Data from a late-breaking abstract presented by Wojciech Jurczak, MD, PhD, of the Maria Sklodowska-Curie National Research Institute of Oncology in Poland, at the 67th ASH Annual Meeting and Exposition “suggest that pirtobrutinib may be considered a potential new standard-of-care treatment for patients with untreated” chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Pirtobrutinib is a highly selective non-covalent Bruton’s tyrosine kinase inhibitor (ncBTKi) that has shown efficacy and safety in patients with relapsed/refractory CLL/SLL, though no previously released phase 3 data assessed the outcomes of a ncBTKi in treatment-naïve patients.
The randomized, open-label, global, phase 3 BRUIN CLL-313 trial assessed the efficacy and safety of pirtobrutinib versus bendamustine plus rituximab (BR) in treatment-naïve patients with CLL/SLL.
Patients with del(17p) mutation, central nervous system involvement, Richter transformation, and significant cardiovascular disease were excluded.
Eligible patients (n=282) were stratified by IGHV mutation status (mutated vs unmutated) and Rai stage (low/intermediate vs high) and randomized 1:1 to receive monotherapy pirtobrutinib 200 mg once daily (n=141) or six cycles of BR (n=141).
After a median follow-up of 28.1 months, progression-free survival (PFS), as assessed by independent review committee (IRC), was significantly improved with pirtobrutinib (P<0.0001); the 24-month PFS rates were 93.4% with pirtobrutinib versus 70.7% with BR, indicating “one of the largest treatment effects ever observed for a single-agent BTKi against the comparator,” the authors noted.
The PFS benefit observed with pirtobrutinib was sustained in clinically relevant patient subgroups, including those with mutated IGHV (hazard ratio [HR], 0.293) and unmutated IGHV (HR, 0.172). PFS as assessed by the investigators was also consistent with IRC findings (HR, 0.186; P<0.0001).
The HR for overall survival for pirtobrutinib versus BR was 0.257 (P=0.0261), “despite an effective crossover rate of 52.9% (n=18/34 patients with investigator-assessed progressive disease),” the authors noted. The median treatment duration was 32.3 months for 140 patients receiving pirtobrutinib and 5.6 months for 132 patients receiving BR.
Grade ≥3 treatment-related adverse events were reported in 40.0% of the pirtobrutinib group and 67.4% of the BR group. Grade 5 treatment-related AEs were reported in one and four patients, respectively.
Treatment-related treatment discontinuations occurred in six (4.3%) pirtobrutinib-treated patients and 20 (15.2%) BR-treated patients. In the pirtobrutinib group, two patients (1.4%) experienced atrial fibrillation/flutter, occurring in just one of 20 patients aged ≥75 years, indicating that this could be a potential treatment consideration in “older patients who may receive only one line of therapy,” the authors noted.
Reference
Jurczak W, Kwiatek M, Czyz, et al. 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. Abstract LBA-3. Presented at the 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, Florida.
