Noncovalent BTK Inhibitor Pirtobrutinib in Relapsed or Refractory B-Cell Malignancies

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In the phase I/II BRUIN trial reported in The Lancet, Anthony R. Mato, MD, and colleagues found that the noncovalent Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib produced durable responses in patients with relapsed or refractory B-cell malignancies, including those previously treated with covalent BTK inhibitors.

As noted by the investigators, pharmacokinetic and pharmacodynamic characteristics of covalent BTK inhibitors may result in incomplete target inhibition toward the end of dosing intervals that could facilitate drug resistance. Pirtobrutinib is a highly selective, reversible noncovalent inhibitor with equal potency against wild-type and resistant C481-mutant BTK that was designed to maintain high BTK inhibition at trough levels, irrespective of the rate of BTK turnover.

Anthony R. Mato, MD

Anthony R. Mato, MD

Study Details

The trial enrolled 323 patients from sites in six countries—including 170 with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), 61 with mantle cell lymphoma (MCL), 26 with Waldenström’s macroglobulinemia, and 66 with other B-cell lymphomas—between March 2019 and September 2020. Patients received pirtobrutinib across dose levels of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day, with treatment continuing until disease progression or unacceptable toxicity.


Pirtobrutinib exhibited linear dose-proportional exposures. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The recommended phase II dose was 200 mg daily.

The most common adverse events of any grade were fatigue (20%), diarrhea (17%), and contusion (13%). The most common adverse event of grade ≥ 3 was neutropenia (10%); neutropenia was also the only grade 4 event observed (4%). No correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events was observed. No grade 3 atrial fibrillation or flutter was observed; grade 3 hemorrhage was observed in one patient in association with mechanical trauma. Treatment-related adverse events resulted in discontinuation of treatment in five patients (1%).


  • Among patients with CLL or SLL previously treated with a covalent BTK inhibitor, the overall response rate was 62%.
  • Among patients with MCL previously treated with covalent BTK inhibitors, the response rate was 52%.


Of the 323 patients, 269 patients were efficacy-evaluable, including 139 with CLL or SLL, 56 with MCL, 19 with Waldenström’s macroglobulinemia, and 55 with other B-cell lymphomas. The 54 patients not included in the efficacy analysis were all still receiving pirtobrutinib without disease progression awaiting response assessment at the time of data lock.

Responses were observed at all dose levels. Median follow up was 6 months for patients with CLL or SLL and 6 months for those with MCL. Among 121 evaluable patients with CLL or SLL previously treated with a covalent BTK inhibitor, the overall response rate was 62%, including response rates of 67% among 79 patients with CLL and previous covalent BTK inhibitor resistance; 52% of 42 with covalent BTK inhibitor intolerance; 71% of 24 with BTK C481 mutation; and 66% of 65 with wild-type BTK. Among 52 patients with MCL previously treated with covalent BTK inhibitors, the response rate was 52%. Overall, among 117 patients with CLL, SLL, or MCL with response, all but 8 remained progression-free at data lock.  

A response was observed in 68% of 19 patients with Waldenström’s macroglobulinemia, 50% of 8 patients with follicular lymphoma, 75% of 8 with Richter’s transformation identified before enrollment, 24% of 25 with diffuse large B-cell lymphoma, and 22% of 9 patients with marginal zone lymphoma.

The investigators concluded, “Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.”

Dr. Mato, of Memorial Sloan Kettering Cancer Center, and Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, are the corresponding authors for The Lancet article.

Disclosure: The study was funded by Loxo Oncology. For full disclosures of the study authors, visit

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