Comparative efficacy of Bruton tyrosine kinase inhibitors in the treatment of relapsed/refractory chronic lymphocytic leukemia: A network meta-analysis (NMA).

Abstract

7048 Background: Next-generation Bruton’s tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory (R/R) CLL; defined based on the presence of genetic mutations and a high unmet need. Given the lack of head-to-head trials comparing these treatments in R/R CLL, a NMA was performed to estimate the relative efficacy of BTKis used to treat high-risk patients. Methods: Randomized controlled trials ALPINE (zanubrutinib vs. ibrutinib), ELEVATE-RR (acalabrutinib vs. ibrutinib), and ASCEND (acalabrutinib vs. bendamustine + rituximab/idelalisib + rituximab [BR/IR]) were included in the NMA. High-risk populations were defined based on the pre-specified subgroups within each trial, including patients with del17p and/or TP53 mutations in ALPINE (zanubrutinib: 75/327 and ibrutinib: 75/325), ASCEND (acalabrutinib: 44/155 and BR/IR: 42/155), and del17p/del11q in ELEVATE-RR (acalabrutinib: 268/268 and ibrutinib: 265/265). Bayesian NMAs were used to estimate hazard ratios (HRs) or odds ratios (ORs) with 95% credible intervals (CrIs), and probability better (PB) for zanubrutinib versus all other treatments. Outcomes analysed included investigator-assessed progression-free survival (PFS), overall survival (OS), overall response (ORR), and complete response (CR). Given the timing of the included trials in relation to the COVID-19 pandemic, ALPINE data were analyzed with and without adjustment for COVID-19 related deaths. Results: The NMA found a statistically significant improvement in PFS for zanubrutinib over acalabrutinib in high-risk patients and a trend towards improvement in OS, ORR, and CR (Table). Zanubrutinib led to statistically significant improvements in PFS versus ibrutinib (HR [95% CrI]: 0.49 [0.30, 0.78], PB: 99.9%) and BR/IR (0.12 [0.05, 0.26], PB: 100.0%). For OS, zanubrutinib showed a trend towards improvement versus ibrutinib (0.59 [0.31, 1.12] PB: 94.8%) and BR/IR (0.64 [0.24, 1.74] PB: 80.7%). Conclusions: This NMA found zanubrutinib to be the most efficacious BTKi for patients with high-risk R/R CLL, offering significantly delayed disease progression, and favourable survival and response vs. alternative BTKi treatments. [Table: see text]