Pirtobrutinib Outperforms Standard Options in Relapsed/Refractory CLL/SLL
Pirtobrutinib shows significant benefits in progression-free survival and tolerability for relapsed CLL patients compared to standard treatments.
Histologic image of chronic lymphoblastic leukemia (CLL) cells
Pirtobrutinib (Jaypirca) led to improvements in progression-free survival (PFS) and time to next treatment (TTNT) with a favorable tolerability profile when compared with idelalisib (Zydelig) and rituximab (Rituxan; idela-R) and bendamustine/rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) previously treated with covalent Bruton tyrosine kinase inhibitors (cBTKi).
Findings from the phase 3 BRUIN CLL-321 study (NCT04666038) showed that pirtobrutinib led to a PFS hazard ratio (HR) of 0.54 (95% CI, 0.39-0.75; P =.0002) and a median PFS of 14 months (95% CI, 11.2-16.6) vs 8.7 months (95% CI, 8.1-10.4) with investigator’s choice of idela-R or BR.
The median TTNT was 24 months (95% CI, 17.8-29.7) with pirtobrutinib vs 10.9 months (95% CI, 8.7-12.5) with investigator’s choice (HR, 0.37; 95% CI, 0.25-0.52).
“To this end, TTNT is of clinical relevance, as patients in usual clinical practice do not have regular interval computed tomography scans in the absence of clinical signs of [progressive disease],” authors wrote in the study published in the Journal of Clinical Oncology.
Study Design and Patient Characteristics
A total of 238 patients were randomly assigned 1:1 to receive 200 mg once-daily pirtobrutinib or investigator’s choice of idela-R or BR and were stratified by previous use of venetoclax (Venclexta) and del(17p).
At the time of data cutoff, 46 of 116 (39.7%) patients receiving pirtobrutinib remained on treatment, 5 (6.5%) of 77 patients receiving idela-R remained on treatment, and all 32 patients receiving BR were off treatment, with 15 (46.9%) patients completing all 6 cycles of BR.
Of 66 patients on idela-R or BR who experienced progressive disease, 50 crossed over to receive pirtobrutinib. More than half of those who crossed over (n = 29) remained on pirtobrutinib at time of data cutoff.
The median study follow-up for all patients was 17.2 months (95% CI, 9.7-23). Baseline patient characteristics were balanced between arms and stratification factors, with 50.4% of patients receiving previous venetoclax treatment in each group. Del(17p) was present in 46.2% and 44.5% of patients in the pirtobrutinib and IdelaR/BR groups, respectively. The median age was 66 years (range, 42-90), 70% of patients were male, and 58% had an ECOG performance status ≥ 1. The median number of lines of previous therapy was 3 in both pirtobrutinib (range, 1-13) and idela-R/BR (range, 1-11) arms.
Safety Profile
Treatment-emergent adverse events (TEAEs) of any grade occurred in 108 (93.1%) patients receiving pirtobrutinib and 107 (98.2%) receiving idela-R/BR. Pneumonia was the most frequently occurring TEAE in patients receiving pirtobrutinib (22.4%) vs idela-R/BR (11.9%), followed by anemia (19.8%) and neutropenia (18.1%). The most frequently occurring AE in patients receiving idela-R/BR were diarrhea (31.2%), pyrexia (26.6%), and fatigue and nausea (20.2% each).
Bleeding AEs were primarily low grade; however, 3 patients on pirtobrutinib experienced grade 3 hemorrhage and 1 patient receiving idela-R experience experienced grade 5 hemorrhage. Three (2.6%) patients experienced atrial fibrillation during with pirtobrutinib, and 2 had a previous history of atrial fibrillation associated with previous cBTKi exposure. One patient in the idela-R/BR group experienced de novo atrial fibrillation. Hypertension of any grade was similar between groups, reported in 8 (6.9%) patients receiving pirtobrutinib and 4 (3.7%) receiving idela-R/BR.
Dose reductions occurred in 13 (11.2%) patients receiving pirtobrutinib and 40 (36.7%) receiving idela-R/BR. Treatment discontinuation due to AE occurred in 20 (17.2%) patients receiving pirtobrutinib; 6 (5.2%) were due to treatment-related AEs. Thirty-eight (34.9%) patients receiving idela-R/BR discontinued treatment due to AE with 23 (21.1%) considered treatment-related. Grade 5 TEAEs occurred in 12 (10.3%) patients receiving pirtobrutinib and 10 (9.2%) patients receiving idela-R/BR, with none while on treatment in either group, none considered related to pirtobrutinib, and 1 considered related to BR. Grade 5 COVID-19 infection occurred in 2 (1.7%) patients receiving pirtobrutinib and 1 (0.9%) receiving idela-R/BR. Three patients receiving idela-R/BR experienced Richter transformation.
