Updated results from the BRUIN study demonstrated that pirtobrutinib has promising efficacy in heavily pretreated, poor-prognosis patients with mantle cell lymphoma (MCL) following multiple prior lines of therapy, including a covalent BTK inhibitor; these data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Covalent BTK inhibitors have transformed the management of MCL, but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTK inhibitors share pharmacologic liabilities that collectively may lead to suboptimal BTK target coverage,” explained Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, and co-investigators.

To address these limitations, pirtobrutinib, a highly selective non-covalent BTK inhibitor that inhibits both wild type and C481-mutated BTK, was developed, Dr Wang et al said.

As of the efficacy cutoff date of September 27, 2020, the multicenter phase 1/2 dose escalating study enrolled 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) with advanced B-cell malignancies who received more than 2 prior lines of therapy. Patients were administered oral pirtobrutinib monotherapy in a standard 3+3 design in 28-day cycles, and were treated on 7 dose levels (25-300mg once a day).

The primary objective for the first phase of the study was to determine the recommended phase 2 dose. The primary objective for phase 2 was overall response rate (ORR). Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable patients included all dosed patients who underwent their first response evaluation or discontinued therapy. Responses were assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13, and was measured according to the Lugano Classification.

For MCL patients, the median patient age was 69 (range 50-87). Among the 61 total MCL patients, the median number of prior lines of therapy was 3, and most of them had received a prior BTK inhibitor (93%), an anti-CD20 antibody (98%), or chemotherapy (92%). No dose-limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) was not reached (n=323). The recommended phase 2 dose was 200 mg once a day.

The most frequent treatment-emergent adverse events (AEs) regardless of attribution or grade were seen in more than 10 percent of patients (n=323). The most common AE of grade 3 or more was neutropenia (10%). Five (1%) patients discontinued treatment due to treatment-emergent AEs. Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) patients, respectively.

In all, 52 prior BTK inhibitor treated MCL patients were efficacy evaluable, and had an ORR of 52 percent (95% CI, 38-66; 13 CR, 14 PR, 9 SD, 11 PD, and 5 discontinued prior to first response assessment). The median follow-up was 6 months. Responses were observed in 9 out of 14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy.

“Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index,” concluded Dr Wang et al.

Pirtobrutinib also showed pharmacokinetic exposures that exceeded its BTK IC96 at trough, and was well tolerated in patients with MCL following multiple prior lines of therapy.—Emily Bader

Wang M, Shah N, Alencar A, et al. Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 381.