Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma

Abstract

Purpose: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis.

Methods: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety.

Results: The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event.

Conclusion: Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.

FIG 1.

Efficacy of pirtobrutinib in patients with relapsed/refractory mantle-cell lymphoma. Change in tumor burden from baseline was measured by changes in the sum of product of diameters on axial CT images of index lesions. Waterfall plot includes patients with baseline and at least one evaluable postbaseline tumor measurement. Data for 18 patients are not shown in the waterfall plot because of no measurable target lesions identified by CT at baseline, discontinuation before first response assessment, or lack of adequate imaging in follow-up. ^aIndicates patients with >100% increase in SPD. cBTKi, covalent Bruton tyrosine kinase inhibitor; CT, computed tomography; SPD, sum of product of diameter.

FIG 2.

Kaplan-Meier plot of (A) DOR, (B) PFS, and (C) OS in patients with cBTKi pre-treated MCL treated with pirtobrutinib. cBTKi, covalent Bruton tyrosine kinase inhibitor; DOR, duration of response; MCL, mantle-cell lymphoma; NR, not reached; OS, overall survival; PFS, progression-free survival.