Acalabrutinib vs Rituximab Plus Idelalisib (IdR) or Bendamustine (BR) by Investigator Choice in Relapsed/Refractory (RR) Chronic Lymphocytic Leukemia: Phase 3 ASCEND Study

Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor that has shown clinical benefit in patients (pts) with RR CLL. In this randomized, global, multicenter, open-label Phase 3 study, the efficacy and safety of acalabrutinib monotherapy were evaluated vs the investigator's choice of IdR or BR in RR CLL (NCT02970318). Methods: Eligible pts with RR CLL were randomized 1:1 to 100 mg oral acalabrutinib BID until progression vs 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 Day 1 and 2 of each cycle combined with R [375 or 500 mg/m2 IV] on Day 1 of each 28-d cycle for ≤6 cycles). Stratification was by del(17p) status (y vs n), ECOG status (0-1 vs 2), and prior therapy lines (1-3 vs ≥4). The primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included overall survival (OS), overall response rate (ORR; by IRC), and safety. Pts with confirmed progression on IdR/BR could cross over to receive acalabrutinib monotherapy. Results: 310 pts were randomized to acalabrutinib (n=155) or IdR/BR (n=155 [IdR, n=119; BR, n=36]); median age was 67 y (range, 32-90); 16% had del(17p); 27% had del(11q); 42% had Rai stage III/IV CLL. Median (range) no. of prior therapies was 1 (1-8) for acalabrutinib and 2 (1-10) for IdR/BR. Discontinuation due to AEs occurred in 11% of pts on acalabrutinib vs 49% Id, 12% R in IdR, 11% B and 17% R in BR. At a median follow-up of 16.1 mo, acalabrutinib significantly prolonged IRC-assessed PFS vs IdR/BR (median NR vs 16.5 mo; HR 0.31, 95% CI 0.20-0.49, P<.0001; Figure). PFS rates at 12 mo 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 vs IdR/BR (81% vs 75%; p<.22). 12-mo OS rates were 94% and 91% (with 15 and 18 deaths) for acalabrutinib and IdR/BR, respectively. 23% of IdR/BR pts 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 pts 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 2nd primary malignancies (excluding NMSC; 6.5% vs 2.6%).