J Clin Oncol 2023 May 16
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.
Related Questions
Following the BRUIN data in mantle cell lymphoma, will you routinely treat with pirtobrutinib following a covalent BTKi?
Yes, this drug has demonstrated clear efficacy in a difficult-to-treat population and perhaps to date, the best safety data with a BTK inhibitor we have seen (low rates of cardiac, bleeding, and GI adverse events). There is a head-to-head study of pirtobrutinib versus covalent BTK inhibitors ongoing...
Will you recommend pirtobrutinib following a prior covalent BTKi in patients with cardiac comorbidities?
In the MCL patients treated on the BRUIN trial, treatment was well tolerated in general with a low rate of treatment discontinuation or dose reduction. As far as cardiac toxicities, no grade ≥3 treatment emergent AEs of hypertension were observed. Atrial fibrillation/flutter (AF) was reported in 6 (...
What subsequent therapies did patients receive after progressing on pirtobrutinib in the mantle cell BRUIN trial population?
Not all post-protocol therapy was reported; however, nearly 20% of patients who were treated with pirtobrutinib on trial went on to receive CAR-T therapy. Pirtobrutinib’s ideal use is dependent on patient and disease characteristics. In the BRUIN trial, the median PFS, DOR, and OS of MCL patients wa...
Are there biomarkers or other factors to help predict which patients with MCL are most likely to benefit, or not, from pirtobrutinib following a prior covalent BTKi?
In the phase I/II BRUIN trial, responses with pirtobrutinib occurred across prespecified subgroups regardless of demographics, number of prior lines of therapy, or prior therapy. Responses were seen in patients with blastoid and pleomorphic histology, regardless of the number of prior lines of thera...
What are the factors that convince you to not immediately treat mantle cell lymphoma and to follow a course of "active surveillance"?
A subset of patients with MCL have a significantly longer survival (often more than 7-10 years) and a more indolent disease course. Two separate groups have reported patients who did not receive up-front chemotherapy at the time of diagnosis but were instead actively monitored, the watch-a...
Can acalabrutinib be used after ibrutinib failure in relapsed/refractory mantle cell lymphoma?
Acalabrutinib binds to the same pocket as ibrutinib on BTK. Theoretically, if a patient is ibrutinib resistant, acalabrutinib would not be effective. Ideally, there should have been a small trial testing this hypothesis. However, because of the theoretic concerns, nobody wants to do this trial. As w...