Comparative Efficacy of Acalabrutinib in Frontline Treatment of Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-analysis

• Published in: Clinical therapeutics Vol. 42; no. 10; pp. 1955 - 1974.e15
• Main Authors: Davids, Matthew S., Waweru, Catherine, Le Nouveau, Pauline, Padhiar, Amie, Singh, Gautamjeet, Abhyankar, Sarang, Leblond, Veronique
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2020; Elsevier Limited
• Subjects: acalabrutinib; Age; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bayes Theorem; Bayesian analysis; Benzamides - administration & dosage; Chlorambucil; Chronic lymphocytic leukemia; Clinical trials; Fludarabine; frontline treatment; Humans; Immunotherapy; Inhibitor drugs; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Literature reviews; Lymphatic leukemia; Lymphoma; Meta-analysis; Monoclonal antibodies; Mutation; network meta-analysis; Oncology; Patients; Pyrazines - administration & dosage; Randomized Controlled Trials as Topic; Regulatory approval; Rituximab; Survival; Systematic review; Targeted cancer therapy; chronic lymphocytic leukemia; network meta-analysis; frontline treatment; acalabrutinib
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2020.08.017

The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline treatments for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, through a network meta-analysis (NMA). The efficacy of acalabrutinib from ELEVATE-TN (study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) was compared to bendamustine + rituximab, chlorambucil-based therapy, alemtuzumab, ibrutinib mono/combination therapy and venetoclax + obinutuzumab using data from eight randomized controlled trials (RCTs). Relevant RCTs were identified using a systematic literature review. Two evidence networks were constructed: Network A, composed solely of RCTs that met the inclusion criteria; and Network B, composed of 7 RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil + obinutuzumab from iLLUMINATE. Bayesian NMAs were conducted on progression-free survival (PFS) and overall survival (OS) endpoints; results were reported by using hazard ratios (HRs) and 95% credible intervals (CrIs). HRs were considered significant if their CrIs did not cross 1. Treatments were ranked by using the surface under the cumulative ranking area (SUCRA) values. Expert opinion from 2 hematologists was sought to validate results. Both networks showed a significant improvement in PFS for acalabrutinib + obinutuzumab over all comparators. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B. Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax + obinutuzumab in Network B but not Network A. Although OS HRs all favored acalabrutinib, most were not significant and were characterized by wide CrIs, indicating a high level of uncertainty. Acalabrutinib + obinutuzumab ranked highest in terms of PFS improvement (SUCRA values, 98% and 100%) and OS improvement (SUCRA values, 92% and 94%), followed by acalabrutinib monotherapy (SUCRA values for PFS, 88% and 90%; OS, 83% and 87%) in Networks A and B, respectively. Acalabrutinib was associated with favorable PFS and OS compared with frontline CLL therapies and ranked highest in treatment efficacy over the other comparators. The NMA was limited by heterogeneity in patient baseline characteristics across trials, variable treatment regimens, and short study follow-up times. Despite these limitations, the NMA provides insights into the relative efficacy of acalabrutinib compared with frontline CLL therapies in the absence of head-to-head clinical trials. PFS HRs for acalabrutinib versus comparators in frontline CLL. Abbreviations: CLL: chronic lymphocytic leukemia; CrI: credible interval; HR: hazard ratio; NMA: network meta-analysis; PFS: progression-free survival; RCT: randomized controlled trial. [Display omitted]