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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.To evaluate pirtobrutinib safety and efficacy in patients with MCL.BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy.Global; community hospitals, academic medical centers.Patients with advanced B-cell malignancies.Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles.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.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 in10% 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.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.