Phase 1/2 Trial Demonstrates Activity of Pirtobrutinib in CLL, B-Cell Malignancies

Research investigating the highly selective, reversible BTK inhibitor pirtobrutinib found the drug was safe and active for treating patients with chronic lymphocytic leukemia as well as other B-cell malignancies.

A trial investigating the maximum tolerated dose of pirtobrutinib found the drug was safe and active in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), specifically in patients who were previously treated with covalent Bruton tyrosine kinase (BTK) inhibitors, according to data published in The Lancet.1

In all patients with CLL/SLL evaluable for response (n = 139), the overall response rate (ORR) was 63% (95% CI, 55%-71%). When examining pirtobrutinib in 121 evaluable patients with CLL/SLL who were previously treated with a covalent BTK inhibitor, the ORR was 62% (95% CI, 53%-71%). Pirtobrutinib may represent an agent capable of addressing an unmet medical need in these patients who have previously received standard-of-care BTK inhibitors.

More, a similar ORR was recorded for patients with CLL with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481 mutations (71%), and BTK wild-type disease (66%). Other B-cell malignancies, such as mantle cell lymphoma (MCL), were also represented in the cohort. In MCL, the ORR was 52% (95% CI, 38%-65%).

“In this first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinaemia, and follicular lymphoma,” wrote the investigators. “Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment.”

The research team recruited and treated 323 patients with pirtobrutinib across 7 different dose levels of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day with linear dose-proportional exposures. The maximum tolerated dose was not reached and there were no dose-limiting toxicities observed.

The most common adverse events (defined as occurring in 10% of patients or more) included fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia in 32 patients (10%). A total of 5 patients discontinued treatment due to treatment-related adverse events.

This multicenter, open-label, phase 1/2 trial (NCT03740529) recruited patients with previously treated B-cell malignancies to evaluate the safety and efficacy of pirtobrutinib. The primary end points included the maximum tolerated dose for the phase 1 portion and ORR for the phase 2 portion of the trial.

“The available findings, including those from our study, demonstrate that many B-cell malignancies maintain dependence on B-cell receptor signaling mediated by BTK after progression on covalent BTK inhibitors,” wrote the investigators. “The efficacy of BTK inhibition delivered through the unique properties of pirtobrutinib might allow patients with these B-cell malignancies to further extend the clinical benefit delivered through BTK inhibition by permitting sequential use of inhibitors that bind through covalent and non-covalent mechanisms.”

A major limitation of the research is the need for extended follow-up times for patients due to the long natural history of B-cell malignancies. These would allow the team of investigators to better assess the durability of responses to pirtobrutinib. More, longer follow-up is necessary to scrutinize the preliminary safety profile observed with pirtobrutinib, even though the initial profile is encouraging for the treatment of patients with this disease type.

“Patients with B-cell malignancies who have been previously treated with the most commonly used regimens represent an area of growing and urgent unmet need,” Anthony Mato, MD, lead author of the research, said in a press release.2 “These data establish that the third-generation BTK inhibitor pirtobrutinib possesses a compelling efficacy and safety profile with the potential to address this exact unmet need.”

Future phase 3 clinical trials are planned to expand on the findings from this phase 1/2 study of pirtobrutinib.


1. Mato AR, 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.

2. Loxo Oncology at Lilly Announces Publication of Pirtobrutinib (LOXO-305) Phase 1/2 Data in The Lancet. News release. Loxo Oncology. Published March 5, 2021. Accessed March 26, 2021.