Acalabrutinib versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory CLL: The Randomised, Controlled, Phase 3 ASCEND Trial

Background: Acalabrutinib is a highly selective, potent inhibitor of Bruton tyrosine kinase, an essential part of the B-cell signalling pathway. Methods: ASCEND is a global, multicentre, randomised, open-label, Phase 3 study. Eligible patients, aged ≥18 years with relapsed/refractory chronic lymphocytic leukemia (CLL), were randomised 1:1 centrally via an interactive voice/web response system, and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status, and prior lines of therapy, to receive oral acalabrutinib 100 mg twice daily (BID) or investigator's choice (ie, idelalisib BID plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intention-to-treat population. Safety was assessed in all patients who received any treatment. Findings: From February 21, 2017 to January 17, 2018, 310 patients were randomised to acalabrutinib (n=155) or investigator's choice therapy (n=155 [I-R, n=119; B-R, n=36). Patients had received a median of two prior therapies (range 1-10). After a median follow-up of 16·1 months (interquartile range 14·0-18·2), median PFS was significantly longer with acalabrutinib (not reached [95% CI 14·9-not reached]) compared with investigator's choice (16·5 months [95% CI 14·0-17·1]; HR 0·31 [95% CI 0·20-0·49]; p<0.0001). Estimated PFS at 12 months was 88% (95% CI 81%-92%) for acalabrutinib and 68% (95% CI 59%-75%) for investigator's choice. Serious adverse events occurred in 29% (44/154) of patients treated with acalabrutinib, 56% (66/118) with I-R, and 26% (9/35) with B-R. Deaths occurred in 10% (15/154), 11% (13/118), and 14% (5/35) of patients in the acalabrutinib, I-R, and B-R arms, respectively. Interpretation: Acalabrutinib monotherapy significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with relapsed/refractory CLL. Trial Registration: Enrolment for this trial is complete (ClinicalTrials.gov, NCT02970318). Funding Statement: Acerta Pharma, a member of the AstraZeneca Group. Declaration of Interests: PG reports grants and personal fees from AbbVie, Gilead, Janssen, and Sunesis; personal fees from ArQule, Adaptive, AstraZeneca, BeiGene, Celgene/Juno, and Dynamo; and grants from Novartis; AP reports honoraria for lectures from Celgene Poland, MSD Poland, Novartis Poland, Roche Poland, Servier Poland, Shire, and Takeda Poland; advisory board member for Janssen Cilag and Roche Poland; and sponsored scientific conference attendance from Celgene, Roche, and Takeda; DL reports personal fees from Gilead and Roche; TK has received personal fees from AstraZeneca; MS reports personal fees from Acerta Pharma, Gilead and Roche; SD has received funding from Acerta Pharma; PC has received funding from Acerta Pharma; AJ has received personal fees from AstraZeneca and funding from Acerta Pharma; EA has received Advisory Board fees from AstraZeneca; WL was an employee of Acerta Pharma at the time of the study; PP, is an employee of, and holds equity in, Acerta, and holds equity in AstraZeneca; CQ is an employee of Acerta Pharma; WJ reports personal fees and grants from AstraZeneca; grants and personal fees from Janssen and TG Therapeutics; grants from Merck; and personal fees from Loxo. MW, PK, IK, AI, JDLS, GM, and JHL have no conflicts of interest to report. Ethics Approval Statement: The institutional review board or independent ethics committee at each site approved the protocol. The study was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All patients provided written informed consent.