Wojciech Jurczak MD PhD; ASH 2025: Big Study Suggests Non-Covalent BTK Inhibitor Pirtobrutinib Could be New Standard-of-Care for Patients with Untreated Chronic Lymphocytic Leukemia

Wojciech Jurczak MD PhD; ASH 2025: Big Study Suggests Non-Covalent BTK Inhibitor Pirtobrutinib Could be New Standard-of-Care for Patients with Untreated Chronic Lymphocytic Leukemia

An interview with:

Wojciech Jurczak MD PhD, Professor of Hematology, National Research Institute of Oncology, Krakow, Poland

ORLANDO, USA— A non-covalent inhibitor of Bruton’s tyrosine kinase looks superior to the current standard of care as initial therapy for patients with chronic lymphocytic leukemia. That’s in research from Poland reported at the 2025 American Society of Hematology Annual Meeting in which the randomized CLL/SLL (BRUIN CLL-313; NCT05023980) phase three study compared pirtobrutinib with bendamustine plus rituximab in treatment-naïve patients.

Lead author Wojciech Jurczak MD PhD, Professor of Hematology at the National Research Institute of Oncology in Krakow, Poland, has been telling the Audio Journal of Oncology’s Peter Goodwin about the results:

AUDIO JOURNAL OF ONCOLOGY; Wojciech Jurczak MD PhD

IN: [GOODWIN] “Peter Goodwin…….

OUT:    …….Peter Goodwin.  10:19

AMERICAN SOCIETY OF HEMATOLOGY ABSTRACT Number: LBA 3

Publication:

https://ashpublications.org/blood/article/146/Supplement%202/LBA-3/556927/Pirtobrutinib-vs-bendamustine-plus-rituximab-BR-in

STUDY TITLE:

Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients

Blood (2025) 146 (Supplement 2): LBA-3.

https://doi.org/10.1182/blood-2025-LBA-3

AUTHORS:

Wojciech Jurczak, Michal Kwiatek, Jaroslaw Czyz, Ederson de Mattos, Ki-Seong Eom, Alexander Egle, Anna Panovská, Zhanet Grudeva-Popova, Hsuan-Jen Shih,

Luis Felipe Casado Montero, Paolo Sportoletti, Vu Minh Hua, James D’Olimpio,

Shinsuke Iida, Rodrigo Ito, Katherine Bao, Anne Fink, Weiji Su, Amy Ruppert Stark,

Alejandro Levy, Tomasz Wrobel

INSTITUTIONS:

1 National Research Institute of Oncology, Krakow, Poland,

2 AIDPORT Clinical Trials Hospital, Skorzewo, Poland,

3 Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland,

4 Hospital Amaral Carvalho Jau, São Paulo, Brazil,

5 Catholic Hematology Hospital, Seoul St. Mary’s Hospital, The

Catholic University of Korea, Seoul, Korea, Rep. of South,

6 Paracelsus University Hospital, Salzburg, Austria,

7 Masaryk University, Brno, Czech Republic,

8 Medical University of Plovdiv, Plovdiv, Bulgaria,

9 Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan,

10 HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain,

11 Institute of Hematology Centro di Ricerca Emato- Oncologica (CREO), University of Perugia, Perugia, Italy,

12 Liverpool Hospital, New South Wales, Australia,

13 Clinical Research Alliance, Westbury, United States,

14 Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan,

15 Eli Lilly and Company, Indianapolis, IN, United States,

16 Wroclaw Medical University, Wroclaw, Poland

Abstract

Introduction: Pirtobrutinib is a highly selective, non-covalent (nc) Bruton tyrosine kinase inhibitor (BTKi) that has demonstrated safety and efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including pts previously treated with a cBTKi. While cBTKi have significantly improved progression-free survival (PFS) for untreated pts with CLL/SLL, there are no Phase 3 data assessing a ncBTKi specifically in the treatment-naïve setting, and significant improvements in overall survival (OS) are uncommon with monotherapy cBTKi. A recent head-to-head phase 3 trial (BRUIN CLL-314 presented at this meeting, ASH abstract 25-2587; NCT05254743) showed a favorable overall response rate (ORR) and a positive PFS trend with pirtobrutinib compared to the cBTKi ibrutinib in a subset of pts with treatment-naïve CLL. Here we present the first results from a randomized, open-label, global phase 3 trial specifically assessing the efficacy and safety of pirtobrutinib versus bendamustine plus rituximab (BR) in treatment-naïve pts with CLL/SLL (BRUIN CLL-313; NCT05023980).

