Safety and Tolerability of Pirtobrutinib Monotherapy in Patients with B-Cell Malignancies Who Were Previously Intolerant to a Covalent BTK Inhibitor: Results from the Phase 1/2 BRUIN Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have markedly improved outcomes in several B-cell malignancies. Despite this progress, treatment discontinuation due to cBTKi intolerance remains a significant barrier, ultimately limiting efficacy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients (pts) with poor-prognosis B-cell malignancies following prior therapy, including prior cBTKi (Mato et al. Lancet, 2021). Here, we evaluated the safety and tolerability of pirtobrutinib monotherapy specifically in pts with relapsed/refractory (R/R) B-cell malignancies who were intolerant to a prior cBTKi.

Methods: For this analysis, pts with R/R B-cell malignancies enrolled to the multicenter phase 1/2 BRUIN study (NCT03740529) with documented intolerance to prior cBTKi were analyzed. Intolerance was defined as having discontinued any prior cBTKi due to persistent/recurrent adverse events as assessed by the physician, in the absence of progressive disease. Pirtobrutinib monotherapy was administered once daily in 28-day cycles until disease progression or discontinuation due to toxicity. Analyses were performed descriptively.

Results: As of 31 January 2022, 566 pts (CLL/SLL, n=276; MCL, n=150; other NHL, n=140) treated with pirtobrutinib had received a prior cBTKi-containing regimen (prior lines of cBTKi containing regimens: 1 regimen, n=454; 2 regimens, n=93; ≥3 regimens, n=19). Among these 566 pts, 123 (22%) pts (CLL/SLL, n=79; MCL, n=20; other NHL, n=24) discontinued a prior cBTKi due to toxicity. This cBTKi intolerant cohort had received one or more of the following: ibrutinib (n=118, 96%), acalabrutinib (n=29, 24%), or zanubrutinib (n=6, 5%). At the time of enrollment to BRUIN, the median age for pts with prior cBTKi intolerance was 70 years (IQR: 64-75), and ECOG PS was 0, 1 and 2 in 58%, 35%, and 7% of pts, respectively. The most common adverse events (AEs) leading to prior cBTKi discontinuation were cardiac disorders [n=40, 33%; primarily atrial fibrillation (n=31, 25%)], infections (n=13, 11%), neutropenia (n=12, 10%), rash (n=12, 10%), bleeding/hemorrhage (n=11, 9%), arthralgias/myalgias (n=10, 8%), gastrointestinal disorders [n=9, 7%; diarrhea (n=6, 5%)], and fatigue (n=8, 7%). In these 123 pts with prior cBTKi intolerance, median time on pirtobrutinib treatment was 11 months (IQR, 4-18), with 63% (n=78) of pts remaining on pirtobrutinib at the time of data cut-off date. Of the 45 pts who had discontinued pirtobrutinib, the majority did so for progressive disease (62%, n=28). Overall, 9 (7%) pts discontinued pirtobrutinib for AEs which showed no particular pattern. Discontinuations related to pirtobrutinib occurred in 4 pts (1 each) including: myalgia, neutropenia, rash maculo-papular, and staphylococcal sepsis, and discontinuations unrelated to pirtobrutinib occurred in 5 pts (1 each) including: anxiety, abdominal pain and blood alkaline phosphatase increase, chronic respiratory failure, pneumonia, and COVID-19 and dyspnea. Treatment-emergent adverse events (TEAEs) on pirtobrutinib were manageable with dose reductions in 10 pts (8%) primarily due to neutropenia (n=6). The median pirtobrutinib relative dose intensity was 98% (IQR, 92-100). Pirtobrutinib TEAEs recurring in the same patient and same AE category as those leading to prior cBTKi intolerance are listed in the Table. Overall recurrence of a grade ≥3 pirtobrutinib TEAE in the same patient and category as that leading to prior cBTKi discontinuation was observed in only 13% (n=16/123) of pts.

Conclusions: Pirtobrutinib monotherapy was safe and well-tolerated in the majority of pts with B-cell malignancies with documented intolerance to prior cBTKi therapy. Most pts did not experience high-grade recurrence of the AE that led to discontinuation of the prior cBTKi, and among those who did, none discontinued pirtobrutinib for this AE. Pirtobrutinib may be an important consideration to extend the benefit of BTK inhibition among pts with intolerance to a prior cBTKi.