TY - JOUR
T1 - Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia
T2 - Results of the First Randomized Phase III Trial
AU - Byrd, John C.
AU - Hillmen, Peter
AU - Ghia, Paolo
AU - Kater, Arnon P.
AU - Chanan-Khan, Asher
AU - Furman, Richard R.
AU - O’Brien, Susan
AU - Nuri Yenerel, Mustafa
AU - Illés, Arpad
AU - Kay, Neil
AU - Garcia-Marco, Jose A.
AU - Mato, Anthony
AU - Pinilla-Ibarz, Javier
AU - Seymour, John F.
AU - Lepretre, Stephane
AU - Stilgenbauer, Stephan
AU - Robak, Tadeusz
AU - Rothbaum, Wayne
AU - Izumi, Raquel
AU - Hamdy, Ahmed
AU - Patel, Priti
AU - Higgins, Kara
AU - Sohoni, Sophia
AU - Jurczak, Wojciech
N1 - Funding Information:
The authors would like to thank the investigators and coordinators at each of the clinical sites and the patients who participated in this trial and their families. Medical writing assistance, funded by AstraZeneca, was provided by Allison Green, PhD, and Cindy Gobbel, PhD, of Peloton Advantage, LLC, an OPEN Health Company.
Funding Information:
Supported by the National Cancer Institute R35 CA197734, Four Winds Foundation, Sullivan CLL Foundation, and the D. Warren Brown Foundation.
Publisher Copyright:
Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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 5 268; ibrutinib, n 5 265) 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 5 .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.
AB - 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 5 268; ibrutinib, n 5 265) 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 5 .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.
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U2 - 10.1200/JCO.21.01210
DO - 10.1200/JCO.21.01210
M3 - Article
C2 - 34310172
AN - SCOPUS:85116055078
SN - 0732-183X
VL - 39
SP - 3441
EP - 3452
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 31
ER -