Pirtobrutinib Improves PFS in Treatment-Naive CLL/SLL

"[Pirtobrutinib was] effective in whichever subgroup we analyzed," according to study investigator Wojciech Jurczak, MD, PhD.

Single-agent pirtobrutinib (Jaypirca) significantly and meaningfully prolonged progression-free survival (PFS) vs bendamustine (Treanda) plus rituximab (Rituxan; BR) among patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from the phase 3 BRUIN CLL-313 study (NCT05023980) presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.1

The results indicated that pirtobrutinib reduced the risk of disease progression or death by approximately 80% vs standard chemoimmunotherapy (HR, 0.199; 95% CI, 0.107–0.367; P <.0001). Investigators noted that the data support the agent as a potential new standard of care for untreated patients, particularly older adults who may be limited to a single line of therapy.

“It was a knockout,” Wojciech Jurczak, MD, PhD, Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology in Kraków, Poland, said during the presentation. “If we compare the similar comparisons of bendamustine, other BTK inhibitors like ibrutinib [Imbruvica] or zanubrutinib [Brukinsa], the hazard ratio is about 0.35.

“[Pirtobrutinib was] effective in whichever subgroup we analyzed,” added Jurczak.

Efficacy Outcomes

At the 24-month landmark, the progression-free survival rate was 93.4% (95% CI, 87.6%–96.5%) for patients treated with pirtobrutinib vs 70.7% (95% CI, 61.5%–78.1%) for those treated with BR. This benefit was consistent across key subgroups, including patients with mutated IGHV (HR, 0.293) and unmutated IGHV (HR, 0.172).

Although overall survival (OS) data remain immature, a notable trend favored the pirtobrutinib arm (HR, 0.257; 95% CI, 0.070–0.934; P =.0261). The 24-month OS rate was 97.8% for the pirtobrutinib group compared with 90.8% for the BR group. This survival signal is particularly relevant given the high crossover rate allowed in the study design; 52.9% of patients in the BR arm crossed over to receive pirtobrutinib following confirmed disease progression.

Study Design

The open-label phase 3 trial enrolled 282 patients with previously untreated CLL/SLL meeting iwCLL 2018 criteria for therapy. Patients were randomized 1:1 to receive oral pirtobrutinib 200 mg once daily or up to 6 cycles of bendamustine (90 mg/m²) plus rituximab (375-500 mg/m²). Randomization was stratified by IGHV mutation status and Rai stage.

Key exclusion criteria included the presence of del(17p), known central nervous system involvement, Richter transformation, or significant cardiovascular disease. The data cutoff for the current analysis was July 11, 2025.

Safety and Tolerability Profile

Pirtobrutinib exhibited a favorable safety profile consistent with previous reports in the relapsed/refractory setting. Despite a significantly longer median treatment duration for pirtobrutinib (32.3 months) compared with the fixed-duration BR regimen (5.6 months), the rate of severe adverse events (AEs) was lower in the experimental arm.

Grade 3 or higher treatment-emergent AEs (TEAEs) occurred in 40.0% of patients receiving pirtobrutinib compared with 67.4% of those receiving BR. Furthermore, treatment discontinuation due to TEAEs was significantly less frequent with pirtobrutinib (4.3%) than with BR (15.2%).

Specific adverse events of interest for BTK inhibitors showed low incidence rates in the pirtobrutinib arm. Atrial fibrillation and atrial flutter (any grade) were reported in 1.4% of patients treated with pirtobrutinib compared with 0.7% in the BR arm. Among patients aged 75 years or older receiving pirtobrutinib, only 1 experienced atrial fibrillation or flutter. Rates of grade 3 or higher infections were also lower with pirtobrutinib (13.6%) compared with BR (57.1%), as were rates of grade 3 or higher neutropenia (7.1% vs 12.1%, respectively).

“Now, if we took this data together with BRUIN CLL-314 study [NCT05254743], which was presented this conference where pirtobrutinib was opposed to ibrutinib and was also a positive study,2 we can be optimistic about the approval of the compound, possibly in early 2026,” concluded Jurczak.1

References

1. Jurczak W, Kwiatek M, Czyz J, 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. Blood. 2025;146(suppl 2):LBA-3. doi:10.1182/blood-2025-LBA-3
2. Woyach J, Qiu L, Grosicki S, et al. 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. Blood. 2025;146(suppl 1): 683. doi:10.1182/blood-2025-683