Noncovalent BTK Inhibitor Pirtobrutinib in Patients With Mantle Cell Lymphoma Previously Treated With Covalent BTK Inhibitors

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In the phase I/II BRUIN trial reported in the Journal of Clinical Oncology, Michael Wang, MD, and colleagues found that the noncovalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib produced durable responses in patients with mantle cell lymphoma who were previously treated with covalent BTK inhibitors.

Michael Wang, MD

Michael Wang, MD

Study Details

In the study, patients from sites in eight countries enrolled between March 2019 and January 2022 received pirtobrutinib at doses of 25 to 300 mg once daily during the phase I portion of the study or the recommended phase II dose of 200 mg once daily. Efficacy was evaluated in the first 90 consecutively enrolled eligible patients. Of these, 82% had discontinued therapy with a prior covalent BTK inhibitor due to disease progression. A total of 79 patients (87.8%) received at least one dose at 200 mg once daily, and 77 (85.6%) received 200 mg once daily as the starting dose. The primary endpoint was overall response rate on independent review committee assessment.


Among the 90 patients included in the efficacy analysis, objective response was observed in 52 (57.8%, 95% confidence interval [CI] = 46.9%–68.1%), including complete response in 18 (20.0%). Median duration of response was 21.6 months (95% CI = 7.5 months to not reached), with 73.6%, 57.1%, and 52.4% of responses ongoing at 6, 12, and 18 months, respectively. An additional 14 patients (15.6%) had stable disease.

Median progression-free survival on independent review committee assessment was 7.4 months (95% CI = 5.3–12.5 months). Median overall survival was not reached, with rates at 12 and 18 months of 67.6% and 59.3%, respectively.


  • Pirtobrutinib produced objective response in 58% of patients, including complete response in 20%.
  • Median duration of response was 21.6 months.

Adverse Events

Among a total of 164 patients receiving pirtobrutinib for mantle cell lymphoma, the most common grade ≥ 3 adverse events were infections (17.1%), neutropenia (13.4%), pneumonia (8.5%), thrombocytopenia (6.7%), and anemia (4.9%). Additional grade ≥ 3 adverse events included hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%); no grade ≥ 3 bruising was observed. Adverse events led to discontinuation of treatment in 9.1% of patients (drug-related in 3.0%). Adverse events led to death in 11 patients, with no deaths considered related to treatment.

The investigators concluded, “Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTK inhibitor, and the first BTK inhibitor of any kind to demonstrate durable efficacy following prior covalent BTK inhibitor therapy in heavily pretreated [patients with] relapsed/refractory mantle cell lymphoma. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.”

Dr. Wang, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly and Company. For full disclosures of the study authors, visit


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.