Pirtobrutinib (Jaypirca) demonstrated meaningful clinical activity following prior covalent BTK inhibitor and BCL2 inhibitor treatment in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a pooled analysis presented at the 2026 SOHO Annual Meeting.1
The analysis pooled outcomes for patients who had prior covalent BTK inhibitor and BCL2 inhibitor exposure across the phase 1/2 BRUIN trial (NCT03740529) and the randomized phase 3 BRUIN CLL-321 trial (NCT04666038), in addition to updated data from the BRUIN trial published in the New England Journal of Medicine.
The pooled overall response rate (ORR) from the updated BRUIN data and BRUIN CLL-321 trial was 72% (95% CI, 67%-76%) among patients previously treated with a covalent BTK inhibitor (n = 366). Among patients who had previously received both a covalent BTK inhibitor and a BCL2 inhibitor from the updated BRUIN data (n = 100), the ORR was 70% (95% CI, 60%-79%).
“Pooled analyses showed consistently high response rates with a favorable safety profile, supporting the role of non-covalent BTK inhibition after covalent BTK inhibitor failure,” lead study author Rishi K. Nanda, DO, MS, and coauthors said in a poster presentation of the data. “These findings support pirtobrutinib as an important component of treatment sequencing in relapsed/refractory CLL and provide a foundation for future studies evaluating optimal sequencing and combination strategies.”
Nanda is a medical resident in the Department of Internal Medicine at the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas.
How was the pooled analysis of pirtobrutinib in R/R CLL conducted?
Pirtobrutinib After Covalent BTK Inhibitor Exposure in R/R CLL: Pooled Highlights
- Patients who received pirtobrutinib with prior covalent BTK inhibitor exposure demonstrated a pooled ORR of 72% (95% CI, 67%-76%) across updated BRUIN data and BRUIN CLL-321
- An ORR of 70% (95% CI, 60%-79%) was shown among patients previously exposed to both a covalent BTK inhibitor and a BCL2 inhibitor
- The pooled analysis revealed a atrial fibrillation/flutter incidence of 3% (95% CI, 1%-5%) with patients who received pirtobrutinib
Investigators of the analysis sought to characterize and identify clinical outcomes for patients with R/R CLL who had either previously received both a covalent BTK inhibitor and a BCL2 inhibitor or a covalent BTK inhibitor alone.
Randomized and early-phase studies were synthesized using random-effects meta-analysis of proportions, with overlapping cohorts identified and accounted for to avoid duplicate patient inclusion.
The phase 1/2 BRUIN trial included 121 efficacy-evaluable patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) and previous covalent BTK inhibitor exposure, 45 of whom had prior BCL2 inhibitor exposure.1,2 Patients from this group had a median of prior 4 lines of therapy.
The updated analysis of the BRUIN cohort included 247 patients with relapsed/refractory CLL or SLL following a covalent BTK inhibitor, 100 of whom also had prior BCL2 inhibitor exposure.3 Patients from this group had a median of prior 3 lines of therapy.
The randomized phase 3 BRUIN CLL-321 trial enrolled 238 patients with relapsed/refractory CLL or SLL after prior covalent BTK inhibitor treatment, with 60 of whom being previously exposed to a BCL2 inhibitor.4 Patients from this group also had a median of prior 4 lines of therapy.
ORR, prorgression-free survival (PFS), time to next treatment (TNTT), and treatment-related adverse effects were noted as primary end points of the analysis.1
What did the safety analysis and additional data for pirtobrutinib show?
The ORRs for pirtobrutinib in patients who had only received prior covalent BTK inhibitors were 62% and 73% for the BRUIN trial and updated BRUIN data, respectively. Respective ORRs from these studies for those who had previously received both covalent BTK inhibitors and a BCL2 inhibitors were 64% and 70%.2,3
Updated BRUIN data also showed a median PFS of 19.6 months and 16.8 months for those who had prior covalent BTK inhibitor exposure and covalent BTK inhibitor exposure and BCL2 inhibitor exposure, respectively.3 In BRUIN CLL-321 , pirtobrutinib demonstrated a median PFS of 14.0 months vs 8.7 months with investigator's choice of therapy (HR, 0.54) and a median TTNT of 24 months vs 10.9 months.4
Pooled safety analysis showed an atrial fibrillation/flutter incidence of 3% (95% CI, 1%-5%) with pirtobrutinib across the included studies.1
References
- Nanda R, Jones D, Larson C, et al. Pirtobrutinib following covalent BTK inhibitor exposure in relapsed/refractory chronic lymphocytic leukemia: A systematic review and pooled analysis. Clinical Lymphoma Myeloma and Leukemia. 2026;26:S633-S634. doi:10.1016/S2152-2650(26)02089-6.
- Mato A, Shah N, Jurczak W et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. The Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
- Mato A, Woyach J, Brown J, et a. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389:33-44. doi:10.1056/NEJMoa2300696
- Sharman J, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166
