Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor that has shown clinical benefit in patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL).
Objective: This randomized, global, multicenter, open-label phase 3 study assessed the efficacy and safety of acalabrutinib monotherapy versus the investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in RR CLL (NCT02970318).
Methods: Eligible patients with RR CLL were randomized 1:1 to 100 mg oral acalabrutinib twice daily (BID) until progression versus IdR (150 mg oral Id BID combined with ≤8 IV infusions of R [375 or 500 mg/m2]), or BR (70 mg/m2 IV B on days 1 and 2 of each cycle combined with R [375 or 500 mg/m2 IV] on day 1 of each 28-day cycle for ≤6 cycles). Stratification was by del(17p) status (yes vs no), ECOG status (0-1 vs 2), and prior therapy lines (1-3 vs ≥4). The primary end point was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary end points included overall survival (OS), overall response rate (ORR, by IRC), and safety. Patients with confirmed progression on IdR/BR could cross over to receive acalabrutinib monotherapy.
Results: A total of 310 patients were randomized to acalabrutinib (n = 155) or IdR/BR (n = 155 [IdR, n = 119; BR, n = 36]); median age was 67 years (range, 32-90); 16% had del(17p); 27% had del(11q); 42% had Rai stage III/IV CLL. Median (range) number of prior therapies was 1 (1-8) for acalabrutinib and 2 (1-10) for IdR/BR. Discontinuation due to adverse events (AEs) occurred in 11% of patients on acalabrutinib versus 49% Id, 12% R in IdR, 11% B, and 17% R in BR.
At a median follow-up of 16.1 months, acalabrutinib significantly prolonged IRC-assessed PFS versus IdR/BR (median not reached vs 16.5 months; hazard ratio 0.31, 95% CI 0.20-0.49, P <.0001). PFS rates at 12 months were 88% with acalabrutinib and 68% with IdR/BR; improvement was seen across subgroups, including del(17p), TP53 mutation, and Rai stage.
ORR by IRC was similar with acalabrutinib versus IdR/BR (81% vs 75%; P <.22); 12-month OS rates were 94% and 91% (with 15 and 18 deaths) for acalabrutinib and IdR/BR, respectively. Of IdR/BR patients, 23% crossed over to acalabrutinib monotherapy.
All-grade AEs (≥15%) with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), anemia and cough (15% each); with IdR, diarrhea (47%), neutropenia (45%), pyrexia (18%), and cough (15%); with BR, neutropenia (34%), infusion-related reaction and fatigue (23% each), nausea (20%), and pyrexia (17%). Grade ≥3 AEs (≥5%) with acalabrutinib were neutropenia (16%), anemia (12%), and pneumonia (5%); with IdR (≥15%), neutropenia (40%) and diarrhea (24%); with BR (≥5%), neutropenia (31%), anemia (9%), and constipation (6%).
AEs of interest were atrial fibrillation (5.2% of patients on acalabrutinib vs 3.3% on IdR/BR), bleeding AEs (26% vs 7.2%; including major hemorrhage [1.9% vs 2.6%]); grade ≥3 infections (15% vs 24%), and second primary malignancies, excluding nonmelanoma skin cancer; (6.5% vs 2.6%).
Conclusion: Acalabrutinib monotherapy significantly improved PFS with a more tolerable safety profile versus IdR/BR in patients with RR CLL.
Note: This abstract has been presented at EHA and ICML 2019.
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