Pirtobrutinib showed promising efficacy and safety as treatment of patients with mantle cell lymphoma, demonstrating the potential to serve an unmet medical need.
Treatment with the highly selective, reversible Bruton’s tyrosine kinase (BTK) inhibitor, pirtobrutinib (formerly LOXO-305) was found to be safe and effective for patients with mantle cell lymphoma (MCL) and other B-cell malignancies, including those previously treated with covalent BTK inhibitors, according to results from the phase 1/2 BRUIN trial (NCT03740529).
“The activity of pirtobrutinib in relapsed, BTK-pretreated MCL is particularly promising and addresses an important unmet clinical need,” wrote the study authors led by Anthony R. Mato, MD, a hematologist/oncologist, and director of the CLL Program at Memorial Sloan Kettering Cancer Center.
With covalent BTK inhibition, management of relapsed or refractory MCL was transformed, but compared with other B-cell malignancies, like chronic lymphocytic leukemia (CLL), responses in patients with MCL are less durable. The population has a known median progression-free survival (PFS) of less than 2 years and a median duration of response (DOR) ranging from 18 to 24 months. Moreover, once patients with MCL progress on a covalent BTK inhibitor, the survival plummets to about 4 to 10 months.
The first-in-human, open-label, phase 1/2 study of pirtobrutinib was conducted in 27 sites across Australia, France, Italy, Poland, the United Kingdom, and the United States. Following a 3 + 3 dose-escalation design, a total of up to 150 patients with MCL, CLL, or small lymphocytic leukemia (SLL) were divided into 6 cohorts based on type of B-cell malignancy, exposure to prior therapy, and BTK C481 mutational status. Those enrolled received single-agent pirtobrutinib orally once daily in 28-day cycles. The drug was administered at 7 dose levels including 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day. Treatment with pirtobrutinib continued until disease progression, unacceptable toxicity, or withdrawal.
Study protocol allowed for subjects who had disease progression but ongoing clinical benefit on treatment with pirtobrutinib to continue treatment at the discretion of investigators. The protocol also allowed intrapatient dose escalation to higher dose levels after the dose-limiting toxicity (DLT) period. Investigators evaluated tumors every 8 weeks in year 1, every 12 weeks in year 2, and every 6 months in the years following.
In phase 1 of the study, the coprimary end points were the maximum tolerated dose and recommended phase 2 dose of pirtobrutinib. The secondary end points for the phase 1 portion of the study include objective response rate (ORR), pharmacokinetics, and safety. In phase 2, the primary end point is ORR by independent review committee assessment, and the secondary end points included investigator-assessed ORR, best overall response, DOR, PFS, overall survival, safety/tolerability, and pharmacokinetics.
The MCL cohort included 61 patients who had a median age of 69 years (range, 63-75) and was 77% male and 23% female. Most of the patients in the cohort had an ECOG performance status of 0 (69%) or 1 (28%). All individuals in the cohort had a median of 3 (range, 2-4) prior lines of therapy and were treated with 3 (range, 2-4) prior BTK therapies. Ninety-three percent of the MCL cohort received prior BTK inhibition, 92% received chemotherapy, and 98% received an anti-CD20 antibody. The remaining patients had prior treatment with a BCL2 inhibitor, PI3K inhibitor, lenalidomide (Revlimid), autologous stem cell transplantation, allogeneic stem cell, and chimeric antigen receptor (CAR) T-cell therapy. The majority of the patients discontinued their prior treatment due to disease progression (77%), but 23% discontinued due to toxicity.
Of the 61 patients with MCL treated with pirtobrutinib, 56 were evaluable for efficacy. Patients were followed for a median of 6 months (IQR, 3-9). The ORR observed in the MCL cohort was 52% (95% CI, 38%-65%). ORR was also assessed among those pretreated with a BTK inhibitor, and the ORR was similar to the overall MCL population at 52% (95% CI, 38%-66%). Responses in the overall cohort included 14 complete responses, 15 partial responses, and 10 cases of stable disease. Twelve patients in the cohort had progressive disease, and the remaining 5 were not evaluable. Notably, some patients who received prior cellular therapy had a response to pirtobrutinib, including 64% of those who had prior autologous or allogeneic transplant, and 100% of those who had prior CAR T-cell therapy (n = 2).
The median time to first response was 1.8 months (IQR, 1.8-1.9). At data cutoff, 57% remained on pirtobrutinib treatment. Of the 29 patients with MCL who responded to therapy, 5 discontinued treatment due to either disease progression or withdrawal.
Data from patients with B-cell malignancies, including MCL, who received pirtobrutinib showed that the most common any-grade adverse events (AEs) were fatigue (20%), diarrhea (17%), contusion (13%), and neutropenia (13%). The most common treatment-related AEs of any grade were diarrhea and contusion in 9% of patients each. In addition, AEs of special interest included any-grade bruising (16%), rash (11%), arthralgia (5%), hemorrhage (5%), hypertension (5%), and atrial fibrillation or flutter (1%).
Patients receiving the study drug at dose levels of 25 mg to 300 mg daily were evaluated. There were no dose-limiting toxicities observed in the study and the maximum tolerated dose was not established.
The efficacy and safety of pirtobrutinib in patients with MCL and other B-cell malignancies was considered promising and has led to the development of global phase 3 studies in MCL, SLL, and CLL.
Mato AM, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277);892-901. doi:10.1016/S0140-6736(21)00224-5