Background Despite the marked efficacy of covalent BTK inhibitors (BTKi) in MCL, WM, and MZL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Moreover, pharmacological liabilities of these agents such as low oral bioavailability or short half-life, can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). To address these limitations, pirtobrutinib (LOXO-305), a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal low nM potency was developed. Aims To evaluate safety and efficacy of pirtobrutinib in previously treated MCL and other NHLs. Methods BRUIN is a multicenter phase 1/2 trial (NCT03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Oral pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary endpoint was MTD/RP2D identification. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Safety was assessed in all pts (n=323). Response was assessed according to Lugano Classification or iWWM. Results As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts, 68 (42-84) for WM pts, and 68 (27-86) for other NHLs pts. Median number of prior lines of therapy was 3 (range, 1-8) for MCL, 3 (2-11) for WM, and 4 (2-10) for other NHLs. 93% of MCL, 70% of WM and 36% other NHL pts had received a prior BTKi. Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. Consistent with pirtobrutinib’s selectivity, the only treatment emergent adverse events regardless of attribution or grade in >10% of pts (n=323) were fatigue (20%), diarrhea (17%) and contusion (13%). Grade 3 atrial fibrillation/flutter was not observed; 1 pt had grade 3 hemorrhage in the setting of mechanical trauma. Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected. At the efficacy cutoff date, 35 (57%) MCL pts, 18 (69%) WM pts and 34 (52%) other NHL pts remained on therapy. Among the 52 efficacy evaluable prior BTKi treated MCL pts, the ORR was 52% with 13 CR, 14 PR and 9 SD. Median follow up was 6 months (range 0.7-18.3+) for MCL. Responses in MCL were observed in 9/14 pts (64%) with prior autologous or allogeneic transplant, and 2 of 2 with prior CAR-T cell therapy. Among the 19 efficacy-evaluable pts with WM, the ORR was 68% (9 PR, 4 MR, 3 SD), and 69% in prior BTKi treated pts. 10 of 13 WM responders were ongoing (follow-up time from initial response: 0.8-9.2 months). For the 55 efficacy-evaluable other NHL pts, best response was as follows: DLBCL - 24% ORR (4 CR, 2 PR, 2 SD, 12 PD, 5 NE), FL - 50% ORR (2 CR, 2 PR, 1 SD, 3 PD), MZL - 22% ORR (2 PR, 7 SD), Richter’s transformation - 75% ORR (6 PR, 1 SD, 1 NE) and Other (2 B-PLL, 3 Low grade transformation) 1 SD, 2 PD, 2 NE. Conclusion Pirtobrutinib demonstrated promising efficacy in MCL pts following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib also showed efficacy in previously treated other NHLs. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index.