Investigational BTK Inhibitor Shows Promise in Chronic, Small Lymphocytic Leukemia

Pirtobrutinib, a next-generation, highly selected, non-covalent Bruton tyrosine kinase (BTK) inhibitor, shows significant promise for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), according to a session at the Society of Hematologic Oncology 2021 Annual Meeting.

In the session, researcher Catherine C. Coombs, MD, from the University of North Carolina Cancer Center, reviewed findings from the phase 1/2 BRUIN study of pirtobrutinib. Coombs said the drug could be particularly important because its efficacy is relatively unaffected by previous BTK inhibitor discontinuation, which can pose a significant issue for some patients.

Many newly diagnosed patients with CLL or SLL receive ibrutinib, another BTK inhibitor. Discontinuation of ibrutinib due to intolerance or disease progression, however, can cause significant problems. Many patients who discontinue treatment have significantly lower efficacy to later lines of therapy, Coombs said.

Pirtobrutinib has shown in vivo efficacy similar to ibrutinib in wild type, but superior efficacy in C481-mutant BTK, Coombs said. The BRUIN study examined this efficacy further, in addition to the safety of pirtobrutinib.

The study had broad eligibility requirements and the enrolled participants were a typical population for a CLL study, in that they were heavily pre-treated and most had prior therapy with BTK inhibition. The majority of participants were males with a median age of 69 years.

The efficacy analysis found that a large majority of patients experienced a significant reduction in their lymph node size, with a 63% overall response rate (ORR) in all CLL and SLL patients. This rate is not markedly different from the subcohort of patients who had been previously treated with BTK inhibitors, which had an ORR of 62%. Importantly, Coombs said this efficacy does not depend on prior therapy, reason for prior BTK inhibitor discontinuation, or C481 mutation status.

Furthermore, the ORR increased over time, going from 63% to 86% for patients receiving pirtobrutinib for 10 months or longer. As of the presentation, Coombs said 94% of responding patients are ongoing and in response. Only 5 patients have discontinued, including 4 due to disease progression and 1 electively.

Only 1.5% of participants discontinued due to treatment-emergent adverse events (AEs) and AEs of interest were rare, Coombs said. The most common AEs were fatigue, diarrhea, and contusion, and AEs of special interest were bruising, rash, arthralgia, hemorrhage, hypertension, and atrial fibrillation.

Based on these findings, Coombs said pirtobrutinib demonstrates promising efficacy in patients with CLL or SLL who have been previously treated with all classes of available therapy. Responses were observed across all dose levels and the favorable safety and tolerability profile are consistent with the design of pirtobrutinib as a highly selective and non-covalent BTK inhibitor.

REFERENCE

Coombs, C. Pirtobrutinib, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study. Presented at: Society of Hematologic Oncology 2021 Annual Meeting. September 9, 2021. Accessed September 9, 2021. https://soho.6connex.com/event/AnnualMeeting/en-us#!/Lobby