John C Byrd1, Peter Hillmen2, Paolo Ghia3,4, Arnon P Kater5, Asher Chanan-Khan6, Richard R Furman7, Susan O'Brien8, Mustafa Nuri Yenerel9, Arpad Illés10, Neil Kay11, Jose A Garcia-Marco12, Anthony Mato13, Javier Pinilla-Ibarz14, John F Seymour15, Stephane Lepretre16,17, Stephan Stilgenbauer18, Tadeusz Robak19, Wayne Rothbaum20, Raquel Izumi20, Ahmed Hamdy20, Priti Patel21, Kara Higgins21, Sophia Sohoni21, Wojciech Jurczak22. 1. The Ohio State University Comprehensive Cancer Center, Columbus, OH. 2. St James's University Hospital, Leeds, UK. 3. Università Vita-Salute San Raffaele, Milano, Italy. 4. IRCCS Ospedale San Raffaele, Milano, Italy. 5. Amsterdam University Medical Centers, University of Amsterdam, on behalf of Hovon, Amsterdam, the Netherlands. 6. Mayo Clinic Jacksonville, Jacksonville, FL. 7. Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY. 8. Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA. 9. Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 10. University of Debrecen, Debrecen, Hungary. 11. Mayo Clinic Rochester, Rochester, MN. 12. Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. 13. University of Pennsylvania, Philadelphia, PA. 14. Moffitt Cancer Center, Tampa, FL. 15. Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia. 16. Centre Henri Becquerel, Rouen, France. 17. Normandie University UNIROUEN, Rouen, France. 18. Internal Medicine III, University of Ulm, Ulm, Germany. 19. Medical University of Lodz, Lodz, Poland. 20. Acerta, South San Francisco, CA. 21. AstraZeneca, South San Francisco, CA. 22. Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.
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.
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.
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