Pirtobrutinib receives accelerated FDA approval for the treatment of R/R mantle cell lymphoma

The Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) following two or more prior lines of systemic therapy (including a Bruton’s tyrosine kinase (BTK) inhibitor) on January 27th, 20231.

Pirtobrutinib is a non-covalent BTK inhibitor, which inhibits malignant BTK-overexpressing B-cell growth by inhibition of the B-cell antigen receptor (BCR) and BTK-activated signaling pathways2. BTK resistance is an ongoing challenge in the treatment of B-cell malignancies, as a high proportion of patients eventually develop resistance to covalent BTK inhibitors such as ibrutinib, leading to relapse and disease progression3. However, unlike other approved BTK inhibitors, pirtobrutinib bonds non-covalently to both wild-type and C481 mutated BTK, which maintains efficacy in patients who have progressed on a covalent BTK inhibitor due to resistance mutations3.

The approval of pirtobrutinib for R/R MCL is based on the BRUIN trial (NCT03740529)4, a Phase I/II open-label, multicenter, single-arm study that assessed pirtobrutinib monotherapy in 120 patients with R/R MCL previously treated with a BTK inhibitor. The study reported an overall response rate (ORR) with pirtobrutinib of 50% (95% CI: 41, 59) and estimated median duration of response (DOR) of 8.3 months (95% CI: 5.7, NE)1. Pirtobrutinib was associated with a manageable toxicity profile, and the most common adverse events included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Neutropenia, lymphocytopenia and thrombocytopenia were the most common adverse events of grade 3 1.

In an exclusive interview at the Society of Hematologic Oncology (SOHO) 2022 meeting, Jonathon Cohen, MD, MS, Emory University School of Medicine, Atlanta, GA, discussed the results of the Phase I/II BRUIN study, stating that, “[pirtobrutinib is] a great option for patients who are intolerant or who don’t experience prolonged remission with conventional BTK inhibitors.”

The approval of pirtobrutinib is a step forward in overcoming BTK inhibitor resistance and provides a promising new treatment option for patients with R/R MCL.


1. US Food and Drug Administration. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. Available from: here. (Last accessed 30/01/2023)
2. National Center for Biotechnology Information. PubChem Compound Summary for CID 129269915, Pirtobrutinib. Available from: here. (Last accessed 30/01/2023)
3. Mato AR, Shah NN, Wojciech J, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 March 6;397(10277):892-901.
4. Cohen JB, Shah NN, Alencar AJ, et al. MCL-133 Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results From the Phase 1/2 BRUIN Study. Clinical Lymphoma Myeloma and Leukemia. 2022 October;22 Suppl 2:S394-s5.

Written by Amy Preston
Edited by Elitsa Kamberska and Thomas Southgate