Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment landscape of mantle cell lymphoma (MCL). Despite the efficacy of covalent BTKi, treatment failure often occurs through development of resistance or intolerance. 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 covalent BTKi (Mato et al. Lancet, 2021). Here, we report updated MCL results from the BRUIN study (NCT03740529).

Methods: Pts with previously treated B-cell malignancies, including MCL, were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter BRUIN study. Key endpoints included overall response rate (ORR) based on Lugano 2014 criteria, duration of response (DOR), and safety. The response evaluable cohort consisted of the first 90 MCL pts enrolled to either phase 1 or 2 who had measurable disease, had received a prior covalent BTKi containing regimen, and had no known central nervous system involvement. A data cut of 31 January 2022 was chosen to ensure the majority of the cohort had a minimum of 9 months of follow-up from the initial response. The safety cohort consisted of all pts with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy (n=725).

Results: Among the 90 pts with MCL who had received a prior BTKi, the median age was 70 (range, 46–87) years and the median number of prior lines of therapy was 3 (range, 1-8). Additional prior therapies included anti-CD20 antibody (96%), chemotherapy (88%), immunomodulator (21%), stem cell transplant (21%), BCL-2 inhibitor (16%), CAR-T-cell therapy (4%), and PI3K inhibitor (3%). The majority of pts (82%, n=74) discontinued prior BTKi therapy due to disease progression. Overall, 86% (n=77) received the recommended phase 2 dose of 200 mg once daily as starting dose. In this group of heavily pretreated relapsed/refractory (R/R) MCL pts, including all with prior BTKi use, the ORR by IRC was 58% (95% CI, 47-68), including 18 complete responses (20%) and 34 with partial responses (38%). Responses were observed in 6/8 pts (75%) with blastoid MCL and in 6/12 pts (50%) with pleomorphic MCL. At a median follow-up time of 12 months, the median DOR among the 52 responding pts was 22 months (95% CI, 7.5-not estimable [NE]). The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39-72) and 52% (95% CI, 34-68), respectively. Patients who discontinued their prior BTKi due to disease progression (n=74) had an ORR of 50% (95% CI, 38-62) and a median DOR of 14.8 months (95% CI, 5.6-NE). In the safety cohort of all pirtobrutinib treated pts with B-cell malignancies (n=725), the most common TEAEs, regardless of attribution, were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). The most frequent Grade ≥3 TEAE was neutropenia (20%, n=143). Low rates of Grade ≥3 TEAEs of hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were observed. Overall, 15 (2%) pts discontinued due to a treatment-related AE.

Conclusion: In this updated analysis with additional pts and extended follow-up, pirtobrutinib continues to demonstrate promising and durable efficacy in heavily pre-treated R/R MCL pts who have been treated with a prior covalent BTKi. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity.