Results from the BRUIN CLL-313 clinical trial (NCT05023980), funded by Eli Lilly & Co, demonstrate that the Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca®; Eli Lilly & Co, previously known as LOXO-305) increased the rate of survival without disease progression and was well tolerated with a more favorable safety profile when compared with bendamustine (Bendeka®; Cephalon/Teva) plus rituximab (Rituxan®; Genentech and Biogen) in patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[1]
The data were presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition held December 6 – 9, 2025, in Orlando, Florida.[1]
“We were able to prove that pirtobrutinib is an excellent drug both in terms of efficacy and tolerance,” explained lead study author Wojciech Jurczak, MD, Ph.D., professor of hematology at the The Maria Sklodowska-Curie 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,” Jurczak added.
Head-to-head study
Previous studies have shown pirtobrutinib, a first-generation non-covalent BTK inhibitor, to be efficacious against CLL/SLL that is relapsed or refractory (R/R) 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.
Study design
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,” Jurczak said.
He further 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.
Adverse events
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 bendamustine plus rituximab 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.
Potential for first-line treatment
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, 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.
Jurczak 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.
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Clinical trials
A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-313) – ClinicalTrials.gov ID NCT05023980
Highlights of Prescribing Information
Pirtobrutinib (Jaypirca®; Eli Lilly & Co)[Prescribing Information]
Bendamustine (Bendeka®; Cephalon/Teva)[Prescribing information]
Rituximab (Rituxan®; Genentech and Biogen)[Prescribing Information]
Reference
[1] Jurczak W, Kwiatek M, Czyz J, De Mattos, Eom KS, Egle A, Panovská A, Grudeva-Popova Z, Shih HJ, Casado Montero LF, Sportoletti P, Minh Hua V, D’Olimpio J, Iida S, Ito R, Bao K, Fink A, Su W, Ruppert Stark A, Levy A, Wrobel T. 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. 67th ASH® / American Society of Hematology Annual Meeting. Abstract LBA-3 [Abstract]
Featured image: 2022 American Society of Hematology 64th Annual Meeting. Photo courtesy 2022 – 2025 © ASH/Matt Herp. Used with permission.
DOI
, funded by Eli Lilly & Co, demonstrate that the Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca®; Eli Lilly & Co, previously known as LOXO-305) increased the rate of survival without disease progression and was well tolerated with a more favorable safety profile when compared with bendamustine (Bendeka®; Cephalon/Teva) plus rituximab (Rituxan®; Genentech and Biogen) in patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[1]){kind=link}