Pirtobrutinib Demonstrates Promising Efficacy in Mantle Cell Lymphoma Following BTK Inhibitor Treatment

Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis mantle cell lymphoma (MCL) following multiple prior lines of therapy, including with a covalent Bruton’s tyrosine kinase (BTK) inhibitor, according to a recent phase 1/2 study published in Clinical Lymphoma, Myeloma & Leukemia.

“Covalent BTK inhibitors have transformed the management of MCL, but most patients will require additional treatment,” wrote Jonathon B Cohen, MD, Winship Cancer Institute, Emory University, Atlanta, GA and colleagues. “Pirtobrutinib is a highly selective, non-covalent (reversible) BTK [inhibitor] that inhibits both wild-type and C481-mutated BTK with equal low nM potency.”

The BRUIN trial is an ongoing multicenter phase 1/2 study of pirtobrutinib monotherapy in patients with advanced B-cell malignancies. In phase 1 of the study, oral pirtobrutinib was distributed and dose-escalated in a standard 3+3 design. In phase 2, oral pirtobrutinib was give as continuous therapy in 28-day cycles. The primary phase 1 objective was to determine the recommended phase 2 dose, and the primary phase 2 objective was overall response rate (ORR). Secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics.

As of September 27, 2020, 323 patients were treated on 7 dose levels (25 mg to 300 mg once daily). No dose-limiting toxicities were reported, and a maximum-tolerated dose was not reached (n = 323). 200 mg once daily was selected as the recommended phase 2 dose.

The median follow-up was 6 months. The trial found that fatigue (20%), diarrhea (17%), and contusion (13%) were the most frequent treatment-emergent adverse events, regardless of attribution or grade, seen in >10% of patients. Investigators also found the most common grade ≥3 adverse events was neutropenia (10%). 5 (1%) patients discontinued due to treatment-related adverse events. 52 of the patients who had previously been treated with a BTK inhibitor were efficacy evaluable, with an ORR of 52% (95% confidence interval [CI] 38 to 66; 13 with complete response [25%], 14 with partial response [27%], 9 with stable disease [17%]), 11 with progressive disease [21%], and 5 [10%] discontinued prior to first response assessment). Responses were observed in 9 out of 14 patients (64%) with prior autologous or allogeneic stem cell transplant, and in 2 out 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 BTK [inhibitor]. Pirtobrutinib was well-tolerated and exhibited a wide therapeutic index,” concluded Dr Cohen and colleagues.

Source:

Cohen JB, Shah NN, Alencar AJ, et al. MCL-133 Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in previously treated mantle cell lymphoma: Updated results from the phase 1/2 BRUIN study. Clin Lymphoma Myeloma Leuk. 2022;22 Suppl 2:S394-S395. doi:10.1016/S2152-2650(22)01569-5