Jennifer A. Woyach MD, ASH 2024: The Non-Covalent Bruton’s Tyrosine Kinase-Inhibitor Pirtobrutinib is As Effective, While Less Toxic, In Relapsed/Refractory Chronic Lymphocytic Leukemia

Jennifer A. Woyach MD, ASH 2024: The Non-Covalent Bruton’s Tyrosine Kinase-Inhibitor Pirtobrutinib is As Effective, While Less Toxic, In Relapsed/Refractory Chronic Lymphocytic Leukemia

An interview with:

Jennifer A. Woyach MD, Director of Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States

ORLANDO, USA—The possibility of using a less toxic Bruton’s tyrosine kinase (BTK) inhibitor to treat chronic lymphocytic leukemia/small lymphocytic lymphoma—especially in treatment naïve patients— could become a reality according to promising findings from the first randomized phase III study comparing a non-covalent with a covalent BTK inhibitor. Study findings were announced at the American Society of Hematology 2025 Annual Meeting by Jennifer A. Woyach MD, Director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in  Columbus, USA.  After her talk at the conference Dr. Woyach discussed the data with the Audio Journal of Oncology’s Peter Goodwin:

AUDIO JOURNAL OF ONCOLOGY: Jennifer Woyach MD

IN: [GOODWIN]“Peter Goodwin here in Orlando Florida ….

OUT:  ….in Orlando Florida, I’m Peter Goodwin.    5:39 secs

PUBLICATION REFERENCE:

https://ashpublications.org/blood/article/146/Supplement%201/683/551183/Pirtobrutinib-vs-ibrutinib-in-treatment-naive-and

Blood (2025) 146 (Supplement 1): 683.

https://doi.org/10.1182/blood-2025-683

TITLE:

Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor

Jennifer Woyach,  Lugui Qiu,  Sebastian Grosicki,  Tomasz Wrobel,  Marcelo Capra,  Jaroslaw Czyz,  Shuhua Yi,  Ki-Seong Eom,  Anna Panovská, Wojciech Jurczak,  Kamel Laribi,  Lutz Jacobasch,  Ross Baker,  Richy Agajanian,  Alejandro Berkovits,  Muhit Özcan,  Stephane Lepretre,  Catherine Coombs, Paula Cramer,  Katharine Lewis,  Marisa Hill,  Katherine Bao,  Yuanyuan Bian,  Amy Ruppert Stark,  Ching Ching Leow,  William Wierda

2025 ASH Orlando, Abstract: 683

Abstract Title :

Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor

Category: 600s – Hematologic Malignancy

Review Category: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological

Lead Author:

Jennifer A. Woyach MD, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States

Institutions:

1 The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States,

2 State 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,

3 Medical University of Silesia, Department of Cancer Prevention, Katowice, Poland,

4 Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University of Wroclaw, Wroclaw, Poland,

5 Centro Integrado de Hematologia e Oncologia, Hospital Mãe de Deus, Porto Alegre, Brazil, 6 Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Departament of Hematology, Bydgoszcz, Torun, Poland,

7 Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Rep. of South,

8 Department of Internal Medicine -Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic,

9 Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland,

10 Department of Hematology, Centre Hospitalier Le Mans, Le Mans, France,

11 Praxis of Haematology and Oncology, Dresden, Germany,

12 Western Australia Centre for Thrombosis and Haemostasis, Perth Blood Institute,

Murdoch University, Perth, Australia,

13 The Oncology Institute of Hope and Innovation, Whittier, CA, United States,

14 Inmunocel, Santiago, Chile, 15 Ankara University, School of Medicine, Ankara, Türkiye, 16 Centre de Lutte Contre le Cancer – Centre Henri Becquerel, Rouen, France,

17 University of California Irvine, Irvine, CA, United States,

18 Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany,

19 Sir Charles Gairdner Hospital, Division of Haematology, Nedlands, Western Australia, Australia,

20 Medical School, University of Western Australia, Division of Internal Medicine, Perth, Western Australia, Australia,

21 Eli Lilly and Company, Indianapolis, United States,

22 University of Texas MD Anderson Cancer Center, Houston, TX,

Abstract:

Introduction: Covalent Bruton tyrosine kinase inhibitors (cBTKi) are a mainstay of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment. Pirtobrutinib is a highly selective, non-covalent BTKi with proven efficacy in CLL/SLL patients (pts) previously treated with a cBTKi. We report results from the first head-to-head comparison of pirtobrutinib versus ibrutinib in treatment-naïve (TN) pts and pts with cBTKi-naive relapsed/refractory (R/R) CLL/SLL (NCT05254743).

