Author(s): Jeff P. Sharman, MD1; Talha Munir, PhD, MBBS2; Sebastian Grosicki, MD, PhD3; Lindsey E. Roeker, MD4; John M. Burke, MD5; Christine I. Chen, MHPE, MD6; Norbert Grzasko, MD, PhD7; George Follows, PhD, MA, BM, BCh, FRCP8; Zoltán Mátrai, MD, PhD9; Alessandro Sanna, MD X10; Lugui Qiu, MD11; Ru Feng, MD12; Vu Minh Hua, PhD, MBBS, FRACP, FRCPA13; Wojciech Jurczak, MD, PhD14; Matthias Ritgen, MD15; Shuhua Yi, MD X16; Francesc Bosch, MD, PhD17; Catherine C. Coombs, MD18; Katherine Bao, PhD19; Vishalkumar Patel, MD19; Bin Liu, MSc, MPH19; Livia Compte, MD, PhD19; Ananya Guntur, PhD19; Denise Y. Wang, PhD19; Marisa Hill, MS, MD19; Ching Ching Leow, PhD19; Paolo Ghia, MD, PhD20; Paul M. Barr, MD X21;
PURPOSE
Pirtobrutinib, a noncovalent, Bruton tyrosine kinase inhibitor (BTKi), has shown clinical efficacy and a favorable safety profile. BRUIN CLL-321 was an open-label, randomized phase III study conducted exclusively in patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with cBTKi, and compared pirtobrutinib with investigator's choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BR).
METHODS
Patients were randomly assigned 1:1 to receive pirtobrutinib (200 mg once daily) or IC of IdelaR or BR, and were stratified by previous use of venetoclax and del(17p). The primary end point was independent review committee–assessed progression-free survival (PFS). Secondary end points included time to next treatment or death (TTNT), overall survival (OS), and safety. The primary PFS end point was met at the time of the primary analysis (August 29, 2023), and updated results are reported from the final OS analysis (August 29, 2024).
RESULTS
A total of 238 patients were randomly assigned to receive pirtobrutinib (n = 119) or IC (n = 119; IdelaR [n = 82], BR [n = 37]). The PFS hazard ratio (HR) was 0.54 ([95% CI, 0.39 to 0.75]; P = .0002), with a median PFS of 14 months (95% CI, 11.2 to 16.6) in the pirtobrutinib group and 8.7 months (95% CI, 8.1 to 10.4) with IC. The unadjusted OS HR was 1.09 ([95% CI, 0.68 to 1.75]; P = .7202), and 18-month OS rate was 73.4% (95% CI, 63.9 to 80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9 to 78.7) with IC. Median TTNT was 24 months (95% CI, 17.8 to 29.7) with pirtobrutinib versus 10.9 months (95% CI, 8.7 to 12.5) with IC (HR, 0.37 [95% CI, 0.25 to 0.52]). At a median follow-up of 17.2 months, grade ≥3 treatment-emergent adverse events (AEs) were lower with pirtobrutinib (57.7%) than IC (73.4%). Treatment discontinuation due to AE occurred in 20 (17.2%) patients receiving pirtobrutinib and 38 (34.9%) patients receiving IC.
CONCLUSION
Pirtobrutinib improved PFS and TTNT, and demonstrated favorable tolerability, versus IdelaR/BR in exclusively cBTKi pretreated patients with CLL/SLL.
Author Affiliations
1Willamette Valley Cancer Institute and Research Center, US Oncology Research, Eugene, OR; 2Department of Haematology, St James's University Hospital, Leeds, United Kingdom; 3Department of Cancer Prevention, Medical University of Silesia, Katowice, Poland; 4Memorial Sloan Kettering Cancer Center NY, New York, NY; 5Sarah Cannon Research Institute and Rocky Mountain Cancer Centers, Aurora, CO; 6Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada; 7Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland; 8GenesisCare, Cambridge, United Kingdom; 9Central Hospital of Southern Pest, National Institute for Haematology and Infectology, Budapest, Hungary; 10Department of Hematology, AOU Careggi—University of Florence, Firenze, Italy; 11National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; 12Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 13Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; 14Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland; 15Universitätsklinik Schleswig-Holstein, Kiel, Germany; 16State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; 17Department of Haematology, University Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain; 18University of California Irvine, Irvine, CA; 19Eli Lilly and Company, Indianapolis, IN; 20Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy; 21Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
