Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial

Abstract

Purpose: Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).

Methods: Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).

Results: Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.

Conclusion: In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Trial registration: ClinicalTrials.gov NCT02477696.

FIG 1.

CONSORT diagram. ^aOne patient who was randomly assigned to the ibrutinib treatment arm received acalabrutinib and ibrutinib during the study and was included in the acalabrutinib safety population. ^bIncludes patients who discontinued treatment because of relocation (n = 1), medical monitor decision (n = 1), and starting therapy with ibrutinib (n = 1) but agreed to remain on study for follow-up. ^cIncludes patients who discontinued treatment because of noncompliance (n = 2), withdrawal of consent for treatment or follow-up (n = 1), refusal of medication (n = 1), relocation (n = 2), medical monitor decision (n = 1), early termination because of second primary malignancy (n = 1), and IRC- and medical monitor– or sponsor-confirmed progressive disease (n = 1) but agreed to remain on study for follow-up. ECOG PS, Eastern Cooperative Oncology Group performance status; IRC, Independent Review Committee.

FIG 2.

PFS, OS, and EFS. (A) Kaplan-Meier curve of IRC-assessed PFS (primary end point). (B) Kaplan-Meier curve of OS (secondary end point). (C) Kaplan-Meier curve of IRC EFS. The Kaplan-Meier curves for IRC-assessed PFS cross at 33 months, indicating a violation of the proportional hazards assumption. A sensitivity analysis on the basis of RMST, which is valid under nonproportional hazards, confirmed that acalabrutinib was noninferior to ibrutinib, with a difference in RMST (acalabrutinib-ibrutinib) of 1.1 month (95% CI: −2.17 to 4.36) over 55 months. The lower bound of the 95% CI was compared with an RMST noninferiority margin of −5.83 months, derived from the HR noninferiority margin of 1.429. For the PFS analysis, three ibrutinib-treated patients were censored because of PD or death immediately after missing two or more consecutive visits, and seven acalabrutinib and eight ibrutinib patients were censored at random assignment because of no baseline assessment and/or no adequate postbaseline assessment. EFS, event-free survival; HR, hazard ratio; IRC, Independent Review Committee; NE, not estimable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RMST, restricted mean survival time.

FIG 3.

Prespecified subgroup analysis of IRC-assessed PFS. ^aPer interactive voice-web response system record. ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IGHV, immunoglobulin heavy chain variable region; IRC, Independent Review Committee; PFS, progression-free survival.

FIG 4.

(A) Summary of hypertension and selected cardiac events and cumulative incidence of (B) atrial fibrillation and (C) hypertension. NOTE. Data are reported as no. (%) unless otherwise specified; within each event type (hypertension, cardiac events, and atrial fibrillation), percentages are based on the number of patients with the event. ^aIncludes events with the preferred terms of hypertension, blood pressure increased, and blood pressure systolic increased; two-sided P value on the basis of Barnard’s exact test without multiplicity adjustment, P < .001 (any-grade) and P = .0214 (grade 3 or higher). ^bIncludes events with the preferred terms of atrial fibrillation and atrial flutter (a patient was only counted once if he or she experienced both types of events); atrial flutter was reported in one patient in the acalabrutinib arm and two patients in the ibrutinib arm (one of the two ibrutinib patients also had an atrial fibrillation event and was counted only once for the combined atrial fibrillation or flutter term). ^cPart of the multiple testing procedure; difference in any-grade incidence rates was −6.6% (95% CI: −12.2 to −0.9), P = .02. ^dRisk factors for atrial fibrillation were based on medical review. ^eIncludes patients with a history of diabetes mellitus or type 2 diabetes mellitus. ^fIncludes patients with a history of coronary artery bypass, coronary artery disease, cardiomyopathy, cardiac failure chronic, or cardiac failure congestive. HR, hazard ratio.