BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Author(s): Wojciech Jurczak, MD, PhD¹; Michal Kwiatek, MD, PhD²; Jaroslaw Czyz, MD, PhD³; Ederson Roberto de Mattos, MD⁴; Ki-Seong Eom, MD, PhD⁵; Alexander Egle, MD⁶; Anna Panovska, MD, PhD⁷; Zhanet Grudeva Popova, MD, PhD, MHM⁸; Hsuan-Jen Shih, MD⁹; Luis Felipe Casado Montero, MD¹⁰; Paolo Sportoletti, MD¹¹; Vu Minh Hua, MBBS, PhD, FRACP, FRCPA¹²; James T. D’Olimpio, MD, FACP, FAAHPM¹³; Shinsuke Iida, MD, PhD¹⁴; Rodrigo Ito, MD¹⁵; Katherine Bao, PhD¹⁵; Anne Fink, MPH, RN¹⁵; Weiji Su, PhD¹⁵; Amy S. Ruppert, PhD¹⁵; Alejandro Levy, MD¹⁵; Tomasz Wrobel, MD, PhD¹⁶;

Source: DOI: 10.1200/JCO-25-02380

Dr. Maen Hussein's Thoughts

Pirtobrutinib demonstrated superiority over bendamustine rituximab in IRC assessed progression free survival (PFS) in treatment naïve CLL/SLL, with a 24 month PFS rate of 93.4% versus 70.7%. Overall survival trends favored pirtobrutinib, despite the study design allowing for crossover. Who would have thought this was coming????

PURPOSE

BRUIN CLL-313 is a randomized, open-label, global phase III study comparing the efficacy and safety of pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), against bendamustine plus rituximab (BendaR), a common frontline chemoimmunotherapy, in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

METHODS

Patients with previously untreated CLL/SLL without del(17p) were randomly assigned 1:1 to continuous pirtobrutinib monotherapy or BendaR, stratified by immunoglobulin heavy chain gene mutation status and Rai stage. The primary end point was independent review committee (IRC)–assessed progression-free survival (PFS); secondary end points included overall survival (OS), investigator (INV)–assessed PFS, safety, and tolerability.

RESULTS

Overall, 282 patients were randomly assigned to receive pirtobrutinib (n = 141) or BendaR (n = 141). IRC-assessed PFS was significantly improved with pirtobrutinib versus BendaR (hazard ratio [HR], 0.199 [95% CI, 0.107 to 0.367]; P < .0001), and the 24-month PFS rate was 93.4% (95% CI, 87.6 to 96.5) and 70.7% (95% CI, 61.5 to 78.1), respectively. INV-assessed PFS similarly favored pirtobrutinib (HR, 0.186 [95% CI, 0.093 to 0.371]). Interim analysis of OS favored pirtobrutinib (median follow-up 32 months; HR, 0.257 [95% CI, 0.070 to 0.934]) despite an effective crossover rate of 52.9%. In patients receiving pirtobrutinib versus BendaR: adverse event (AE)–related dose reductions occurred in 3.6% versus 31.1% of patients; grade ≥3 treatment-emergent AEs (TEAEs) occurred in 40.0% versus 67.4% of patients; and treatment discontinuations because of TEAEs occurred in 4.3% versus 15.2% of patients, respectively.

CONCLUSION

Pirtobrutinib demonstrated superiority over BendaR in IRC-assessed PFS in treatment-naïve CLL/SLL. OS trends favored pirtobrutinib despite the study design allowing for crossover. Pirtobrutinib was well tolerated, consistent with its known safety profile, and more favorable than BendaR.

Author Affiliations

¹National Research Institute of Oncology, Krakow, Poland; ²AIDPORT Clinical Trials Hospital, Skorzewo, Poland; ³Department of Hematology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland; ⁴Hematology Department, Hospital Amaral Carvalho, Jau, Brazil; ⁵Catholic Hematology Hospital, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Korea; ⁶Third Medical Department for Hematology, Oncology, Hemostaseology, Infectious Disease and Rheumatology, Paracelsus University Hospital, Salzburg, Austria; ⁷Department of Internal Medicine, Hematology and Oncology, Masaryk University, Brno, Czech Republic; ⁸Department of Clinical Oncology, Medical University of Plovdiv, Plovdiv, Bulgaria; ⁹Division of Hematology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan R.O.C; ¹⁰HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain; ¹¹Department of Medicine and Surgery, Institute of Hematology Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy; ¹²Liverpool Hospital, Liverpool, NSW, Australia; ¹³Clinical Research Alliance, Westbury, NY; ¹⁴Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; ¹⁵Eli Lilly and Company, Indianapolis, IN; ¹⁶Wroclaw Medical University, Wrocław, Poland

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