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

Jonathon B. Cohen, Nirav N. Shah, Alvaro J. Alencar, James N. Gerson, Manish R. Patel, Bita Fakhri, Wojciech Jurczak, Xuan Ni Tan, Katharine L. Lewis, Timothy Fenske, Catherine C. Coombs, Ian W. Flinn, David J. Lewis, Steven Le Gouill, M. Lia Palomba, Jennifer A. Woyach, John M. Pagel, Nicole Lamanna, Minal A. Barve, Paolo GhiaToby A. Eyre, Pier Luigi Zinzani, Chaitra S. Ujjani, Youngil Koh, Koji Izutsu, Ewa Lech-Maranda, Constantine S. Tam, Suchitra Sundaram, Ming Yin, Binoj Nair, Donald E. Tsai, Minna Balbas, Anthony R. Mato, Chan Y. Cheah, Michael L. Wang

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Context: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency. Objective: To evaluate pirtobrutinib safety and efficacy in patients with MCL. Design: BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy. Setting: Global; community hospitals, academic medical centers. Patients: Patients with advanced B-cell malignancies. Interventions: Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles. Main Outcome Measures: The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics. Results: As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy. Conclusions: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.

Original languageEnglish
Pages (from-to)S394-S395
JournalClinical Lymphoma, Myeloma and Leukemia
StatePublished - Oct 2022


  • BTKi
  • MCL
  • Phase I/II
  • clinical trial
  • mantle cell lymphoma
  • pirtobrutinib


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