lymphocyte count of 48.9 x 109 cells/L, a median absolute neutrophil count of 3.8 x 109 cells/L, and a median platelet count of 119.5 x 109 cells/L.

Among the matched people,21.9% of patients were 75 years or older, the majority of patients (69.7%) were male, and 37.4% of patients had an ECOG PS of 0. The majority of patients (84.5%) were from Europe. Regarding genomic status, 16.2%, 17.4%, 25.2%, and 25.2% of patients developed IGHV, 17p deletion, 11q deletion, and TP53 mutation, respectively. In addition, 28.6% and 49.0% of patients had complex karyotype and bulky disease, respectively. A total of 62.8% of patients had β2-microglobulin levels greater than 3.5 mg/L, and 58.1% had Rai to stage II disease or Binet A/B disease. A total of 25.8%, 11.0%, and 10.3% of patients had received 2, 3, and at least 4 prior treatments, respectively, which included anti-CD20 antibodies (83.9%), alkylating agents other than bendamustine (85.8%), bendamustine (30.3%), and purine analogues (70.3%). The patient's median absolute lymphocyte count was 49 x 109 cells/L, the median absolute neutrophil count was 4*109 cells/L, and the median platelet count was 119.0 x 109 cells/L.

CR results favored zanubrutinib in both the unadjusted population (odds ratio [OR], 2.88; 95% CI, 1.18-7.02; p=0.0198) and the base case-adjusted population (OR, 2.90; 95% CI, 1.13-7.43; p=0.0270). The PFS, OS and CR results of the six sensitivity analysis populations were consistent with the results of the base case-adjusted population.