CLL-120 Pirtobrutinib, A Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study

Catherine C. Coombs, John M. Pagel, Nirav N. Shah, Nicole Lamanna, Talha Munir, Ewa Lech-Maranda, Toby A. Eyre, Jennifer A. Woyach, William G. Wierda, Chan Y. Cheah, Jonathon B. Cohen, Lindsey E. Roeker, Manish R. Patel, Bita Fakhri, Minal A. Barve, Constantine S. Tam, David Lewis, James N. Gerson, Alvaro Alencar, Chaitra UjjaniIan Flinn, Suchitra Sundaram, Shuo Ma, Deepa Jagadeesh, Joanna Rhodes, Justin Taylor, Omar Abdel-Wahab, Paolo Ghia, Stephen J. Schuster, Denise Wang, Binoj Nair, Edward Zhu, Donald E. Tsai, Matthew S. Davids, Jennifer R. Brown, Wojciech Jurczak, Anthony R. Mato

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Context: Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) 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 the safety and efficacy of pirtobrutinib in previously treated CLL/SLL. Design: BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy. Setting: Global; community hospitals, academic medical centers. Patients: Pts with advanced B-cell malignancies. Intervention: Oral pirtobrutinib, phase 1 dose escalated in a standard 3+3 design, phase 2 continuous monotherapy, 28-day cycles. Main Outcome Measures: The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D). The primary objective of phase 2 was ORR. Secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability, and pharmacokinetics. Results: As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other) were treated on 7 dose levels (25-300mg QD). No dose limiting toxicities were reported and MTD was not reached (n=323). 200mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95%CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95%CI 53-71). Responses deepened over time with an ORR of 86% among pts with?>10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other (52%). Of 88 responding pts, all except 5 remained on therapy. Conclusions: Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data from 252 efficacy evaluable BTK pre-treated CLL/SLL patients with a data cutoff date of 16 July 2021 will be presented.

Original languageEnglish
Pages (from-to)S268-S269
JournalClinical Lymphoma, Myeloma and Leukemia
StatePublished - Oct 2022


  • BTKi
  • CLL
  • Phase I/II
  • chronic lymphocytic leukemia
  • clinical trial
  • pirtobrutinib


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