ABCL-040: Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent Bruton's Tyrosine Kinase Inhibitor in Previously Treated Mantle Cell Lymphoma and Other Non-Hodgkin Lymphomas: Phase 1/2 BRUIN Study Results

Context 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. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective To evaluate safety and efficacy of pirtobrutinib in pts with MCL/NHLs. Design BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting Global: community hospitals, academic medical centers. Patients Previously treated pts with advanced B-cell malignancies. Interventions Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria per protocol. 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). Pirtobrutinib demonstrated high oral exposures, with doses ≥100 mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only TEAEs, regardless of attribution or grade in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%) and contusion (13%). 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%. Among the 19 efficacy evaluable pts with WM, the ORR was 68%. For the other 55 efficacy evaluable NHL pts, ORR was 24% (DLBCL), 50% (FL), 22% (MZL), and 75% (Richter's transformation). Conclusion Pirtobrutinib demonstrated promising efficacy in MCL and other NHL pts, was well-tolerated and exhibited a wide therapeutic index.