Methods: Pts with previously untreated CLL/SLL, without del(17p), were randomized 1:1 to receive pirtobrutinib monotherapy (200 mg QD) or 6 cycles of BR, stratified by IGHV mutation status (mutated vs unmutated) and Rai stage (low/intermediate vs high). Pts with known CLL/SLL CNS involvement, Richter transformation, or significant cardiovascular disease were excluded. Responses were evaluated using iwCLL 2018 criteria. The primary endpoint was PFS assessed by independent review committee (IRC), and a stratified log-rank test compared IRC-assessed PFS between pirtobrutinib and BR using a 2-sided alpha level of 0.05. OS was a key secondary endpoint, gated on IRC-assessed PFS, with a small alpha of 0.000001 spent at this interim OS analysis. Other secondary endpoints included investigator (INV)-assessed PFS and safety. Efficacy analyses were based on the intent-to-treat population. Pts assigned to BR were eligible to cross over to receive pirtobrutinib if they had IRC-confirmed disease progression (PD), met study eligibility requirements, and needed therapy per iwCLL criteria. The data cutoff was 11 July 2025.

Results: 282 pts were randomized to receive either pirtobrutinib (n=141) or BR (n=141). At a median follow-up of 28.1 months, the primary endpoint of IRC-assessed PFS was significantly improved with pirtobrutinib compared with BR (HR: 0.199; 95% CI: 0.107, 0.367; p<0.0001). The 24-month PFS rate was 93.4% (95% CI: 87.6, 96.5) for pirtobrutinib and 70.7% (95% CI: 61.5, 78.1) for BR. IRC-assessed PFS benefit was consistently observed with pirtobrutinib among prespecified, clinically relevant patient subgroups, including patients with mutated IGHV (HR: 0.293, 95% CI: 0.094, 0.910), and unmutated IGHV (HR: 0.172, 95% CI: 0.083, 0.357). The PFS by INV was consistent (HR: 0.186; 95% CI: 0.093, 0.371; p<0.0001). The OS HR for pirtobrutinib versus BR was 0.257 (95% CI: 0.070, 0.934; p=0.0261), despite an effective crossover rate of 52.9% (18/34 pts with INV-assessed PD). The median treatment duration was 32.3 months for 140 pts receiving pirtobrutinib and 5.6 months for 132 pts receiving BR. The incidence of grade ≥3 TEAEs was 40.0% with pirtobrutinib and 67.4% with BR. Grade 5 TEAEs occurred in 1 pt receiving pirtobrutinib and 4 pts receiving BR, with none considered pirtobrutinib related and 1 (tumor lysis syndrome) considered BR related. Discontinuation of pirtobrutinib and BR due to TEAE occurred in 6 (4.3%) and 20 (15.2%) pts, respectively. Two pts (1.4%) receiving pirtobrutinib had a TEAE of atrial fibrillation/flutter, including only 1 of 20 pts aged ≥75 years.

Conclusions: In BRUIN CLL-313, pirtobrutinib significantly improved IRC-assessed PFS versus BR for pts with treatment-naïve CLL/SLL with one of the largest treatment effects ever observed for a single-agent BTKi against this comparator. Pirtobrutinib was well tolerated, consistent with its known safety profile, with low rates of discontinuation and atrial fibrillation/flutter. While OS data remained immature, a notable trend favoring pirtobrutinib was observed, despite 52.9% of BR pts crossing over to receive pirtobrutinib after PD. Taken together, these data suggest that pirtobrutinib may be considered a potential new standard-of-care treatment for pts with untreated CLL/SLL, including older pts who may receive only one line of therapy.

