Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.381-381
• Main Authors: Wang, Michael, Shah, Nirav N., Alencar, Alvaro J., Gerson, James N., Patel, Manish R., Fakhri, Bita, Jurczak, Wojciech, Tan, Xuan Ni, Lewis, Katharine, Fenske, Timothy S., Coombs, Catherine C., Flinn, Ian W., Lewis, David John, Le Gouill, Steven, Palomba, M. Lia, Woyach, Jennifer A., Pagel, John M., Lamanna, Nicole, Cohen, Jonathon B., Barve, Minal A., Ghia, Paolo, Eyre, Toby A., Zinzani, Pier Luigi Luigi, Ujjani, Chaitra S., Koh, Youngil, Izutsu, Koji, Lech-Marańda, Ewa, Tam, Constantine S., Sundaram, Suchitra, Yin, Ming, Nair, Binoj, Balbas, Minna, Tsai, Donald, Mato, Anthony R., Cheah, Chan Yoon
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-149138

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397, 10277:892-901). Methods: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). 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 at