Patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who received pirtobrutinib (Jaypirca; Eli Lilly) monotherapy showed an 80% reduction in progression-free survival (PFS) compared with patients receiving bendamustine plus rituximab (BendaR) in the phase 3 BRUIN CLL-313 (NCT05023980) trial.1
Wojciech Jurczak, MD, PhD, head of the department of oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, presented the data during a late-breaking abstract session at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition.
As targeted therapies have become the standard in CLL, these new data provide insights into pirtobrutinib monotherapy’s potential in the first-line setting, which historically has not included non-covalent BTK inhibitors.2 Following its initial accelerated approval in 2023 for patients with CLL or SLL who had received at least 2 prior therapies, including a BTK inhibitor and a BCL-2 inhibitor, pirtobrutinib was recently granted full approval for patients with CLL or SLL in the relapsed/refractory setting who had previously received a covalent BTK inhibitor.3 The former approval was based on findings from the BRUIN (NCT03740529) and the latter based on the BRUIN-CLL-321 (NCT04666038).
“While covalent BTK inhibitors have significantly improved outcomes for untreated patients with CLL, at the time of the study design, there were no phase 3 data yet assessing non-covalent BTK inhibitors, especially in the treatment-naïve setting,” Jurczak said during his presentation of the data. He noted that findings from the head-to-head trial BRUIN CLL-314 (NCT05254743), also presented at ASH this year, demonstrated pirtobrutinib’s superiority to the first-generation BTK inhibitor ibrutinib in the first-line setting.4
In the open-label, global phase 3 BRUIN CLL-313 trial, 282 patients were randomized 1:1 to receive either pirtobrutinib (n = 141) or BendaR (n = 141), with the opportunity for patients in the BendaR arm to cross over to the pirtobrutinib arm upon confirmed disease progression.1 The primary end point was an independent review committee (IRC)–assessed PFS per International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. The key secondary end point was overall survival (OS), and additional end points included overall response rate (ORR) and safety measures.
At a median follow-up of 28.1 months, the pirtobrutinib arm showed significantly improved IRC-assessed PFS vs the BendaR arm (HR, 0.199; 95% CI, 0.107-0.367; P < .0001), and investigator-assessed PFS was consistent with these findings (HR, 0.186; 95% CI, 0.093-0.371; P < .0001). For patients on pirtobrutinib, the 24-month PFS rate was 93.4% (95% CI, 87.6-96.5) vs 70.7% (95% CI, 61.5-78.1) in the BendaR arm.
Across prespecified, clinically relevant subgroups, IRC-assessed PFS improvement was consistent. This included among patients with mutated and unmutated IGHV (HR for mutated IGHV, 0.293; 95% CI, 0.094-0.910) and HR for unmutated IGHV, 0.172; 95% CI, 0.083-0.357).
The IRC-assessed ORR with pirtobrutinib was 94.3% (95% CI, 89.1%-97.5%) vs 80.9% (95% CI, 73.4%-87%) with BendaR. While the OS data were not mature yet at the interim analysis, the pirtobrutinib cohort demonstrated a notable favorable trend in OS, with an HR of 0.257 (95% CI, 0.070-0.934; P = .0261) compared with BendaR. This was despite 18 of 34 patients with investigator-assessed progressive disease crossing over, representing an effective crossover rate of 52.9%.
Pirtobrutinib also showed a favorable safety profile relative to BendaR, with 40% incidence of grade 3 or higher treatment-emergent adverse effects (TEAEs) vs 67.4% with BendaR. Notably, median treatment duration was 32.3 months for 140 patients receiving pirtobrutinib and 5.6 months for 132 patients receiving BendaR.
Grade 5 TEAEs occurred in 1 patient in the pirtobrutinib arm and 4 patients in the BendaR arm. No grade 5 TEAEs were considered treatment-related in the pirtobrutinib arm, and 1—tumor lysis syndrome—was considered treatment-related in the BendaR arm. A total of 6 (4.3%) patients discontinued treatment with pirtobrutinib due to TEAEs, compared with 20 (15.2%) in the BendaR cohort.
“To conclude, pirtobrutinib had a superior progression-free survival vs bendamustine plus rituximab patients with treatment-naïve chronic lymphocytic leukemia, with one of the largest treatment effects ever observed for a single-agent BTK inhibitor against this competitor,” Jurczak said. “…These data suggest that pirtobrutinib may be considered a potential new standard of care for patients with untreated CLL, especially for the elderly or frail patients who may only receive one line of therapy.”
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. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract LBA-3.
2. Targeted therapy drugs for chronic lymphocytic leukemia (CLL). American Cancer Society. Accessed December 12, 2025. https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/treating/targeted-therapy.html
3. Steinzor P. FDA grants full approval to pirtobrutinib for CLL/SLL. AJMC. December 3, 2025. Accessed December 12, 2025. https://www.ajmc.com/view/fda-grants-full-approval-to-pirtobrutinib-for-cll-sll
4. Woyach J, Qui 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. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Poster 683.