ASH PRESS RELEASE:

(ORLANDO, Dec. 9, 2025) – In a new trial, the Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib increased the rate of survival without disease progression and was well tolerated with a more favorable safety profile when compared with bendamustine plus rituximab (BR) in patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The data were presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition.

“We were able to prove that pirtobrutinib is an excellent drug both in terms of efficacy and tolerance,” said lead study author Wojciech Jurczak, MD, PhD, professor of hematology at the National Research Institute of Oncology in Kraków, Poland. “Our data show that it is not just overcoming resistance but is even more specific and selective than previous BTK inhibitors.”

Previous studies have shown pirtobrutinib, a first-generation non-covalent BTK inhibitor, to be efficacious against CLL/SLL that is relapsed or refractory after initial treatments. The current trial is the first to use pirtobrutinib in a first-line setting against a combination of bendamustine, a chemotherapy, and rituximab, a monoclonal antibody, which together constitute a common first-line combination treatment for CLL/SLL.

BTK inhibitors work by blocking the BTK enzyme, which plays a role in B cell growth and proliferation. Pirtobrutinib is developed to overcome the tendency for cancer cells to become resistant to previous-generation covalent BTK inhibitors.

CLL and SLL are slow-growing forms of non-Hodgkin lymphoma that develop when lymphocytes grow out of control and abnormal B cells build up in bone marrow (CLL) or lymph nodes (SLL). Each year, an estimated 4.5 out of every 100,000 adults are diagnosed with CLL or SLL.

The trial randomized 282 patients to receive a daily oral dose of pirtobrutinib continuously unless they developed unacceptable side effects, or six cycles of BR, administered via intravenous infusion every 28 days. At a median follow-up of 28 months, the rate of progression-free survival was significantly better with pirtobrutinib (93.4%) versus BR (70.7%), meeting the trial’s primary endpoint.

The progression-free survival trends were consistent across subgroups including among patients of different ages and among patients with or without Immunoglobin Heavy Chain Variable (IGHV) mutations, supporting pirtobrutinib as a new standard of care for first-line CLL/SLL treatment, said Dr. Jurczak. He noted that pirtobrutinib is more convenient for patients compared with covalent BTK inhibitors, some of which involve complex requirements around the timing of administration in relation to eating and drinking.

Overall survival will be formally assessed at a later date given the need for longer follow-up, but preliminary results favor pirtobrutinib for this secondary endpoint. Over half (52.9%) of patients in the BR arm who experienced disease progression crossed over to receive pirtobrutinib. From a statistical perspective, this amount of crossover would be expected to dilute any overall survival difference between study groups, so researchers noted that the trend toward improved overall survival is especially noteworthy.

Patients receiving pirtobrutinib experienced lower rates of adverse events, with 40.0% of patients in the pirtobrutinib arm experiencing treatment-related adverse events of grade 3 or higher compared with 67.4% in the BR arm. Treatment discontinuation due to adverse events was also less common in the pirtobrutinib arm (4.3%) compared with the BR arm (15.2%). The rate of atrial fibrillation or flutter in the pirtobrutinib arm was 1.4%, consistent with what would be expected among patients of a similar age in the general population.

Researchers said that the results suggest pirtobrutinib has strong potential as a first-line treatment for CLL/SLL. However, the study used a continuous administration strategy and was also limited by pirtobrutinib’s interactions with antibiotics and antifungals. To pave the way for practical adoption of pirtobrutinib as first-line treatment, Dr. Jurczak suggested that additional work is needed to develop a fixed-duration regimen for the drug and to determine which agents are best to use after pirtobrutinib if the cancer returns. He also noted that pirtobrutinib should be paused if patients develop infections during treatment, given the drug’s interaction with antibiotics and antifungals.

Additional studies are underway to assess a lower dosing strategy for pirtobrutinib and move toward fixed-duration rather than continuous administration.

This study was funded by Lilly, maker of pirtobrutinib.

Wojciech Jurczak  ASH 2025