Pirtobrutinib in Patients with Previously Treated Mantle Cell Lymphoma

According to updated data from the phase I/II BRUIN study, presented at the 2021 American Society of Hematology Annual Meeting, pirtobrutinib, a non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, showed promising efficacy in patients with previously treated mantle cell lymphoma (MCL). The therapy also was well tolerated among this population of heavily pretreated patients with poor prognosis who had undergone several previous therapies, including a covalent BTK inhibitor.

Pirtobrutinib avoids some limiting factors of covalent BTK inhibitors, such as low oral bioavailability and short half-life, that may reduce their efficacy in tumors with high BTK protein turnover like MCL, according to the study’s lead author, Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Per study protocol, patients received oral pirtobrutinib monotherapy with a 3+3 dose-escalation design in 28-day cycles to patients with advanced B-cell malignancies who had received more than two prior lines of therapy. The primary phase I objective was the recommended phase II dose. The primary phase II outcome was overall response rate (ORR), with secondary outcomes including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, tolerability, and pharmacokinetics. Among 61 patients with MCL, 93%, 98%, and 92% had previously received a BTKi, anti-CD20 antibody, or chemotherapy, respectively.

At the time of presentation, a total of 323 patients had been treated with seven dose levels ranging from 25 to 300 mg once daily. Fatigue, diarrhea, and contusion were the most frequent adverse events (AEs) reported in over 10% of patients (n = 323). Neutropenia was the most common grade ≥3 AE and five patients discontinued due to treatment-related AEs. Treatment-related hemorrhage occurred in five patients and hypertension occurred in four.

At the study’s efficacy data cutoff, the 52 evaluable patients with MCL had an ORR of 52%. Responses included 13 complete remissions, 14 partial remissions, nine stable diseases, and 11 progressive diseases. The median follow-up duration was six months (range = 0.7-18.3+). Responses were observed in nine of 14 total patients who had prior stem cell transplant, and in all two of the patients who had prior chimeric antigen receptor T-cell therapy.

According to Dr. Wang, these updated data from approximately 60 new patients with MCL and 10 more months of follow-up confirm that treatment with pirtobrutinib “exhibited a wide therapeutic index” and a good tolerability profile.