Methods:

Eligible pts were randomized 1:1 to receive pirtobrutinib (200 mg QD) or ibrutinib (420 mg QD), stratified by del(17p) status and number of prior lines of therapy (0 vs 1 vs ≥ 2). Treatment was administered until progression or development of unacceptable toxicity. Primary endpoints were non-inferiority (NI) of overall response rate (ORR; partial response or better by independent review committee [IRC]/iwCLL 2018), in intent-to-treat (ITT) and R/R populations, with ORR ratio NI margins of 0.88 and 0.86, respectively. PFS was a secondary endpoint to be tested for superiority at a future timepoint. We present the final ORR analyses in ITT and R/R populations, and descriptive analyses of secondary endpoints, including in the TN population, using a 10June2025 data cut.

Results:

From 18August2022 to 17June2024, 662 pts were randomized to receive pirtobrutinib (n=331) or ibrutinib (n=331). For both arms, the median age was 67 (pirtobrutinib range, 39-90; ibrutinib, 34-86), and the median number of prior therapies was 1. The ITT population included 225 TN and 437 R/R pts. Among pirtobrutinib vs ibrutinib pts with evaluable samples, unmutated IGHV was 68% (199/293) vs 66% (183/277), complex karyotype ≥3 abnormalities was 40% (104/259) vs 34% (78/227), and del(17p) was 15% (50/331) vs 16% (52/331), respectively. The study met its primary endpoint demonstrating statistically significant NI of ORR of pirtobrutinib vs ibrutinib in both the ITT population (87.0% [95%CI,82.9-90.4] vs 78.6% [95%CI,73.7-82.9]; ORR ratio=1.11 [95%CI,1.03-1.19]; 2-sided p<0.0001) and R/R population (84.0% [95%CI,78.5-88.6] vs 74.8% [95%CI,68.5-80.4]; ORR ratio=1.12 [95%CI,1.02-1.24]; 2-sided p<0.0001), respectively. In the TN population, ORR was 92.9% (95%CI,86.4-96.9) with pirtobrutinib vs 85.8% (95%CI,78.0-91.7) with ibrutinib. ORR consistently favored pirtobrutinib vs ibrutinib across subgroups in both the ITT and R/R population, including del(17p) (ITT, 80.0% vs 75.0%; R/R, 80.6% vs 80.0%) and without del(17p) (ITT, 88.3% vs 79.2%; R/R, 84.7% vs 73.8%). PFS data were not yet mature, but favored pirtobrutinib in ITT (HR, 0.57 [95%CI,0.39-0.83]), R/R (HR, 0.73 [95%CI,0.47-1.13]), and TN (HR, 0.24 [95%CI,0.10-0.59]) pts, with a median follow up of 21.8 months, 18.2 months, and 22.5 months, respectively. The 18-month PFS rates (95%CI) in pirtobrutinib and ibrutinib arms were86.9% (82.4-90.3) vs 82.3% (77.3-86.3) in ITT, 81.7% (75.1-86.7) vs 79.2% (72.3-84.6) in R/R, and 95.3% (89.1-98.0) vs 87.6% (79.7-92.6) in TN, respectively. There was no detriment in overall survival (HR, 0.961 [95%CI,0.55-1.69]) for the ITT population. The most common treatment-emergent adverse events were similar between arms. Adverse events (AE) of interest, such as atrial fibrillation/flutter occurred in 2.4% of pirtobrutinib and 13.5% of ibrutinib pts; hypertension in 10.6% and 15.1% of pts, respectively. Fewer AE-related dose reductions were seen with pirtobrutinib (7.9%) vs ibrutinib (18.2%). Treatment discontinuation due to progressive disease was more common with ibrutinib (pirtobrutinib, n=15 [4.5%] vs ibrutinib, n=36 [10.9%]), and similar for AE (pirtobrutinib, n=26 [7.9%] vs ibrutinib, n=24 [7.3%]). Treatment is ongoing in 81.3% of pirtobrutinib and 69.5% of ibrutinib pts.

Conclusion:

In this first head-to-head study, in cBTKi-naïve CLL/SLL, including pts with treatment naïve CLL, pirtobrutinib demonstrated NI of ORR vs ibrutinib in both ITT and R/R populations. PFS, while not yet mature, trended in favor of pirtobrutinib, with the most pronounced effect in the TN population, which had the longest follow-up at this data cut.

Jennifer Woyach AJ Oncology ASH 2025