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

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.